Nuestros investigadores

Jesús San Miguel Izquierdo

Departamento
Dirección de Medicina Clínica y Traslacional
Clínica Universidad de Navarra. Universidad de Navarra
Facultad de Medicina. Universidad de Navarra
Líneas de investigación
Hematología, Mieloma múltiple, Inmunofenotipo, Factores pronósticos en leucemias, Enfermedad mínima residual
Índice H
110, (WoS, 09/10/2020)

Publicaciones científicas más recientes (desde 2010)

Autores: Burgos Rodríguez, Leire; Puig, N.; Cedeña, M. T. ; et al.
Revista: JOURNAL OF HEMATOLOGY AND ONCOLOGY
ISSN 1756-8722  Vol. 13  Nº 1  2020  págs. 82
The landscape of multiple myeloma (MM) has changed considerably in the past two decades regarding new treatments, insight into disease biology and innovation in the techniques available to assess measurable residual disease (MRD) as the most accurate method to evaluate treatment efficacy. The sensitivity and standardization achieved by these techniques together with unprecedented rates of complete remission (CR) induced by new regimens, raised enormous interest in MRD as a surrogate biomarker of patients' outcome and endpoint in clinical trials. By contrast, there is reluctance and general lack of consensus on how to use MRD outside clinical trials. Here, we discuss critical aspects related with the implementation of MRD in clinical practice.
Autores: Terpos, E., (Autor de correspondencia); Engelhardt, M., (Autor de correspondencia); Cook, G.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 34  Nº 8  2020  págs. 2000 - 2011
Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed
Autores: Mikhael, J., (Autor de correspondencia); Richter, J. ; Vij, R.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 34  Nº 12  2020  págs. 3298 - 3309
A Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with >= 3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38-85), 5 (2-14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses >= 10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade <= 2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade <= 2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses >= 10 mg/kg.
Autores: Mateos, M. V.; Kumar, S., (Autor de correspondencia); Dimopoulos, M. A.; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 10  Nº 10  2020 
Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2-3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with >= 3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
Autores: Da Silva Maia, Catarina Alexandra; Puig, N. ; Cedena, M. T.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 135  Nº 26  2020  págs. 2375 - 2387
Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.
Autores: Vij, R., (Autor de correspondencia); Nath, R.; Afar, D. E. H.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 26  Nº 10  2020  págs. 2308 - 2317
Purpose: ABBV-838 is an antibody-drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-inhuman, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM). Patients and Methods: Eligible patients (>= 18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel. Results: As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838-related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively. Conclusions: These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy.
Autores: Bahlis, N. J., (Autor de correspondencia); Dimopoulos, M. A. ; White, D. J.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 34  Nº 7  2020  págs. 1875 - 1884
In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with >= 1 prior line received Rd (lenalidomide, 25 mg, on Days 1-21 of each 28-day cycle; dexamethasone, 40 mg, weekly) +/- daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35-0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10(-5); 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31-0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42-0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.
Autores: Cavo, M. , (Autor de correspondencia); Dimopoulos, M. A. ; San Miguel Izquierdo, Jesús; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 20  Nº 7  2020  págs. 480 - 489
ntroduction: Bortezomib, melphalan, and prednisone (VMP) is the standard of care for transplant-ineligible newly diagnosed multiple myeloma. The phase III VISTA trial established the bortezomib dosing schedule for VMP. To mitigate bortezomib-associated toxicity, the phase III ALCYONE study of daratumumab plus VMP (D-VMP) versus VMP used modified bortezomib dosing. D-VMP demonstrated improved progression-free survival and overall response rate. Propensity score matching enables indirect comparisons by controlling for differences in baseline covariates. Patients and methods: The efficacy and safety of both arms of ALCYONE were compared with VISTA VMP using propensity score matching. ALCYONE D-VMP and VMP patients were matched on selected baseline characteristics to VISTA VMP patients, reducing or eliminating systematic differences between treatment groups. Results: After matching, median progression-free survival and overall response rate were comparable for ALCYONE VMP and VISTA VMP, and were significantly improved with ALCYONE D-VMP versus VISTA VMP. Rates of grade 3/4 peripheral sensory neuropathy were significantly lower for both arms of ALCYONE versus VISTA VMP, with or without matching. Conclusion: This propensity score matching analysis demonstrates significant improvements in efficacy with ALCYONE D-VMP versus VISTA VMP and a significantly lower incidence of peripheral sensory neuropathy in both arms of ALCYONE versus VISTA VMP, although safety improvements may be due to different bortezomib administration routes (ALCYONE, subcutaneous; VISTA, intravenous).
Autores: Paiva, Bruno; Puig, N.; Cedena, M. T.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 38  Nº 8  2020  págs. 784 - 792
PURPOSE: Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). PATIENTS AND METHODS: In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 * 10-6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial.
Autores: Parasrampuria, D. A.; He, J. M.; Zhang, L. P.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 189  Nº 5  2020  págs. 860 - 868
Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42 center dot 2 vs. 38 center dot 5 mg/m(2)) and ALCYONE patients stayed on treatment longer (mean: 7 center dot 2 vs. 5 center dot 8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with >= 39 center dot 0 versus < 39 center dot 0 mg/m(2) cumulative dose (hazard ratio, 0 center dot 119; P < 0 center dot 0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.
Autores: Medina, A.; Jimenez, C.; Sarasquete, M. E. , (Autor de correspondencia); et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 10  Nº 2  2020  págs. 14
Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (>= 7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361-0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation >= 7% (HR: 0.291, 95% CI: 0.137-0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.
Autores: Dimopoulos, M. A., (Autor de correspondencia); Lonial, S.; White, D.; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 10  Nº 9  2020  págs. 91
Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1-3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1-3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68-1.00];P = 0.0408 [less than allotted alpha of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1-3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2-3 prior LoTs.
Autores: Mateos, M. V., (Autor de correspondencia); Cavo, M.; Blade, J.; et al.
Revista: LANCET
ISSN 0140-6736  Vol. 395  Nº 10218  2020  págs. 132 - 141
Background Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. Methods ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9,2015, and July 14,2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stern-cell transplantation, because of their age (>= 65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezoinib (1.3 mg/m(2) of body surface area on days 1,4,8,11,22,25,29, and 32 of cycle one and on days 1,8,22, and 29 of cycles two through nine), oral melphalan (9 mg/m(2) once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m(2) once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cydes two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intentionto-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. Findings 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40.1 months (IQR 374-434), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0.60 (95% CI 0.46-0.80; p=0.0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78.0% (95% CI 73.2-82.0) in the D-VMP group and 67.9% (62.6-72.6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0.42 [0.34-0.51]; p<0.0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [1.5%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28[10%]). Interpretation D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stern-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns.
Autores: Garcés Latre, Juan José; Bretones, G. ; Burgos Rodríguez, Leire; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 34  Nº 11  2020  págs. 3007 - 3018
Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that similar to 22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (>= 95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, >= 82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.
Autores: Caballero-Velazquez, T.; Calderon-Cabrera, C.; Lopez-Corral, L.; et al.
Revista: BONE MARROW TRANSPLANTATION
ISSN 0268-3369  Vol. 55  Nº 2  2020  págs. 419 - 430
This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days -9 and -2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day -5 and tacrolimus (Tk) from -3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2-4 and 3-4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD.
Autores: Ordóñez Ciriza, Raquel; Kulis, M.; Russiñol, N.; et al.
Revista: GENOME RESEARCH
ISSN 1088-9051  Vol. 30  Nº 9  2020  págs. 1217 - 1227
Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
Autores: Pérez Ruiz, Cristina; Botta, C.; Zabaleta, A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 136  Nº 2  2020  págs. 199 - 209
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14-CD15+CD33+HLADR- cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC-related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
Autores: Luo, M. M., (Autor de correspondencia); Usmani, S. Z. ; Mateos, M. V. ; et al.
Revista: JOURNAL OF CLINICAL PHARMACOLOGY
ISSN 0091-2700  2020 
We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (C-trough) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the <= 65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients <= 50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.
Autores: Morales Lozano, María Isabel; Viering, O.; Samnick, S. ; et al.
Revista: CANCERS
ISSN 2072-6694  Vol. 12  Nº 4  2020  págs. 1042
C-11-methionine (C-11-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than F-18-fluorodeoxyglucose (F-18-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of C-11-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to F-18-FDG. Twenty-two patients with newly diagnosed, treatment-naive symptomatic MM who had undergone C-11-MET and F-18-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion C-11-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), C-11-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in C-11-MET than in F-18-FDG (p < 0.05, respectively). C-11-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that C-11-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than F-18-FDG. Its implications for prognosis evaluation need further investigation.
Autores: Garcés Latre, Juan José; Simicek, M.; Vicari, M.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 34  Nº 2  2020  págs. 589 - 603
The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r¿¿¿0.94, P¿=¿10-16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial-mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-¿ and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n¿=¿553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús; Goldschmidt, H. ; et al.
Revista: LEUKEMIA AND LYMPHOMA
ISSN 1042-8194  Vol. 61  Nº 3  2020  págs. 680 - 690
For patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible, bortezomib-melphalan-prednisone (VMP) demonstrated superior efficacy based on the VISTA trial. In subsequent trials, twice-weekly bortezomib was limited to the first cycle or completely replaced with once-weekly bortezomib to reduce toxicity. Following a systematic literature review, the efficacy and safety of modified VMP schedules (pooled data from the once-weekly bortezomib VMP arm of the GIMEMA trial and the VMP arm of the ALCYONE trial) were compared to the VISTA schedule using naive and unanchored matching-adjusted indirect comparison (MAIC). Median progression-free survival was similar between VISTA and modified VMP (20.7 months [95% CI, 18.4-24.3] vs 19.6 months [95% CI, 18.8-21.0]). Peripheral neuropathy was significantly reduced with modified VMP versus VISTA VMP (all grades: naive, 32.1% vs 46.8% and MAIC, 32.1% vs 46.7%; both p < .0001). These findings support a modified VMP dosing schedule for patients with NDMM who are transplant ineligible.
Autores: Alameda Serrano, Daniel; Sáez Ochoa, Borja; Lara-Astiaso, D. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 105  Nº 9  2020  págs. E470 - E473
Autores: Alameda Serrano, Daniel; Sáez Ochoa, Borja; Lara, D.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 105  Nº 9  2020  págs. e470
Autores: Einsele, H. ; Weisel, K. ; Goldschmidt, H.; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 43  Nº SUPPL 4  2020  págs. 90 - 91
Autores: Weisel, K.; Einsele, H. ; Goldschmidt, H. ; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 43  Nº SUPPL 4  2020  págs. 93 - 94
Autores: Lindsay, J.; Dimopoulos, M. ; Weisel, K.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 189  Nº Supl. 1  2020  págs. 23 - 24
Autores: Cook, G.; Kaufman, J. L.; Usmani, S. Z.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 189  Nº Supl. 1  2020  págs. 20
Autores: Niederwieser, D.; Richardson, P.; Attal, M.; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 43  Nº Supl. 1  2020  págs. 40 - 41
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Martinez-Lopez, J.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 33  Nº 4  2019  págs. 1056 - 1056
Following the publication of this article, the author notes that the following information was missed from the acknowledgments section.
Autores: Hillengass, J. , (Autor de correspondencia); Usmani, S. ; Rajkumar, S. V.; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 20  Nº 6  2019  págs. E302 - E312
Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.
Autores: Mateos, M. V.; Ludwig, H. ; Bazarbachi, A. ; et al.
Revista: HEMASPHERE
ISSN 2572-9241  Vol. 3  Nº 1  2019  págs. e163
The introduction of new agents and management strategies over the past decade has resulted in a major step change in treatment outcomes with deepening responses and increased survival for patients with multiple myeloma. In daily clinical practice, healthcare professionals are now faced with challenges including, optimal treatment sequencing and changing treatment goals. In light of this, a group of experts met to discuss diagnostic and treatment guidelines, examine current clinical practice, and consider how new clinical trial data may be integrated into the management of multiple myeloma in the future.
Autores: Mateos, M. V. , (Autor de correspondencia); Blacklock, H. ; Schjesvold, F. ; et al.
Revista: THE LANCET. HAEMATOLOGY
ISSN 2352-3026  Vol. 6  Nº 9  2019  págs. e459 - e469
ackground: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). Methods: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at leas
Autores: Rosinol, L. ; Oriol, A. ; Rios, R. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 134  Nº 16  2019  págs. 1337 - 1345
Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged <= 65 years with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and post-transplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 x 10(-6) sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade >= 3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade >= 2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment.
Autores: Lopez-Corral, L., (Autor de correspondencia); Caballero-Velazquez, T.; Lopez-Godino, O. ; et al.
Revista: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
ISSN 1083-8791  Vol. 25  Nº 9  2019  págs. 1703 - 1712
Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P < .001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P < .001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment.
Autores: Moreno Narro, Laura; Pérez Ruiz, Cristina; Zabaleta Azpiroz, Aintzane; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 25  Nº 10  2019  págs. 3176 - 3187
Purpose: Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAb) is required to understand which patients with multiple myeloma (MM) benefit the most from a given mAb, alone or in combination therapy. Although there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce. Experimental Design: We performed a comprehensive analysis of the MoA of isatuximab. Results: Isatuximab induces internalization of CD38 but not its significant release from MMcell surface. In addition, we uncovered an association between levels of CD38 expression and different MoA: (i) Isatuximab was unable to induce direct apoptosis on MM cells with CD38 levels closer to those in patients with MM, (ii) isatuximab sensitized CD38(hi) MMcells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38(lo) and CD38(hi) tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38(hi) MM cells, whereas (v) complement-dependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38(hi) B-lymphocyte precursors and natural killer (NK) lymphocytes ex vivo-the latter through activation followed by exhaustion and eventually phagocytosis. Conclusions: This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma cell protection, augmenting NK lymphocyte-mediated ADCC, or facilitating ADCP in CD38(lo) MM patients.
Autores: Facon, T., (Autor de correspondencia); Lee, J. H.; Moreau, P.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 133  Nº 18  2019  págs. 1953 - 1963
The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1: 1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m(2): C1D1, C1D2; 36 mg/m(2) thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m(2); D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m(2)) and prednisone (60 mg/m(2)) were administered on D1-4. The primary endpoint was progression-free survival (PFS). Nine hundred fifty-five patients were randomized (intention-to-treat population: KMP, n = 478; VMP, n = 477). Median PFS was 22.3 months with KMP vs 22.1 months with VMP (hazard ratio [HR], 0.906; 95% confidence interval [CI], 0.746-1.101; P = .159). Median overall survival was similar and not reached in either group (HR, 1.08; 95% CI, 0.82-1.43). Overall response rate was 84.3% for KMP and 78.8% for VMP. Complete response rate was 25.9% for KMP and 23.1% for VMP. Minimal residual disease-negative rates were 15.7% (KMP) and 15.5% (VMP). Adverse events (AEs) of interest (any grade) occurring with a >= 5% higher patient incidence in the KMP arm were acute renal failure (13.9% [KMP] vs 6.2% [VMP]) and cardiac failure (10.8% vs 4.3%). Grade >= 3 AE rates were 74.7% (KMP) and 76.2% (VMP). Grade >= 2 peripheral neuropathy was lower for KMP vs VMP (2.5% vs 35.1%). Treatment with KMP in CLARION did not yield a statistically significant difference in PFS vs VMP.
Autores: Lahuerta, J. J., (Autor de correspondencia); Jimenez-Ubieto, A. ; Paiva, Bruno; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 133  Nº 25  2019  págs. 2664 - 2668
Response criteria for multiple myeloma (MM) require monoclonal protein (M-protein)-negative status on both serum immunofixation electrophoresis (sIFE) and urine (uIFE) immunofixation electrophoresis for classification of complete response (CR). However, uIFE is not always performed for sIFE-negative patients. We analyzed M-protein evaluations from 384 MM patients (excluding those with light-chain-only disease) treated in the GEM2012MENOS65 (NCT01916252) trial to determine the uIFE-positive rate in patients who became sIFE-negative posttreatment and evaluate rates of minimal residual disease (MRD)-negative status and progression-free survival (PFS) among patients achieving CR, CR but without uIFE available (uncertain CR; uCR), or very good partial response (VGPR). Among 107 patients with M-protein exclusively in serum at diagnosis who became sIFE-negative posttreatment and who had uIFE available, the uIFE-positive rate was 0%. Among 161 patients with M-protein in both serumand urine at diagnosis who became sIFE-negative posttreatment, 3 (1.8%) were uIFE positive. Among patients achieving CR vs uCR, there were no significant differences in postconsolidation MRD-negative (< 10(-6); 76% vs 75%; P = .9) and 2-year PFS (85% vs 88%; P = .4) rates; rates were significantly lower among patients achieving VGPR. Our results suggest that uIFE is not necessary for defining CR in MM patients other than those with light-chain-only disease.
Autores: Puig, N. ; Paiva, Bruno (Autor de correspondencia); Lasa, M.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 33  Nº 5  2019  págs. 1256 - 1267
Early diagnosis and risk stratification are key to improve outcomes in light-chain (AL) amyloidosis. Here we used multidimensional-flow-cytometry (MFC) to characterize bone marrow (BM) plasma cells (PCs) from a series of 166 patients including newly-diagnosed AL amyloidosis (N = 9 4) , MGUS (N = 20) and multiple myeloma (MM, N = 52) vs. healthy adults (N= 30). MFC detected clonality in virtually all AL amyloidosis (99%) patients. Furthermore, we developed an automated risk-stratification system based on BMPCs features, with independent prognostic impact on progression-free and overall survival of AL amyloidosis patients (hazard ratio: >= 2.9;P <= .03). Simultaneous assessment of the clonal PCs immunophenotypic protein expression profile and the BM cellular composition, mapped AL amyloidosis in the crossroad between MGUS and MM; however, lack of homogenously-positive CD56 expression, reduction of B-cell precursors and a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, emerged as hallmarks of AL amyloidosis (ROC-AUC = 0.74;P < .001), and might potentially be used as biomarkers for the identification of MGUS and MM patients, who are candidates for monitoring pre-symptomatic organ damage related to AL amyloidosis. Altogether, this study addressed the need for consensus on how to use flow cytometry in AL amyloidosis, and proposes a standardized MFCbased automated risk classification ready for implementation in clinical practice.
Autores: Attal, M., (Autor de correspondencia); Richardson, P. G. , (Autor de correspondencia); Rajkumar, S. V. ; et al.
Revista: LANCET
ISSN 0140-6736  Vol. 394  Nº 10214  2019  págs. 2096 - 2107
BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ¿75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (<75 years vs ¿75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab-pomalidomide-dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338. FINDINGS: Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab-pomalidomide-dexamethasone, and 153 to pomalidomide-dexamethasone. At a median follow-up of 11·6 months (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) in the pomalidomide-dexamethasone group; hazard ratio 0·596, 95% CI 0·44-0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab-pomalidomide-dexamethasone group and 14 (9%) in the pomalidomide-dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection). INTERPRETATION: The addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor. FUNDING: Sanofi. VIDEO ABSTRACT.
Autores: Sanoja-Flores, L.; Flores-Montero, J.; Puig, N.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 134  Nº 24  2019  págs. 2218 - 2222
Autores: Usmani, S. Z. , (Autor de correspondencia); Schjesvold, F.; Oriol, A. ; et al.
Revista: THE LANCET. HAEMATOLOGY
ISSN 2352-3026  Vol. 6  Nº 9  2019  págs. e448 -e458
Background: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). Methods: KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-ass
Autores: Dimopoulos, M. A., (Autor de correspondencia); Laubach, J. P.; Gutierrez, M. A. E.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 102  Nº 6  2019  págs. 494 - 503
Objectives To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. Methods Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. Results A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received >= 1 dose of ixazomib maintenance. Grade >= 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in <= 2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. Conclusions Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.
Autores: Rodríguez Otero, Paula; Mateos, M. V. ; Martinez-Lopez, J.; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 9  Nº 4  2019  págs. 36
Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) >= 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb >= 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years.
Autores: Walker, B. A.; Mavrommatis, K.; Wardell, C. P. ; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 33  Nº 1  2019  págs. 159 - 170
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R-2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R-2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (>= 4 copies) of CKSJB (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
Autores: Richardson, P. G., (Autor de correspondencia); Oriol, A.; Beksac, M.; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 20  Nº 6  2019  págs. 781 - 794
Background As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged >= 18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of beta(2) microglobulin at screening. Bortezomib (1.3 mg/m(2)) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1,4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings Between Jan 7, 2013, and May 15,2017,559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15.9 months (IQR 9.9-21.7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11.20 months [95% CI 9.66-13-73] vs 7.10 months [5.88-8-48]; hazard ratio 0.61, 95% CI 0.49-0-77; p<0-0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%1 of 270 patients; nine p.m vs no patients had febrile neutropenia), infections (86 [31%] vs 48 118%1), and thrombocytopenia (76 [27%1 vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=11) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia In=11, hepatic encephalopathy [n=1.]). Interpretation Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
Autores: Moreau, P., (Autor de correspondencia); Sonneveld, P.; Boccadoro, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  Nº 12  2019  págs. 2358 - 2360
Adoptive cellular therapy using chimeric antigen receptor T-cell (CAR-T) therapy is currently being evaluated in patients with relapsed / refractory multiple myeloma (MM). The majority of CAR-T cell programs now being tested in clinical trials are targeting B-cell maturation antigen. Several recent phase I / II trials show promising preliminary results in patients with MM progressing on proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies targeting CD38. CAR-T cell therapy is a potentially life-threatening strategy that can only be administered in experienced centers. For the moment, CAR-T cell therapy for MM is still experimental, but once this strategy has been approved in relapsed/refractory MM, it will become one of the most important indications for this therapy in Europe and world-wide. This manuscript proposes practical considerations for the use of CAR-T cell therapy in MM, and discusses several important issues for its future development.
Autores: Usmani, S. Z., (Autor de correspondencia); Nahi, H.; Mateos, M. V.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 134  Nº 8  2019  págs. 668 - 677
Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV daratumumab in a similar patient population.
Autores: Mateos, M. V. , (Autor de correspondencia); Orlowski, R. Z.; Ocio, E. M.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 186  Nº 5  2019  págs. e117 - e121
Autores: Richardson, P. G.; Attal, M.; Rajkumar, S. V.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 37  Nº 15  2019 
Autores: Rocchi, S.; Goldschmidt, H. ; Rosinol, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 9 - 9
Autores: Dimopoulos, M. A.; Dytfeld, D.; Grosicki, S. ; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E164 - E165
Autores: Dimopoulos, M. A. ; Weisel, K. ; Lonial, S.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E15 - E16
Autores: Dimopoulos, M. A. ; Weisel, K. ; Moreau, P.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E32 - E33
Autores: Cedena, M. T. ; Puig, N.; Paiva, B.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 15 - 15
Autores: Garcés Latre, Juan José; Simicek, M.; Growkova, K.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  Nº s3  2019  págs. 13 - 14
Autores: De Ramon, C.; Garcia-Alvarez, M.; Alcoceba, M. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 9 - 9
Autores: Carrasco-Leon, A. ; Ezponda Itoiz, Teresa; Meydan, C. ; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E354 - E355
Autores: Pérez Ruiz, Cristina; Botta, C.; Zabaleta Azpiroz, Aintzane; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 149 - 149
Autores: Medina, A.; Jimenez, C. ; Puig, N.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E47
Autores: Chari, A.; Goldschmidt, H. ; San Miguel Izquierdo, Jesús; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E16 - E17
Autores: San Miguel Izquierdo, Jesús; Rodriguez-Otero, P.; Dimopoulos, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 152 - 153
Autores: Alameda Serrano, Daniel; Puig, N. ; Cedena, M. T. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 12 - 12
Autores: Goicoechea, I. ; Puig, N.; Cedena, M. T.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 5 - 5
Autores: Botta, C. ; Pérez Ruiz, Cristina; Goicoechea Oroz, Ibai; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E351 - E352
Autores: Garcés Latre, Juan José; Bretones, G. ; Burgos Rodríguez, Leire; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E351
Autores: San Miguel Izquierdo, Jesús; Mateos, M. V.; Gonzalez, V.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 37  Nº 15  2019 
Autores: Kaufman, J. L.; Dimopoulos, M. A. ; Leiba, M.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 37  Nº 15  2019 
Autores: Carazo Melo, Fernando; San José Enériz, Edurne; Garate Iturriagagoitia, Leire; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 134  Nº supl.1  2019 
Autores: Da Silva Maia, Catarina Alexandra; Botta, C.; Pérez Ruiz, Cristina; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E94
Autores: Musto, P. ; Anderson, K. C.; Attal, M.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº 4  2018  págs. 1074 - 1074
Autores: Gay, F., (Autor de correspondencia); Jackson, G.; Rosinol, L.; et al.
Revista: JAMA ONCOLOGY
ISSN 2374-2437  Vol. 4  Nº 10  2018  págs. 1389 - 1397
IMPORTANCE Several trials demonstrated the impact of novel agent-based maintenance in newly diagnosed multiplemyeloma (NDMM), but there is no current evidence demonstrating the superiority of one regimen over the other, owing to the lack of direct/indirect comparisons. OBJECTIVE To analyze and compare the effectiveness of different maintenance regimens in NDMM via a network meta-analysis. DATA SOURCES We performed 2 independent searches in PubMed and Cochrane databases, and thenwe identified all the records registered after 1999 and on or before November 20, 2017. STUDY SELECTION By blinded review, we identified prospective phase 3 randomized trials evaluating novel agent-based maintenance in patients with NDMM; the included studies compared at least 2 maintenance approaches; comparators included placebo and no maintenance. From 364 screened records, 11 studies were included. DATA EXTRACTION AND SYNTHESIS We followed (independent extraction) the guidelines provided by the PRISMA Report and the EQUATOR Network. The evidence was synthesized using a network meta-analysis (NMA). To allow comparison of all treatments, no maintenance was selected as common comparator and the effect of placebo was assumed to be the same as no treatment. The best option was identified by a Bayesian consistency model based on hazard ratio (HR), 95% credible interval (CrI), probability of being the best treatment (PbBT), and median ranking distribution (MedR). MAIN OUTCOMES AND MEASURES Outcomes of interestwere progression-free survival (PFS) and overall survival (OS). RESULTS Eleven trials and 8 treatments including a total of 5073 participants were included. By PFS analysis, lenalidomide-based regimens (lenalidomide-prednisone, lenalidomide alone) were identified as the most effective options (HR, 0.39 [95% CrI, 0.28-0.53] and 0.47 [95% CrI, 0.39-0.55], respectively; MedR, 1 and 2; overall PbBT, 74%). Four treatments (thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, thalidomide alone) showed an HR in favor of maintenance. By OS analysis, lenalidomide alone was identified as the best option (HR, 0.76; 95% CrI, 0.51-1.16; MedR, 2; PbBT, 38%), followed by bortezomib-thalidomide and bortezomib-prednisone. Similar features were noticed in the restricted network including transplant trials, in the sensitivity analysis, and in most of the prognostic subgroups. CONCLUSIONS AND RELEVANCE Based on PFS and OS results of this NMA, lenalidomide maintenance appears to be the best treatment option, by synthesizing the available evidence of novel agent-based maintenance in the past 20 years.
Autores: Richardson, P. G., (Autor de correspondencia); San Miguel Izquierdo, Jesús; Moreau, P.; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 8  2018  págs. 109
Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/refractory MM on novel agent-based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients' treatment approaches.
Autores: Ludwig, H. , (Autor de correspondencia); Delforge, M.; Facon, T.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 32  Nº 7  2018  págs. 1542 - 1560
During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Paiva, Bruno
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº 23  2018  págs. 2424 - 2425
In this issue of Blood, Perrot et al reveal that patients with multiple myeloma (MM) who are eligible for transplantation and have undetectable minimal residual disease (MRD) by next-generation sequencing (NGS) during maintenance therapy have excellent outcomes.
Autores: Martínez Calle, Nicolás (Autor de correspondencia); Rodríguez Otero, Paula; Villar Fernández, Sara; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº 7  2018  págs. E318 - E321
Autores: Mateos, M. V.; Dimopoulos, M. A.; Cavo, M.; et al.
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 1533-4406  Vol. 378  Nº 6  2018  págs. 518 - 528
BACKGROUND: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. RESULTS: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients. CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).
Autores: Dimopoulos, M. A., (Autor de correspondencia); San Miguel Izquierdo, Jesús; Belch, A.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº 12  2018  págs. 2088 - 2096
In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow-up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow-up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P <0.0001). The overall response rate was 92.9% versus 76.4%, and 51.2% versus 21.0% achieved a complete response or better, respectively (both P <0.0001). At the 10e5 sensitivity threshold, 26.2% versus 6.4% were minimal residual disease-negative, respectively (P <0.0001). Post hoc analyses of clinical relevant patient subgroups demonstrated that progression-free survival was significantly prolonged for daratumumab plus lenalidomide/dexamethasone versus lenalidomide/dexamethasone regardless of number of prior lines of therapy. Patients previously treated with lenalidomide or thalidomide and those refractory to bortezomib received similar benefits (all P <0.01). Treatment benefit with daratumumab plus lenalidomide/dexamethasone was maintained in high-risk patients (median progression-free survival 22.6 vs 10.2 months; hazard ratio, 0.53; 95% confidence interval, 0.25-1.13; P = 0.0921) and patients with treatment-free intervals of >12 and =12 months, >6 and =6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02076009.
Autores: Misiewicz-Krzeminska, I. ; Corchete, L. A.; Rojas, E. A.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº 5  2018  págs. 880 - 889
Protein analysis in bone marrow samples from patients with multiple myeloma has been limited by the low concentration of proteins obtained after CD138(+) cell selection. A novel approach based on capillary nano-immunoassay could make it possible to quantify dozens of proteins from each myeloma sample in an automated manner. Here we present a method for the accurate and robust quantification of the expression of multiple proteins extracted from CD138-purified multiple myeloma samples frozen in RLT Plus buffer, which is commonly used for nucleic acid preservation and isolation. Additionally, the biological and clinical value of this analysis for a panel of 12 proteins essential to the pathogenesis of multiple myeloma was evaluated in 63 patients with newly diagnosed multiple myeloma. The analysis of the prognostic impact of CRBN/Cereblon and IKZF1/Ikaros mRNA/protein showed that only the protein levels were able to predict progression-free survival of patients; mRNA levels were not associated with prognosis. Interestingly, high levels of Cereblon and Ikaros proteins were associated with longer progression-free survival only in patients who received immunomodulatory drugs and not in those treated with other drugs. In conclusion, the capillary nano-immunoassay platform provides a novel opportunity for automated quantification of the expression of more than 20 proteins in CD138(+) primary multiple myeloma samples.
Autores: Arana Berganza, Paula; Paiva, Bruno; Cedena, M. T.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 32  Nº 4  2018  págs. 971 - 978
Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19(pos), CD27(neg), CD38(lo), CD45(pos), CD81(pos), CD117(neg) and CD138(lo) expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38(low)CD81(pos)CD117(neg) expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR: 1.69; P = 0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Martinez-Lopez, J.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 32  Nº 11  2018  págs. 2427 - 2434
Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (<6 months duration) emerged as one important predictor of early myeloma-related mortality associated with a significant increase in the risk of death related to myeloma progression. The identification of these patients at high risk of early death is relevant for innovative trials aiming to maintain the depth of first response, since many of them will not receive subsequent lines of therapy.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Gutierrez, M. A. E.; Spicka, I. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº 9  2018  págs. 1518 - 1526
This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m(2) [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients.
Autores: García Barchino, María José; Sarasquete, M. E.; Panizo Santos, Carlos Manuel; et al.
Revista: JOURNAL OF PATHOLOGY
ISSN 0022-3417  Vol. 245  Nº 1  2018  págs. 61 - 73
The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV- tumours, EBV+ DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2(-/-) IL2c(-/-) mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Autores: Sanoja-Flores, L.; Flores-Montero, J. ; Garcés Latre, Juan José; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 8  2018  págs. 117
Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p < 0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p < 0.0001) and a shorter survival in MM patients with active disease requiring treatment (p <= 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.
Autores: Moulopoulos, L. A. , (Autor de correspondencia); Koutoulidis, V. ; Hillengass, J.; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 8  Nº 10  2018  págs. 95
Whole Body Low Dose CT (WBLDCT) has important advantages as a first-line imaging modality for bone disease assessment in patients with plasma cell disorders and has been included in the 2014 International Myeloma Working Group (IMWG) criteria for multiple myeloma (MM) definition. Nevertheless, standardization guidelines for the optimal use of WBLDCT in MM patients are still lacking, preventing its more widespread use, both in daily practice and clinical trials. The aim of this report by the Bone Group of the IMWG is to provide practical recommendations for the acquisition, interpretation and reporting of WBLDCT in patients with multiple myeloma and other plasma cell disorders.
Autores: Ledergor, G.; Weiner, A.; Zada, M.; et al.
Revista: NATURE MEDICINE
ISSN 1078-8956  Vol. 24  Nº 12  2018  págs. 1867 - 1876
Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.
Autores: Mateos, M. V. , (Autor de correspondencia); Goldschmidt, H.; San Miguel Izquierdo, Jesús; et al.
Revista: HEMATOLOGICAL ONCOLOGY
ISSN 0278-0232  Vol. 36  Nº 2  2018  págs. 463 - 470
We performed analyses of the randomized phase 3 ASPIRE and ENDEAVOR trials to investigate the efficacy of carfilzomib among subgroups of relapsed or refractory multiple myeloma patients who had early or late disease relapse following initiation of the immediately prior therapy. In ASPIRE and ENDEAVOR, patients had received 1 to 3 prior lines of therapy. Patients in ASPIRE received carfilzomib, lenalidomide, and dexamethasone (KRd) or lenalidomide and dexamethasone (Rd), and patients in ENDEAVOR received carfilzomib and dexamethasone (Kd) or bortezomib and dexamethasone (Vd). Patients with relapse 1year after initiating the most recent prior line of therapy were categorized as early relapsers, and patients with relapse after >1year were categorized as late relapsers. The median progression-free survival (PFS) in ASPIRE for early relapsers was 21.4 months for KRd vs 10.7months for Rd (hazard ratio [HR]: 0.714; 95% confidence interval [CI]: 0.508-1.004; P = 0.0257), and for late relapsers was 29.7 months for KRd vs 18.2 months for Rd (HR: 0.675; 95% CI: 0.533-0.854; P = 0.0005). The overall response rate (ORR) for early relapsers was 83.2% for KRd vs 54.8% for Rd, and for late relapsers was 89.0% for KRd vs 69.7% for Rd. The median PFS in ENDEAVOR (Kd vs Vd) for early relapsers was 13.9months vs 5.7months (HR: 0.598; 95% CI: 0.423-0.846; P = 0.0017), and for late relapsers was 22.2months vs 10.2months (HR: 0.486; 95% CI: 0.382-0.620; P < 0.0001). The ORR (Kd vs Vd) for early relapsers was 63.4% vs 49.1% and for late relapsers was 81.8% vs 66.8%. In conclusion, patients with relapsed or refractory multiple myeloma who received carfilzomib-containing regimens had improved PFS and ORR compared with control groups, regardless of whether they had an early or late relapse following the most recent prior therapy.
Autores: Siegel, D. S., (Autor de correspondencia); Dimopoulos, M. A.; Ludwig, H.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 36  Nº 8  2018  págs. 728 734
PurposeIn the ASPIRE study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide plus dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma, progression-free survival was significantly improved in the carfilzomib group (hazard ratio, 0.69; two-sided P < .001). This prespecified analysis reports final overall survival (OS) data and updated safety results.Patients and MethodsAdults with relapsed multiple myeloma (one to three prior lines of therapy) were eligible and randomly assigned at a one-to-one ratio to receive KRd or Rd in 28-day cycles until withdrawal of consent, disease progression, or occurrence of unacceptable toxicity. After 18 cycles, all patients received Rd only. Progression-free survival was the primary end point; OS was a key secondary end point. OS was compared between treatment arms using a stratified log-rank test.ResultsMedian OS was 48.3 months (95% CI, 42.4 to 52.8 months) for KRd versus 40.4 months (95% CI, 33.6 to 44.4 months) for Rd (hazard ratio, 0.79; 95% CI, 0.67 to 0.95; one-sided P = .0045). In patients receiving one prior line of therapy, median OS was 11.4 months longer for KRd versus Rd; it was 6.5 months longer for KRd versus Rd among patients receiving two prior lines of therapy. Rates of treatment discontinuation because of adverse events (AEs) were 19.9% (KRd) and 21.5% (Rd). Grade 3 AE rates were 87.0% (KRd) and 83.3% (Rd). Selected grade 3 AEs of interest (grouped terms; KRd v Rd) included acute renal failure (3.8% v 3.3%), cardiac failure (4.3% v 2.1%), ischemic heart disease (3.8% v 2.3%), hypertension (6.4% v 2.3%), hematopoietic thrombocytopenia (20.2% v 14.9%), and peripheral neuropathy (2.8% v 3.1%).ConclusionKRd demonstrated a statistically significant and clinically meaningful reduction in the risk of death versus Rd, improving survival by 7.9 months. The KRd efficacy advantage is most pronounced at first relapse. (C) 2018 by American Society of Clinical Oncology
Autores: Dimopoulos, M. A., (Autor de correspondencia); Dytfeld, D.; Grosicki, S.; et al.
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 0028-4793  Vol. 379  Nº 19  2018  págs. 1811 - 1822
BACKGROUND: The immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor. METHODS: Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group. CONCLUSIONS: Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132 .).
Autores: Usmani, S. Z. , (Autor de correspondencia); Hoering, A.; Cavo, M.; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 8  Nº 123  2018 
Purpose: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. Patients & Methods: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan-Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. Results: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin >= 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels >= 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/mu L (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was similar to 0.9, and the statistical cure fraction was 14.3%. Conclusions: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival.
Autores: Walker, B. A. ; Mavrommatis, K.; Wardell, C. P.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº 6  2018  págs. 587 - 597
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1, IDH2, HUWE1, KLHL6, and PTPN11. Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3, DIS3, and PRKD2; t(11;14) with mutations in CCND1 and IRF4; t(14;16) with mutations in MAF, BRAF, DIS3, and ATM; and hyperdiploidy with gain 11q, mutations in FAM46C, and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.
Autores: Ruiz-Heredia, Y.; Sanchez-Vega, B.; Onecha, E.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº 11  2018  págs. E544 - E548
Autores: San Miguel Izquierdo, Jesús; Facon, T. ; Dimopoulos, M. A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Mateos, M. V.; Goldschmidt, H.; San Miguel Izquierdo, Jesús; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Ubieto, A. J. ; Paiva, Bruno; Martinez-Lopez, J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Suppl 1  2018  págs. 474
Background: The international criteria for definition CR, requires, among other parametres, a negative IF both in serum and urine; however, urine IF is not always performed. In the belief that this lack could bias the comparison between trials, the First Trial Independent Response Adjudication Committee (FTIRAC) recommended that patients who met all CR criteria except the availability of a urine IF should be classified as VGPR (Blood 2014; 124 [abstract 3460]) but this criteria is not always applied which may translate into differences in CR rates between trials. However, it is unknown (1) if this conversion has a real clinical basis, (2) if urine IF results alter the clinical meaning of CR, or (3) on the contrary, if patients in CR with and those without a documented negative urine IF have a similar prognosis, in which case this rule would underestimate the CR rates, increasing the biases and magnifying the problem that was intended to improve. Aim: To determine the value of urine negative IF in the definition of CR.
Autores: Cuenca, I.; Sanchez-Vega, B. ; Paiva, Bruno; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 91 - 91
Autores: Cavo, M. ; Dimopoulos, M. A.; San Miguel Izquierdo, Jesús; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 41  2018  págs. 182 - 183
Autores: Tamariz Amador, Luis Esteban; Riesgo García, Álvaro; Hernández-Santamaría, T. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 118 - 118
Autores: Cavo, M. ; Iida, S.; Blade, J.; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 41  2018  págs. 182
Autores: Medina, A.; Jimenez, C.; Sarasquete, M. E.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Bahlis, N. ; Dimopoulos, M. A.; White, D. J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl.1  2018  págs. 1996
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Lopez, J. M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 4503
Autores: Ruiz, C. P.; Zabaleta Azpiroz, Aintzane; Puig, N.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Clemens, P. L.; Xu, S.; Luo, M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 2006
Autores: Medina, A.; Jimenez, C.; Puig, N. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 116
Autores: Medina-Herrera, A.; Jimenez, C. ; Puig, N. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 103 - 103
Autores: San Miguel Izquierdo, Jesús; Mateos, M. V. ; Goldschmidt, H.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Puig, N.; Paiva, Bruno; Lasa, M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Alameda Serrano, Daniel; Vicari, M. ; Lara-Astiaso, D.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 188
Autores: Lonial, S.; Dimopoulos, M. ; Weisel, K.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 18  Nº Supl.1  2018  págs. S253
Autores: Chari, A.; Mateos, M. V.; van de Donk, N. W. C. J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 1995
Autores: Oriol, A. ; Richardson, P.; Beksac, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 90 - 91
Autores: Dachs, L. R. ; Oriol, A.; Teruel, A. I.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Paiva, Bruno; Martinez-Cuadron, D.; Bergua-Burgues, J. M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 433
Autores: Cavo, M.; Goldschmidt, H.; Rosinol, L.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Jiménez-Ubieto, A.; Martinez-Lopez, J.; Rosinol, L. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Suppl 1  2018  págs. 1943
Introduction: To discriminate different outcomes among patients in CR, the International Myeloma Working Group (IMWG )introduced more stringent CR (sCR) criteria by adding to the pre-existing CR parameters the requirement of a normal free-light chain ratio (sFLCr) plus the absence of clonal plasma cells (PCs) in bone marrow (BM) by immunohistochemistry (IHC). In 2011,the low-sensitivity cytometrycriteria were included as alternative methodology to IHC to define sCR. Aim: To validate the preliminary data of our previous study (Blood 2015. 126:858-62) regarding the lack of influence of an abnormal sFLCr in the outcome of MM patients, through the analysis of a more extensiveseries of newly diagnosed multiple myeloma (NDMM) patients in CR or sCR. Patients and Methods: This study is based on 459 NDMM patients who were transplant candidates and enrolled in the GEM2012MENOS65phase 3trial;evaluable patients were enrolled in a subsequent maintenance trial (NCT02406144).CR and sCR was defined according to the IMWG criteria.
Autores: Goicoechea Oroz, Ibai; Puig, N. ; Cedena, M. T. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 112
Autores: Weisel, K. ; Dimopoulos, M. A.; Lonial, S. ; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 41  Nº Supl 4  2018  págs. 230
Autores: Einsele, H.; Goldschmidt, H.; Weisel, K.; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 41  Nº Supl 4  2018  págs. 134
Autores: Mateos, M. V. ; Chari, A.; Nah, H. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl.1  2018  págs. 32 - 33
Autores: Richardson, P. G.; Moreau, P.; Laubach, J. P.; et al.
Revista: PHARMACOLOGICAL RESEARCH
ISSN 1043-6618  Vol. 117  2017  págs. 185 - 191
Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received >= 2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM. (C) 2016 Published by Elsevier Ltd.
Autores: Rodríguez Otero, Paula; Paiva, Bruno; Engelhardt, M. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº 3  2017  págs. 423 - 432
Immune escape and impaired immune surveillance have been identified as emerging hallmarks of cancer.(1) Multiple myeloma represents a genuine example of disrupted immune surveillance characterized by: impaired antibody production, deregulation of the T and natural killer cell compartment, disruption of antigen presentation machinery, upregulation of inhibitory surface ligands, and recruitment of immunosuppressive cells. Although the potential value of immunotherapeutic interventions had a clear antecedent in the graft-versus-myeloma effect induced by allogeneic stem cell transplant and donor lymphocyte infusions, it is only recently that this field has faced a real revolution. In this review we discuss the current results obtained with immune approaches in patients with multiple myeloma that have placed this disease under the scope of immuno-oncology, bringing new therapeutic opportunities for the treatment of multiple myeloma patients.
Autores: Cavo, M.; Terpos, E.; Nanni, C.; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 18  Nº 4  2017  págs. E206 - E217
The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of (18)fluorodeoxyglucose (F-18-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. F-18-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of F-18-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of F-18-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. F-18-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.
Autores: Musto, P.; Anderson, K. C.; Attal, M.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº 2  2017  págs. 228 - 245
Italian Ministry of Health Current Research [RRC 2015-2360451, RRC 2016-2361120]; Celgene Corporation
Autores: Laubach, J. P. ; San Miguel Izquierdo, Jesús; Hungria, V. ; et al.
Revista: EXPERT REVIEW OF HEMATOLOGY
ISSN 1747-4086  Vol. 10  Nº 3  2017  págs. 229 - 237
Introduction: A significant unmet need exists in patients with relapsed or refractory multiple myeloma ( MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors ( DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival. Panobinostat-associated adverse events included thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy. Research into how to maintain the benefits of DACi while improving tolerability is ongoing. Areas covered: This review focuses on the efficacy and safety of panobinostat and panobinostat-based combinations for MM. Early data from clinical trials investigating the HDAC6 inhibitor ricolinostat are also discussed. Expert commentary: DACi are a unique and effective new class of agents for the treatment of MM, with panobinostat being the first to have clinically meaningful benefit for patients with relapsed or refractory MM. Optimization of dose and schedule, novel combination strategies, and introduction of selective DACi may improve the risk-benefit profile of DACi-based regimens.
Autores: Mateos, M. V. , (Autor de correspondencia); Blade, J.; Lahuerta, J. J.; et al.
Revista: MEDICINA CLINICA
ISSN 0025-7753  Vol. 148  Nº 11  2017  págs. 517 - 523
Autores: Flores-Montero, J.; Sanoja-Flores, L.; Paiva, Bruno; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 31  Nº 10  2017  págs. 2094 - 2103
Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of. 107 cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P = 0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P = 0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.
Autores: Lahuerta, J. J.; Paiva, Bruno; Vidriales, M. B. ; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 35  Nº 25  2017  págs. 2900 - +
Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Espanol de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM. (C) 2017 by American Society of Clinical Oncology
Autores: Moreau, P.; San Miguel Izquierdo, Jesús; Sonneveld, P.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Supl. 4  2017  págs. 52 - 61
Autores: Moreau, P.; Dimopoulos, MA.; Richardson, P. G.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 99  Nº 3  2017  págs. 199 - 206
ObjectivesHeavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. MethodsThis analysis included 1088 patients who received 2 prior therapies, including lenalidomide and bortezomib, and progressed 60days of last therapy. Patients received 28-day cycles of pomalidomide 4mg/day on days 1-21 and low-dose dexamethasone 40mg (20mg if aged > 75years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. ResultsThe most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. ConclusionsPomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines.
Autores: Lopez-Iglesias, A. A.; Herrero, A. B.; Chesi, M.; et al.
Revista: JOURNAL OF HEMATOLOGY & ONCOLOGY
ISSN 1756-8722  Vol. 10  Nº 1  2017  págs. 127
BACKGROUND: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. METHODS: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. RESULTS: EDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6-4.8 ¿M) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk*MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by ¿-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in ¿H2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as ¿H2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. CONCLUSION: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors.
Autores: Avet-Loiseau, H.; Bahlis, N. J.; Chng, W. J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 130  Nº 24  2017  págs. 2610 - 2618
Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537.
Autores: Rosinol, L.; Oriol, A.; Teruel, A. I.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 31  Nº 9  2017  págs. 1922 - 1927
The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN). Maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of intravenous bortezomib at 1.3 mg/m(2) on days 1, 4, 8 and 11 every 3 months) versus T (100 mg daily) versus alfa2-IFN (3 MU three times per week) for up to 3 years. A total of 271 patients were randomized (TV: 91; T: 88; alfa2-IFN: 92). The complete response (CR) rate with maintenance was improved by 21% with TV, 11% with T and 17% with alfa2-IFN (P, not significant). After a median follow-up of 58.6 months, the progression-free survival (PFS) was significantly longer with TV compared with T and alfa2-IFN (50.6 vs 40.3 vs 32.5 months, P = 0.03). Overall survival was not significantly different among the three arms. Grade 2-3 peripheral neuropathy was observed in 48.8%, 34.4% and 1% of patients treated with TV, T and alfa2-IFN, respectively. In conclusion, bortezomib and thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide or alfa2-IFN. (no. EUDRA 2005-001110-41).
Autores: Laubach, J. P. ; Moslehi, J. J. ; Francis, S. A. ; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 178  Nº 4  2017  págs. 547 - 560
This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade >= 3 CHF was 1.3-4.0% in studies in relapsed/refractory MM and 1.2-4.7% in previously untreated MM (2.0-7.6% all grades), with no significant differences between bortezomib- and non-bortezomibbased arms in comparative studies. Incidences of arrhythmias (1.3-5.9% grade >= 2; 0.6-4.1% grade >= 3), IHD (1.2-2.9% all grades; 0.4-2.7% grade >= 3) and cardiac death (0-1.4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomibbased arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.
Autores: Garcia-Sanz, R. ; Corchete, L. A. ; Alcoceba, M.; et al.
Revista: HEMATOLOGICAL ONCOLOGY
ISSN 0278-0232  Vol. 35  Nº 4  2017  págs. 746 - 751
Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However. treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we can led out a genome-wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MA565, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101.1ocated in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses. cytoband enrichment, and pathway analyses were also performed. but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment.
Autores: Martinez-Lopez, J.; Sanchez-Vega, B.; Barrio, S.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 31  Nº 6  2017  págs. 1446 - 1449
Autores: Paiva, Bruno; Puig, N.; Cedena, M. T.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 31  Nº 2  2017  págs. 382 - 392
The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 - CD81 expression axis identifies three bone marrow (BM) PC subsets with distinct age- prevalence, proliferation, replication- history, immunoglobulin- production, and phenotype, consistent with progressively increased differentiation from CD19+ CD81+ into CD19 - CD81+ and CD19 - CD81 - BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 - CD81 -) clones, 38% intermediate- differentiated (CD19 - CD81+) and 3% less- differentiated (CD19+ CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression- free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal- residual- disease samples (n = 40) unraveled that in 20% of patients, less- differentiated PCs subclones become enriched after therapy- induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less- differentiated clonal PCs retain high expression of genes related to preceding B- cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less- differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
Autores: Dimopoulos, M. A. ; Lonial, S. ; White, D. ; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 178  Nº 6  2017  págs. 896 - 905
The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0.70). Median time from diagnosis was 3.5 years. We present extended 3-year follow-up data. Endpoints included progression- free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0.0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0.73; P = 0.0014). Interim OS demonstrated a trend in favour of ELd (P = 0.0257); 1-, 2-and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with >= median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0.47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.
Autores: Dimopoulos, M. A.; Stewart, A. K. ; Masszi, T.; et al.
Revista: BLOOD CANCER JOURNAL
ISSN 2044-5385  Vol. 7  Nº 4  2017  págs. :e554
Carfilzomib, a proteasome inhibitor, is approved as monotherapy and in combination with dexamethasone or lenalidomidedexamethasone (Rd) for relapsed or refractory multiple myeloma. The approval of carfilzomib-lenalidomide-dexamethasone (KRd) was based on results from the randomized, phase 3 study ASPIRE (NCT01080391), which showed KRd significantly improved progression-free survival (PFS) vs Rd (median 26.3 vs 17.6 months; hazard ratio (HR) = 0.690; P = 0.0001). This subgroup analysis of ASPIRE evaluated KRd vs Rd by number of previous lines of therapy and previous exposure to bortezomib, thalidomide or lenalidomide. Treatment with KRd led to a 12-month improvement in median PFS vs Rd after first relapse (HR 0.713) and a 9-month improvement after >= 2 previous lines of therapy (HR 0.720). Treatment with KRd led to an approximate 8-month improvement vs Rd in median PFS in bortezomib-exposed patients (HR 0.699), a 15-month improvement in thalidomide-exposed patients (HR 0.587) and a 5-month improvement in lenalidomideexposed patients (HR 0.796). Objective response and complete response or better rates were higher with KRd vs Rd, irrespective of previous treatment. KRd had a favorable benefit-risk profile and should be considered an appropriate treatment option for patients with 1 or >= 2 previous lines of therapy and those previously exposed to bortezomib, thalidomide or lenalidomide.
Autores: Hajek, R.; Masszi, T.; Petrucci, M. T.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 31  Nº 1  2017  págs. 107 - 114
Onyx Pharmaceuticals, Inc., an Amgen subsidiary
Autores: de Larrea, C. F.; Davila, J.; Isola, I. ; et al.
Revista: BONE MARROW TRANSPLANTATION
ISSN 0268-3369  Vol. 52  Nº 4  2017  págs. 567 - 569
The response evaluation after autologous stem-cell transplantation (ASCT) is usually performed at day + 100 in patients with multiple myeloma (MM). A recent report suggests that improvement in the response can be observed beyond day + 100. The aim of the present study has been to evaluate the rate of improved response and outcome beyond day + 100 after ASCT, with and without maintenance therapy. One hundred and forty-four patients who underwent single ASCT with chemosensitive disease and achieved less than CR at day 100 post ASCT were evaluated. Seventy-four patients (51.4%) did not receive any maintenance with only one of them showing an upgrade in the response. The remaining 70 patients (48.6%) received maintenance therapy; eleven of them (15.7%) improved their response beyond day + 100. The outcome of these patients was better than those who did not upgrade their response in both progression-free survival and overall survival (P = 0.019 and P = 0.031, respectively). In conclusion, the improvement in response beyond day + 100 after ASCT in patients not receiving any therapy is exceedingly rare. A minority of patients receiving maintenance therapy after ASCT upgrades their response and this finding is associated with better outcome.
Autores: Mishima, Y.; Paiva, Bruno; Shi, J. T.; et al.
Revista: CELL REPORTS
ISSN 2211-1247  Vol. 19  Nº 1  2017  págs. 218 - 224
The development of sensitive and non-invasive "liquid biopsies'' presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.
Autores: López-Iglesias, A. A.; González-Méndez, L.; San-Segundo, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº 1  2017  págs. 168 - 175
Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.
Autores: Jiménez, C.; Jara-Acevedo, M.; Corchete, L. A.; et al.
Revista: JOURNAL OF MOLECULAR DIAGNOSTICS
ISSN 1525-1578  Vol. 19  Nº 1  2017  págs. 99 - 106
Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situ hybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require Large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGH translocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions. Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGH and six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC, and BRAF. We identified 14 of 17 IGH translocations previously detected by FISH and three confirmed translocations not detected by FISH, with the additional advantage of breakpoint identification, which can be used as a target for evaluating minimal residual disease. IgH subclass and V(D)J rearrangements were identified in 77% and 65% of patients, respectively. Mutation analysis revealed the presence of missense protein-coding alterations in at least one of the evaluating genes in 16 of 48 patients (33%). This method may represent a time-and cost-effective diagnostic method for the molecular characterization of multiple myeloma.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM
ISSN 1520-4383  Vol. 2017  Nº 1  2017  págs. 498 - 507
Multiple myeloma is the second most frequent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for young patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want definitively to cure the disease. Treatment goals for transplant-eligible and non-transplant-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. For young patients, HDT-ASCT is a standard of care for treatment, and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were once limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes. Extended treatment of young and elderly patients improves the quality and duration of clinical responses; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. This review summarizes progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early vs late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best treatment option for non-transplant-eligible patients.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Hungria, V. T. M.; Yoon, S. S.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 179  Nº 1  2017  págs. 66 - 74
Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56.7%; TP2, 6.0%), diarrhoea (grade 3/4: TP1, 24.1%; TP2, 7.1%), and fatigue (grade 3/4: TP1, 16.3%; TP2, 1.8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.
Autores: Lapa, C. ; García Velloso, María José; Lückerath, K.; et al.
Revista: THERANOSTICS
ISSN 1838-7640  Vol. 7  Nº 11  2017  págs. 2956 - 2964
C-11-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to F-18-2'-deoxy-2'-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET-and FDG-PET/computed tomography (CT) at the University Centers of Wurzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (kappa=0.82 vs kappa=0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra-and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.
Autores: Dimopoulos, M. A.; Stewart, A. K.; Masszi, T.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 177  Nº 3  2017  págs. 404 - 413
A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were 70years old, and in the control group, 115/396 patients were 70years old. Median PFS for patients <70years old was 286months for the carfilzomib group versus 176months for the control group [hazard ratio (HR), 0701]. Median PFS for patients 70years old was 238months for the carfilzomib group versus 160months for the control group (HR, 0753). For patients <70years the overall response rate (ORR) was 860% (carfilzomib group) and 669% (control group); for patients 70years old the ORR was 903% (carfilzomib group) and 661% (control group). Within the carfilzomib group, grade 3 cardiovascular adverse events occurred more frequently among patients 70years old compared with patients <70years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients 70years old. Trial Registration: clinicaltrials.gov identifier: NCT01080391.
Autores: Seckinger A; Delgado García, José Antonio; Moser S; et al.
Revista: CANCER CELL
ISSN 1535-6108  Vol. 31  Nº 3  2017  págs. 396 - 410
We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3(+) T cell/myeloma cell crosslinking, followed by CD4(+)/CD8(+) T cell activation, and secretion of interferon-gamma, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA(+) cells in cynomolgus monkeys. Pharmacokinetics and pharmacodynamics indicate weekly intravenous/subcutaneous administration.
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Orlowski, R. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 319
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Joaquin, M. L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 274 - 275
Autores: Dimopoulos, M. A.; Moreau, P.; Nahi, H. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 108 - 109
Autores: Morales Lozano, María Isabel; García García, Berta; Villar Fernández, Sara; et al.
Revista: REVISTA ESPAÑOLA DE MEDICINA NUCLEAR E IMAGEN MOLECULAR
ISSN 2253-654X  Vol. 36  Nº Supl 1  2017  págs. 10
n pacientes con mieloma múltiple el FDG-PET/CT es una herramienta sensible en la valoración de respuesta, permite la detección de enfermedad extramedular y complementa la valoración de la enfermedad mínima residual. La persistencia de captación de FDG en pacientes en RC puede predecir la recaída
Autores: Mateos, M. V. ; Martinez-Lopez, J.; Hernandez, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 143
Autores: Fernandez, L. L. A.; Cueto-Felqueroso, C. ; Mateos, M. V.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 524
Autores: Ordonez, R.; Kulis, M.; Russinol, N.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 104 - 105
Autores: Sanchez-Vega, B. ; Mateos, R. ; Cuenca, I.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 271
Autores: San Miguel Izquierdo, Jesús; Gutierrez, M. A. E.; Spicka, I.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 111 - 112
Autores: Richardson, P.; Attal, M. ; San Miguel Izquierdo, Jesús; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl 2  2017  págs. 779
Autores: San Miguel Izquierdo, Jesús; Weisel, K.; Cook, G.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 1 - 2
Autores: Carrasco, A.; Ezponda Itoiz, Teresa; Meydan, C.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 102  Nº Supl. 4  2017  págs. 10
Autores: Dimopoulos, M. A.; Lonial, S. ; White, D.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 167 - 168
Autores: Ordóñez Ciriza, Raquel; Kulis, M.; Russinol, N.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 102  Nº Supl. 4  2017  págs. 11 - 12
Autores: Carrasco Leon, Arantxa; Ezponda Itoiz, Teresa; Meydan, C.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 502 - 502
Autores: Cuenca, I. ; Sanchez-Vega, B.; Paiva, Bruno; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 106
Autores: Moreau, P., (Autor de correspondencia); van de Donk, N. W. C. J. ; San Miguel Izquierdo, Jesús; et al.
Revista: DRUGS
ISSN 0012-6667  Vol. 76  Nº 9  2016  págs. 989 - 990
Autores: Lonial, S. ; Durie, B.; Palumbo, A.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 30  Nº 3  2016  págs. 526 - 535
The treatment landscape for patients with multiple myeloma (MM) is constantly evolving. Over the past decade, the introduction of novel agents such as proteasome inhibitors and immunomodulatory drugs has led to notable changes in therapeutic strategy, and improvements in survival, yet MM remains incurable in the vast majority of cases. More recently, a targeted approach to MM treatment has emerged, using monoclonal antibodies (mAbs) to target antigens expressed on the surface of MM cells. MAbs tested to date kill MM cells via the host's immune system and/or by promoting apoptosis, and appear to have generally improved tolerability compared with currently available treatments. Due to their distinct mode of action, mAbs are promising both for patients who have exhausted current regimens, and as part of first-line treatments in newly diagnosed patients. This review examines the recent developments in mAb-based therapy for MM, primarily focused on those agents in ongoing clinical testing.
Autores: Paiva, Bruno (Autor de correspondencia); Merino Roncal, Juana María; San Miguel Izquierdo, Jesús
Revista: CURRENT OPINION IN ONCOLOGY
ISSN 1040-8746  Vol. 28  Nº 6  2016  págs. 511 - 517
Purpose of reviewAlthough the input of multiparameter flow cytometry (MFC) into the clinical management of multiple myeloma patients has faced some reluctance, continuously growing evidence supports the utility of MFC in this disease.Recent findingsMFC immunophenotyping of bone marrow and peripheral blood plasma cells affords cost-effective assessment of clonality, and provides prognostic information on the risk of progression in smoldering multiple myeloma, and the identification of active multiple myeloma patients with dismal outcome (e.g., high numbers of circulating tumor cells) or long-term survival despite suboptimal responses through the characterization of monoclonal gammopathy of undetermined significance-like phenotypes. Extensive data indicate that minimal residual disease (MRD) monitoring can be used as biomarker to evaluate treatment efficacy and act as surrogate for survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in multiple myeloma, which implies systematic usage of highly sensitive cost-effective, readily available, and standardized MRD techniques such as MFC.SummaryNext-generation MFC should be considered mandatory in the routine evaluation of multiple myeloma patients both at diagnosis and after therapy, and represents an attractive technique to integrate with high-throughput DNA and RNA-seq methods to help in understanding the mechanisms behind dissemination and chemoresistance of multiple myeloma.
Autores: Paiva, Bruno; García-Sanz, R.; San Miguel Izquierdo, Jesús
Revista: CANCER TREATMENT AND RESEARCH
ISSN 0927-3042  Vol. 169  2016  págs. 103 - 122
Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as some acute leukemias as well as chronic myeloid and lymphocytic leukemia. Although multiple myeloma (MM) remains as an incurable disease, around half of the patients achieve complete remission (CR), and recent data suggests increasing rates of curability with "total-therapy-like" programs. This landscape is likely to be improved with the advent of new antibodies and small molecules. Therefore, conventional serological and morphological techniques have become suboptimal for sensitive evaluation of highly effective treatment strategies. Although, existing data suggests that MRD could be used as a biomarker to evaluate treatment efficacy, help on therapeutic decisions, and act as surrogate for overall survival, the role of MRD in MM is still a matter of extensive debate. Here, we review the different levels of remission used to define depth of response in MM and their clinical significance, as well as the prognostic value and unique characteristics of MRD detection using immunophenotypic, molecular, and imaging techniques. Key facts The higher efficacy of new treatment strategies for MM demand the incorporation of highly sensitive techniques to monitor treatment efficacy MRD could be used as a more potent surrogate biomarker for survival than standard CR We need to understand the pros and cons of the different MRD techniques The time has come to incorporate highly sensitive, cost-effective, readily available, and standardized MRD techniques into clinical trials to assess its role in therapeutic decisions.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Einsele, H. ; Moreau, P. ;
Revista: ADVANCES IN THERAPY
ISSN 0741-238X  Vol. 33  Nº 11  2016  págs. 1896 - 1920
Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway. In August 2015, the European Commission authorized panobinostat for use in combination with bortezomib and dexamethasone for the treatment of relapsed or relapsed and refractory multiple myeloma (MM) in patients who have received aeyen2 prior regimens including bortezomib and an immunomodulatory drug. In January 2016, the National Institute for Health and Care Excellence recommended panobinostat for use in the same combination and patient population. The authorization and recommendation were based on results from the pivotal phase 3 PANORAMA 1 (NCT01023308) clinical trial, which demonstrated an improvement in median progression-free survival of 7.8 months for the three-drug combination compared with placebo plus bortezomib and dexamethasone in this patient population. This review will discuss the current treatment landscape for relapsed/refractory MM, the mechanism of action of panobinostat, clinical data supporting the European authorization, concerns about safety and strategies for mitigating toxicity, and how panobinostat fits into the current MM landscape in Europe.
Autores: Moreau, P.; van de Donk, N. W. C. J.; San Miguel Izquierdo, Jesús; et al.
Revista: DRUGS
ISSN 1179-1950  Vol. 76  Nº 8  2016  págs. 853 - 867
Monoclonal antibodies (mAbs) are a recent addition to multiple myeloma (MM) therapies and a number of mAbs directed at myeloma cell surface molecules are in development. Daratumumab is a CD38 mAb that has demonstrated substantial activity and good tolerability in four phase I, phase I/II and phase II studies as monotherapy, as well as in combination with current standard treatments in MM. The positive results obtained in the relapsed/refractory setting in patients with advanced-stage disease and in a small number of patients with newly diagnosed disease provide the rationale for the investigation of the agent in a number of ongoing phase III trials. mAbs are generally better tolerated than conventional chemotherapy; however, their use requires other special considerations. Such factors include those common to all mAbs, namely infusion-related reactions, but also factors that are observed with mAbs used in myeloma, such as interference with response assessment, or factors that are related to CD38 mAbs such as daratumumab, for instance blood typing interference. Our review provides an overview of the results from the daratumumab clinical trials conducted to date, as well as practical management considerations for the use of daratumumab based on our experience with the agent.
Autores: Orlowski, R. Z.; Nagler, A.; Sonneveld, P.; et al.
Revista: CANCER
ISSN 1097-0142  Vol. 122  Nº 13  2016  págs. 2050 - 2056
BACKGROUND: Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS: Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS: In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS: Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS.
Autores: Tang, M.; Zhao, R.; van de Velde, H.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1557-3265  Vol. 22  Nº 16  2016  págs. 4206 - 4214
PURPOSE: Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens. EXPERIMENTAL DESIGN: We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics. RESULTS: Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns. CONCLUSIONS: The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens.
Autores: Herrero Sánchez, MC; Rodríguez Serrano, C; Almeida, Julia; et al.
Revista: JOURNAL OF HEMATOLOGY AND ONCOLOGY
ISSN 1756-8722  Vol. 9  Nº 1  2016  págs. 113
These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.
Autores: Dimopoulos, M. A.; Sonneveld, P.; Leung, N.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 34  Nº 13  2016  págs. 1544 - 1557
PURPOSE: The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma-related renal impairment (RI). METHODS: Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. RECOMMENDATIONS: All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m(2) to 140 mg/m(2)) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A).
Autores: Mateos, M. V.; Granell, M.; Oriol, A.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 1365-2141  Vol. 175  Nº 3  2016  págs. 448 - 456
Elotuzumab is an immunostimulatory, humanized immunoglobulin G1 monoclonal antibody that selectively targets and kills signalling lymphocytic activation molecule family member 7-expressing myeloma cells. We evaluated the safety and tolerability of elotuzumab 10mg/kg combined with thalidomide 50-200mg and dexamethasone 40mg (with/without cyclophosphamide 50mg) in patients with relapsed/refractory multiple myeloma (RRMM). The primary endpoint was the proportion of grade 3 non-haematological adverse events (AEs); other endpoints included the number of dose reductions/discontinuations and efficacy. Forty patients were treated, who had a median of three previous therapies, including bortezomib (98%) and lenalidomide (73%). Grade 3 non-haematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral oedema (25%). Six (15%) patients had an infusion reaction. Twenty-six (65%) patients had 1 dose reduction/discontinuation due to an AE, none related to elotuzumab. Overall response rate was 38%; median progression-free survival was 39months. Median overall survival was 163months and the 1-year survival rate was 63%. Minimal incremental toxicity was observed with addition of elotuzumab to thalidomide/dexamethasone with or without cyclophosphamide, and efficacy data suggest clinical benefit in a highly pre-treated population. Elotuzumab combined with thalidomide may provide an additional treatment option for patients with RRMM.
Autores: Gonzalez-Calle, V.; Jorge-Finnigan, C.; Santos-Duran, J. C.; et al.
Revista: CLINICAL CASE REPORTS
ISSN 2050-0904  Vol. 4  Nº 12  2016  págs. 1096 - 1100
rimary cutaneous plasmacytoma should be in the differential diagnosis in case of solitary or multiple erythematous-violaceous nodules or papules. The diagnosis relies on clinical, histological, and immunochemical findings, without underlying evidence of multiple myeloma. Treatment should be individualized, and agents such as bortezomib or lenalidomide have shown to be effective.
Autores: Paiva, Bruno; Mateos, Maria Victoria; Sanchez Abarca, Luis Ignacio; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 127  Nº 9  2016  págs. 1151 - 1162
There is significant interest in immunotherapy for the treatment of high-risk smoldering multiple myeloma (SMM), but no available data on the immune status of this particular disease stage. Such information is important to understand the interplay between immunosurveillance and disease transformation, but also to define whether patients with high-risk SMM might benefit from immunotherapy. Here, we have characterized T lymphocytes (including CD4, CD8, T-cell receptor ¿¿, and regulatory T cells), natural killer (NK) cells, and dendritic cells from 31 high-risk SMM patients included in the treatment arm of the QUIREDEX trial, and with longitudinal peripheral blood samples at baseline and after 3 and 9 cycles of lenalidomide plus low-dose dexamethasone (LenDex). High-risk SMM patients showed at baseline decreased expression of activation-(CD25/CD28/CD54), type 1 T helper-(CD195/interferon-¿/tumor necrosis factor-¿/interleukin-2), and proliferation-related markers (CD119/CD120b) as compared with age-matched healthy individuals. However, LenDex was able to restore the normal expression levels for those markers and induced a marked shift in T-lymphocyte and NK-cell phenotype. Accordingly, high-risk SMM patients treated with LenDex showed higher numbers of functionally active T lymphocytes. Together, our results indicate that high-risk SMM patients have an impaired immune system that could be reactivated by the immunomodulatory effects of lenalidomide, even when combined with low-dos
Autores: Vidriales, M. B.; Perez-Lopez, E.; Pegenaute, C.; et al.
Revista: LEUKEMIA RESEARCH
ISSN 1873-5835  Vol. 40  2016  págs. 1 - 9
The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (>= 0.1%; >= 0.01-0.1%; and <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p = 0.002). Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p = 0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics.
Autores: Sonneveld, P.; Avet-Loiseau, H.; Lonial, S.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 127  Nº 24  2016  págs. 2955 - 2962
The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4; 14), del(17/17p), t(14; 16), t(14; 20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4; 14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4; 14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.
Autores: Paiva, Bruno; Cedena, M. T.; Puig, N.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 127  Nº 25  2016  págs. 3165 - 3174
The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first-to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and >= 10(-5); n = 20, 12%), and MRD positive (<10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and >= 10(-5) vs >= 10(-4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generationMFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249.
Autores: Mateos, M. V.; Oriol, A.; Martínez-López, J.; et al.
Revista: ANNALS OF HEMATOLOGY
ISSN 1432-0584  Vol. 95  Nº 12  2016  págs. 2033 - 2041
Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Here, we compared outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance). A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in this retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m(2)); median dose intensity was lower (2.0 vs 5.1 mg/m(2)/month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen.
Autores: Paiva, Bruno; Martinez-Lopez, J.; Corchete, L. A. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 127  Nº 24  2016  págs. 3035 - 3039
Immunoglobulin light-chain amyloidosis (AL) and multiple myeloma (MM) are 2 distinct monoclonal gammopathies that involve the same cellular compartment: clonal plasma cells (PCs). Despite the fact that knowledge about MM PC biology has significantly increased in the last decade, the same does not apply for AL. Here, we used an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 24 newly diagnosed patients with AL. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and both monoclonal gammopathy of undetermined significance and MM PCs. However, in contrast to MM, highly purified fluorescence-activated cell-sorted clonal PCs from AL (n = 9) showed almost normal transcriptome, with only 38 deregulated genes vs normal PCs; these included a few tumor-suppressor (CDH1, RCAN) and proapoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11) were genomically unstable, with a median of 9 copy number alterations (CNAs) per case, many of such CNAs being similar to those found in MM. Whole-exome sequencing (WES) performed in 5 AL patients revealed a median of 15 nonrecurrent mutations per case. Altogether, our results show that in the absence of a unifying mutation by WES, clonal PCs in AL display phenotypic and CNA profiles similar to MM, but their transcriptome is remarkably similar to that of normal PCs.
Autores: Herrero-Sánchez, M. C.; Rodríguez-Serrano, C.; Almeida, J.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 173  Nº 5  2016  págs. 754 - 768
The mechanistic target of rapamycin (mTOR) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft-versus-host disease (GvHD). Despite its partial ability to block mTOR pathway, the mTORC1 inhibitor rapamycin has shown encouraging results in the control of GvHD. Therefore, we considered that simultaneous targeting of both mTORC1 and mTORC2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in GvHD control. To assess this assumption, we have used the dual mTORC1/mTORC2 inhibitors CC214-1 and CC214-2. In vitro studies confirmed the superior ability of CC214-1 versus rapamycin to block mTORC1 and mTORC2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC214-1 was more efficient in inhibiting naïve T cell activation and the expression of T-cell activation markers. In addition, CC214-1 induced specific tolerance against alloantigens, while preserving anti-cytomegalovirus response. Finally, in a mouse model of GvHD, the administration of CC214-2 significantly improved mice survival and decreased GvHD-induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC214-1 on T lymphocytes and illustrates the role of CC214-2 in the allogeneic transplantation setting as a possible GvHD prophylaxis agent.
Autores: Paiva, Bruno; Corchete LA; Vidriales MB; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 127  Nº 15  2016  págs. 1896-1906
Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such asALCAMthat is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at t
Autores: Misiewicz-Krzeminska, I.; Sarasquete, M. E.; Vicente-Duenas, C.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1557-3265  Vol. 22  Nº 1  2016  págs. 207 - 217
Purpose: Dysregulation of one of the three D-cyclin genes has been observed in virtually all multiple myeloma tumors. The mechanisms by which CCND2 is upregulated in a set of multiple myeloma are not completely deciphered. We investigated the role of post-transcriptional regulation through the interaction between miRNAs and their binding sites at 3'UTR in CCND2 overexpression in multiple myeloma. Experimental Design: Eleven myeloma cell lines and 45 primary myeloma samples were included in the study. Interactions between miRNAs deregulated in multiple myeloma and mRNA targets were analyzed by 3'UTR-luciferase plasmid assay. The presence of CCND2 mRNA isoforms different in length was explored using qRT-PCR, Northern blot, mRNA FISH, and 3' rapid amplification of cDNA ends (RACE)-PCR. Results: We detected the presence of short CCND2 mRNA, both in the multiple myeloma cell lines and primary cells. The results obtained by 3' RACE experiments revealed that changes in CCND2 3'UTR length are explained by alternative polyadenylation. The luciferase assays using plasmids harboring the truncated CCND2 mRNA strongly confirmed the loss of miRNA sites in the shorter CCND2 mRNA isoform. Those multiple myelomas with greater abundance of the shorter 3'UTR isoform were associated with significant higher level of total CCND2 mRNA expression. Furthermore, functional analysis showed significant CCND2 mRNA shortening after CCND1 silencing and an increased relative expression of longer isoform after CCND1 and CCND3 overexpression, suggesting that cyclin D1 and D3 could regulate CCND2 levels through modifications in polyadenylation-cleavage reaction. Conclusions: Overall, these results highlight the impact of CCND2 3'UTR shortening on miRNA-dependent regulation of CCND2 in multiple myeloma.
Autores: Weisel, K. C.; Dimopoulos, M. A.; Moreau, P.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº 7  2016  págs. 872 - 878
Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance >= 30 - < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or >= 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance >= 30 - < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance >= 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to >= 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30.
Autores: San Miguel Izquierdo, Jesús; Hungria, V. T. M.; Yoon, S. S.; et al.
Revista: LANCET HAEMATOLOGY
ISSN 2352-3026  Vol. 3  Nº 11  2016  págs. e506 - e515
Background Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. Methods PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1.3 mg/m(2) intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308. Findings Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40.3 months (95% CI 35.0-44.8) in those who received panobinostat, bortezomib, and dexamethasone versus 35.8 months (29.0-40.6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0.94, 95% CI 0.78-1.14; p=0.54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25.5 months (95% CI 19.6-34.3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19.5 months (14.1-32.5) in 74 who received placebo (HR 1.01, 95% CI 0.68-1.50). Interpretation The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this.
Autores: Krzeminski, P.; Corchete, L. A.; Garcia, J. L.; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 7  Nº 49  2016  págs. 80664 - 80679
Multiple myeloma (MM) remains incurable despite the introduction of novel agents, and a relapsing course is observed in most patients. Although the development of genomic technologies has greatly improved our understanding of MM pathogenesis, the mechanisms underlying relapse have been less thoroughly investigated. In this study, an integrative analysis of DNA copy number, DNA methylation and gene expression was conducted in matched diagnosis and relapse samples from MM patients. Overall, the acquisition of abnormalities at relapse was much more frequent than the loss of lesions present at diagnosis, and DNA losses were significantly more frequent in relapse than in diagnosis samples. Interestingly, copy number abnormalities involving more than 100 Mb of DNA at relapse significantly affect the gene expression of these samples, provoking a particular deregulation of the IL-8 pathway. On the other hand, no significant modifications of gene expression were observed in those samples with less than 100 Mb affected by chromosomal changes. Although several statistical approaches were used to identify genes whose abnormal expression at relapse was regulated by methylation, only two genes that were significantly deregulated in relapse samples (SORL1 and GLT1D1) showed a negative correlation between methylation and expression. Further analysis revealed that DNA methylation was involved in regulating SORL1 expression in MM. Finally, relevant changes in gene expression observed in relapse samples, such us downregulation of CD27 and P2RY8, were most likely not preceded by alterations in the corresponding DNA. Taken together, these results suggest that the genomic heterogeneity described at diagnosis remains at relapse.
Autores: Richardson, P. G.; Harvey, R. D.; Laubach, J. P.; et al.
Revista: EXPERT REVIEW OF CLINICAL PHARMACOLOGY
ISSN 1751-2441  Vol. 9  Nº 1  2016  págs. 35 - 48
Recently, outcomes for patients with multiple myeloma have improved dramatically due to improved and innovative therapies. However, most patients will either relapse or become refractory to current therapy. Thus, a significant unmet need remains for novel agents to treat this patient population. Panobinostat, a potent pan-deacetylase inhibitor with a unique mechanism of action targeting both epigenetic regulation of gene expression and protein metabolism, has preclinical synergy with a number of agents, including the proteasome inhibitor bortezomib. In a phase 3 trial of panobinostat with bortezomib and dexamethasone, addition of panobinostat significantly prolonged the median progression-free survival of patients with relapsed or relapsed and refractory multiple myeloma. This review focuses on clinical development of panobinostat, with particular emphasis on pharmacokinetics and adverse event management.
Autores: Herrero, A. B.; Garcia-Gomez, A.; Garayoa, M.; et al.
Revista: AMERICAN JOURNAL OF PATHOLOGY
ISSN 1525-2191  Vol. 186  Nº 8  2016  págs. 2171 - 2182
IL-8 promotes cancer cell growth, survival, angiogenesis, and metastasis in several tumors. Herein, we investigated the sources of IL-8 production in multiple myeloma (MM) and its potential roles in MM pathogenesis. We found that bone marrow cells from patients with MM secreted higher amounts of IL-8 than healthy donors. IL-8 production was detected in cultures of CD138+ plasma cells and CD138(-) cells isolated from bone marrows of MM patients, and in three of seven human myeloma cell lines (HMCLs) analyzed. Interactions between MM and stromal cells increased IL-8 secretion by stromal cells through cell-cell adhesion and soluble factors. Interestingly, 1L8 expression also increased in HMCLs, stromal cells, and osteoclasts after treatment with the antimyeloma drugs melphalan and bortezomib. In fact, the effect of bortezomib on IL-8 production was higher than that exerted by stromal-MM cell interactions. Addition of exogenous IL-8 did not affect growth of HMCLs, although it protected cells from death induced by serum starvation through a caspase-independent mechanism. Furthermore, IL-8 induced by stromal-MM cell interactions strongly contributed to osteoclast formation in vitro, because osteoclastogenesis was markedly reduced by IL-8 specific neutralizing antibodies. In conclusion, our results implicate IL-8 in myeloma bone disease and point to the potential utility of an anti IL-8 therapy to prevent unwanted effects of IL-8 up-regulation on survival, angiogenesis, and osteolysis in MM.
Autores: Dimopoulos, M. A.; Oriol, A.; San Miguel Izquierdo, Jesús; et al.
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 1533-4406  Vol. 375  Nº 14  2016  págs. 1319 - 1331
BACKGROUND: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. RESULTS: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. CONCLUSIONS: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).
Autores: Mateos, M. V.; Martínez-López, J.; Hernandez, M. T.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 127  Nº 4  2016  págs. 420 - 425
Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n = 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n 5115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P = .21). The sequential and alternating groups exhibited similar hematologic and non-hematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P 5.65), and 3-year overall survival (72% vs 74%, P 5.63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235.
Autores: Richardson, P. G.; Hungria, V. T. M.; Yoon, S. S.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 127  Nº 6  2016  págs. 713 - 721
Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3PANORAMA1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and >= 2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and >= 2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received >= 2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis.
Autores: Garcia-Sanz, R.; Jimenez, C.; Puig, N.; et al.
Revista: BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY
ISSN 1532-1924  Vol. 29  Nº 2  2016  págs. 136 - 147
Waldenstrom's macroglobulinaemia (WM) is an MYD88(L265P)-mutated lymphoplasmacytic lymphoma that invades bone marrow and secretes monoclonal immunoglobulin M (IgM). WM cells are usually unable to undergo class switch recombination, and have mutated IGHV, with a typical immunophenotype CD19(+)/CD22(low+)/CD23(-)/CD25(+)/CD27(+)/CD45(+)/CD38(low+)/SmIgM(+) (negative for CD5, CD10, CD11c, CD103). This immunophenotype matches memory B cells (smIgM(-/+)/CD10(-)/CD19(+)/CD20(+)/CD27(+)/CD38(low+)/CD45(+)), representing 30% of B cells in the blood. Fifty percent of them have not undergone class switch recombination and are IgM(+). These cells have suffered somatic hypermutation as WM cells. Genetic abnormalities do not abrogate the capacity to progress to plasma cells that usually belong to the clonal WM compartment, with a normal immunophenotype and functional characteristics. However, some WM cells are CD27(-), MYD88(WT), without somatic hypermutation, or with class switch recombination capable of reactivation. Thus, most data support a B-memory-cell origin for WM, but a small fraction of cases may have a different origin.
Autores: Dimopoulos, M. A.; Palumbo, A.; Corradini, P.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 4  2016  págs. 497 - 503
Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40mg(20mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). TheORRwas 32.6%, and the medianDORwas 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. Wepresent the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated.
Autores: Stewart, A. K.; Dimopoulos, M. A.; Masszi, T.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 34  Nº 32  2016  págs. 3921 - 3930
Purpose To determine the effects of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) on health-related quality of life (HR-QoL) in the Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone for the Treatment of Patients With Relapsed Multiple Myeloma (ASPIRE) trial. Methods Patients with relapsed multiple myeloma were randomly assigned to receive KRd or Rd. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and myeloma-specific module were administered at baseline; day 1 of cycles 3, 6, 12, and 18; and after treatment. The Global Health Status/Quality of Life (GHS/QoL) scale and seven subscales (fatigue, nausea and vomiting, pain, physical functioning, role functioning, disease symptoms, and adverse effects of treatment) were compared between groups using a mixed model for repeated measures. The percentages of responders with >= 5- or 15-point GHS/QoL improvement at each cycle were compared between groups. Results Baseline questionnaire compliance was excellent (94.1% of randomly assigned patients). KRd patients had higher GHS/QoL scores versus Rd patients over 18 treatment cycles (two-sided P < .001). The minimal important difference was met at cycle 12 (5.6 points) and approached at cycle 18 (4.8 points). There was no difference between groups for the other prespecified subscales from ASPIRE. A higher proportion of KRd patients met the GHS/QoL responder definition (>= 5-point improvement) with statistical differences at cycle 12 (KRd v Rd patients, 25.5% v 17.4%, respectively) and 18 (KRd v Rd patients, 24.2% v 12.9%, respectively). Conclusion KRd improves GHS/QoL without negatively affecting patient-reported symptoms when compared with Rd. These data further support the benefit of KRd in patients with relapsed multiple myeloma.
Autores: Siegel, D. S.; Weisel, K. C.; Dimopoulos, M. A.; et al.
Revista: LEUKEMIA & LYMPHOMA
ISSN 1029-2403  Vol. 57  Nº 12  2016  págs. 2833 - 2838
Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] >= 30 to <60 mL/min) and without RI (>= 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively; p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010).
Autores: Mateos, M. V. ; Hernandez, M. T. ; Giraldo, P.; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 17  Nº 8  2016  págs. 1127 - 1136
Background The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial. Methods We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1: 1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (<= 6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363. Findings Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0.24 [95% CI 0.14-0.41]; p<0.0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0.43 [95% CI 0.21-0.92], p=0.024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1.34 [95% CI 0.54-3.30]; p=0.50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0.070). Interpretation This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future.
Autores: Ocio, E. M., (Autor de correspondencia); Oriol, A.; Blade, J.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 172  Nº 4  2016  págs. 625 - 628
Autores: Kulis, M. ; Ordonez, R. ; Russinol, N.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Misiewicz-Krzeminska, I.; Rojas, E.; Corchete, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl. 4  2016  págs. 23
Autores: Paiva, Bruno; Puig, N. ; Cedena, M. T.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Moreno, L.; Zabaleta Azpiroz, Aintzane; Alignani, Diego Oscar; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Pérez Persona, E.; Argiñano Pérez, J. M.; Chávez Collazos, P.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 93
Autores: Moreno Narro, Laura; Delgado García, José Antonio; Seckinger, A.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 21
Autores: Mateos, M. V. ; Hernandez, M. T. ; Giraldo, P.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: García García, Berta; Morales Lozano, María Isabel; Guillen Valderrama, Edgar Fernando; et al.
Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070  Vol. 43  Nº Supl.1.  2016  págs. S127 - S127
Autores: Sanoja-Flores, L.; Flores-Montero, J.; Paiva, B.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 22
Autores: Sanchez-Vega, B.; Barrio, S.; Ruiz-Heredia, Y.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl. 4  2016  págs. 22 - 23
Autores: Palumbo, A.; Mateos, M. V.; San Miguel Izquierdo, Jesús; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl. 6  2016  págs. 940TiP
Autores: Seckinger, A.; Delgado García, José Antonio; Moreno, L.; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 39  Nº Supl.3  2016  págs. 207 - 208
Autores: Mateos, M. V.; Blacklock, H.; Rocafiguera, A. O.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl 8  2016  págs.  50TiP
Autores: Lonial, S.; de Oliveira, MR.; Yimer, H.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl. 8  2016  págs. 51TiP
Autores: Lopez, L.; Caballero, T.; Rosinol, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 38 - 39
Autores: Gomez-Toboso, D.; Puig, N.; Canovas, V.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 32
Autores: Oriol, R. A.; Rosinol, L.; San Miguel Izquierdo, Jesús; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 27 - 28
Autores: Burgos Rodríguez, Leire; Alignani, Diego Oscar; Garcés Latre, Juan José; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Moreno, L. ; Zabaleta, A.; Alignani, D.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Ocio, E. M.; Shah, J.; Jagannath, S.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl.6  2016  págs.  941TiP
Autores: Bretones, G.; Paiva, Bruno; Valdes-Mas, R.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Figueroa Mora, María del Rocío; Marcos Jubilar, María; García García, Berta; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl. 1  2016  págs. 524
Autores: Arana Berganza, Paula; Zabaleta, A.; Lasa, M. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Jimenez, C.; Prieto-Conde, M. I.; Garcia-Alvarez, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 29 - 30
Autores: San Miguel Izquierdo, Jesús; Hungria, V. T. M.; Yoon, S. S.;
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 16  Nº 1  2015  págs. E6 - E6
Autores: Laubach, J. P.; Moreau, P.; San Miguel Izquierdo, Jesús; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1557-3265  Vol. 21  Nº 21  2015  págs. 4767 - 4773
Panobinostat is a potent oral deacetylase inhibitor that alters gene expression through epigenetic mechanisms and inhibits protein degradation. It was recently approved by the FDA and EMA for use in combination with bortezomib and dexamethasone in patients with multiple myeloma who have received >= 2 prior regimens, including bortezomib and an immunomodulatory drug. Panobinostat was approved based on results from the phase III PANORAMA 1 trial in patients with relapsed or relapsed and refractory multiple myeloma, which showed that panobinostat plus bortezomib and dexamethasone significantly extended progression- free survival (median, 12.0 months) compared with placebo plus bortezomib and dexamethasone (median, 8.1 months; P < 0.0001). Additional ongoing trials are evaluating panobinostat in combination with other partners in the relapsed/refractory and newly diagnosed treatment settings. This review focuses on panobinostat and its mechanism of action, pharmacokinetics, and clinical data in the treatment of relapsed or relapsed and refractory multiple myeloma.
Autores: Mateos, M. V., (Autor de correspondencia); Ocio, E. M. ; Paiva, Bruno; et al.
Revista: BLOOD REVIEWS
ISSN 0268-960X  Vol. 29  Nº 6  2015  págs. 387 - 403
Multiple myeloma is the second most frequent haematological disease. The introduction of high-dose melphalan followed by autologous haematopoietic cell transplant (HDT/ASCT) for young patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want to definitively cure the disease. Treatment goals for transplant-eligible and non-transplant-eligible patients should be to prolong survival by achieving the best possible response, while ensuring quality of life. The treatment should be individualized on the basis of host and disease features and better monitoring of the response upon use of high-sensitivity techniques for evaluating residual disease. For young patients, HDT/ASCT is a standard of care for treatment and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes. Extended treatment for young and elderly patients improves the quality and duration of clinical responses; however, the optimal scheme, appropriate doses and duration of long-term therapy have not yet been fully determined. This review summarises the progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early versus late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best option for non-transplant-eligible patients.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: AMERICAN SOCIETY OF CLINICAL ONCOLOGY EDUCATIONAL BOOK. AMERICAN SOCIETY OF CLINICAL ONCOLOGY. ANNUAL MEETING
ISSN 1548-8756  2015  págs. e484 - e492
Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of at least 3 g/dL of serum M-protein and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple myeloma (MM) is not uniform and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited and patients with asymptomatic MM at 80% to 90% of progression risk at 2 years are now considered to have MM. Although the current standard of care is not to treat, a randomized trial in patients with high-risk SMM that compared early treatment versus observation demonstrated that early intervention resulted in substantial benefits in terms of time to progression and overall survival (OS). These findings highlight the need to follow a correct diagnosis by an accurate risk stratification to plan an optimized follow-up according to the risk of disease progression.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: HEMATOLOGICAL ONCOLOGY
ISSN 1099-1069  Vol. 33  Nº Supl. 1  2015  págs. 33 - 37
Autores: Richardson, P. G., (Autor de correspondencia); Laubach, J. P.; Lonial, S.; et al.
Revista: EXPERT REVIEW OF ANTICANCER THERAPY
ISSN 1473-7140  Vol. 15  Nº 7  2015  págs. 737 - 748
Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti-myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM.
Autores: Dimopoulos, M. A. , (Autor de correspondencia); Sonneveld, P.; Siegel, D. ; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 26  Nº 11  2015  págs. 2247 - 2256
Review of key results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory multiple myeloma who also have baseline comorbidities or treatment-induced or disease-induced complications (e.g. presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk cytogenetics). Scenario-specific treatment recommendations are also provided.While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of patients with relapsed and/or refractory MM is frequently further complicated by the presence of pre-existing comorbidities that arise from an advanced disease state and of toxicities stemming from prior antimyeloma treatment. Carfilzomib and pomalidomide have recently been approved for the treatment of patients with relapsed and refractory MM. While these agents represent important additions to the available treatment options, the identification of patients who may best benefit from the use of each of therapy is still being investigated. A number of patient-related and disease-related factors may impact treatment efficacy and/or tolerability, and the clinical presentation and medical history of each patient must be carefully considered to optimize treatment. Here, we review results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory MM who also have baseline comorbidities or treatment-induced or disease-induced complications (including the presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk chromosomal abnormalities) to evaluate the safety and efficacy of the two agents in these difficult-to-treat patients and to provide treatment recommendations specific to each scenario.
Autores: Paiva, Bruno; Puig, N. ; Garcia-Sanz, R.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 21  Nº 9  2015  págs. 2001 - 2008
Increasing therapeutic options and prolonged survival in multiple myeloma have raised interest in the concept of depth of response and its importance to predict patients' outcomes. Although the efficacy of current treatment approaches has greatly improved in the past decade, the definition of complete response (CR) remains unaltered and continues to use conventional serological and morphologic techniques. That notwithstanding, there is growing interest in minimal residual disease (MRD) monitoring, which has emerged in recent years as one of the most relevant prognostic factors in multiple myeloma. MRD can be assessed both inside (e.g., immunophenotypic and molecular techniques) and outside the bone marrow (e.g., PET/CT). Here, we focus on flow-and molecular-based assays by which different cooperative groups have demonstrated the efficacy of MRD assessment to predict outcomes even among patients in CR, and irrespectively of disease risk. Although further standardization is still required, the time has come to implement MRD monitoring in prospective clinical trials as a sensitive tool to evaluate treatment efficacy and for risk-adapted treatment, particularly in the consolidation and maintenance settings. Here, we present a comprehensive and critical review on the methodologic aspects, specific characteristics, and clinical significance of MRD monitoring by flow cytometry, PCR, and next-generation sequencing. (C) 2015 AACR.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Kantarjian, H. M.;
Revista: NATURE REVIEWS CLINICAL ONCOLOGY
ISSN 1759-4774  Vol. 12  Nº 2  2015  págs. 71 - 72
In 2014, strides were made in the care of haematological malignancies. In particular, the heterogeneity of multiple myeloma was unravelled, and new diagnostic criteria and frontline standards of care were proposed; new therapeutic approaches have been validated and approved in chronic lymphocytic leukaemia; and in chronic myeloid leukaemia, complete cytogenetic response was confirmed as the primary therapeutic end point.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Paiva, Bruno; Lasarte Sagastibelza, Juan José
Revista: CANCER CELL
ISSN 1535-6108  Vol. 28  Nº 3  2015  págs. 281 - 283
NY-ESO-1 TCR-engineered T cells have shown activity in solid tumors. Recent work supports their use in multiple myeloma by showing that ex vivo antigen-specific expanded T cells traffic to and persist in bone marrow, are well tolerated, and produce promising response rates when infused after stem cell transplantation.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia)
Revista: BLOOD
ISSN 0006-4971  Vol. 125  Nº 20  2015  págs. 3039 - 3040
Autores: Richardson, P. G.; Moreau, P.; Laubach, J. P.; et al.
Revista: FUTURE ONCOLOGY
ISSN 1744-8301  Vol. 11  Nº 8  2015  págs. 1153 - 1168
Ixazomib is an investigational, reversible 20S proteasome inhibitor. It is the first oral proteasome inhibitor under clinical investigation in multiple myeloma (MM). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, ixazomib (MLN2238). Preclinical studies have demonstrated antitumor activity in MM cell lines and xenograft models. In Phase I/II clinical studies ixazomib has had generally manageable toxicities, with limited peripheral neuropathy observed to date. Preliminary data from these studies indicate ixazomib is active as a single agent in relapsed/refractory MM and as part of combination regimens in newly diagnosed patients. Phase III studies in combination with lenalidomide-dexamethasone are ongoing.
Autores: Krzeminski, P.; Sarasquete, M. E.; Misiewicz-Krzeminska, I.; et al.
Revista: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
ISSN 0006-3002  Vol. 1849  Nº 3  2015  págs. 353 - 366
Context: MiR-155 plays a critical role in the development of B-cell malignancies. Previous studies have shown a deregulation of miR-155 in specific cytogenetic subtypes of multiple myeloma (MM). However, the mechanisms that regulate miR-155 expression in MM are not fully understood. Objective: In the present study, we explored the regulation of miRNA-155 in MM by DNA methylation mechanisms and the impact of miR-155 expression in survival of MM patients. Method: Primary samples were obtained from 95 patients with newly diagnosed myeloma. Methylation was analyzed by Methylation Specific PCR, sequencing of bisulfite treated DNA and luciferase assay. Results: qRT-PCR analysis revealed that miR-155 was differentially expressed in MM and its upregulation was associated with longer survival. DNA methylation of CpG island present in the first exon of miR-155 host gene was associated with its low expression in MM cell lines and patient samples. Our results showed for the first time that in vitro methylation of part of the promoter and first exon abrogated the miR-155 expression. We further showed that miR-155 expression in MM cell lines was increased by demethylating 5-aza-dC treatment and decreased by RNA-directed DNA methylation. Additionally, we found that LPS "immunological challenge" was insufficient to induce miR-155 expression in MM cell lines with methylated DNA around transcription start site (TSS). Conclusion: This study provides evidence that DNA methylation contributes to miR-155 expression in myeloma cells. Interestingly, the survival data showed an association between miR-155 expression and outcome of MM.
Autores: Palumbo, A.; Bringhen, S.; Mateos, M. V.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 125  Nº 13  2015  págs. 2068 - 2074
We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1,31%), and frail (score >= 2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P<.001) patients. The cumulative incidence of grade >= 3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials.
Autores: Mateos, M. V.; Richardson, P. G.; Dimopoulos, M. A.; et al.
Revista: AMERICAN JOURNAL OF HEMATOLOGY
ISSN 1096-8652  Vol. 90  Nº 4  2015  págs. 314 - 319
This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P<0.0001; age-adjusted HR 0.561, P=0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P=0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management.
Autores: Paino, T.; Paiva, B.; Sayagues, J. M.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 29  Nº 5  2015  págs. 1186 - 1194
Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma cell (PC) heterogeneity would become increasingly demanded. Here we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional flow cytometry (MFC) and principal component analysis, at diagnosis and during minimal residual disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly diagnosed MM patients. In 10/35 patients, persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated whether distinct fluorescence-activated cell-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by interphase fluorescence in situ hybridization, including selective del(17p13). Collectively, we unravel potential therapeutic selection of preexisting diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PC subclones may become relevant for tailored therapy.
Autores: Garcia-Sanz, R.; Oriol, A.; Moreno, M. J.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 9  2015  págs. 1207 - 1213
This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications.
Autores: Aguirre Ena, Xabier; Castellano, G.; Pascual, M.; et al.
Revista: GENOME RESEARCH
ISSN 1088-9051  Vol. 25  Nº 4  2015  págs. 478 - 487
While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.
Autores: Ocio, E. M.; Fernandez-Lazaro, D.; San-Segundo, L.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 29  Nº 3  2015  págs. 705 - 714
The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.
Autores: Dimopoulos, M. A.; Weisel, K. C.; Song, K. W.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 10  2015  págs. 1327 - 1333
Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had failed. At an updated median follow-up of 15.4 months, the progression-free survival was 4.0 versus 1.9 months (HR, 0.50; P<0.001), and median overall survival was 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone, improved progression-free survival in patients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P < 0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), and in standard-risk patients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the majority of patients treated with high-dose dexamethasone took pomalidomide after discontinuation, the overall survival of patients treated with pomalidomide plus low-dose dexamethasone or highdose dexamethasone was 12.6 versus 7.7 months (HR, 0.45; P=0.008) in patients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), and 14.0 versus 9.0 months (HR, 0.85; P=0.380) in standard-risk subjects. The overall response rate was higher in patients treated with pomalidomide plus low-dose dexamethasone than in those treated with high-dose dexamethasone both among standard-risk patients (35.2% versus 9.7%) and those with del(17p) (31.8% versus 4.3%), whereas it was similar in patients with t(4; 14) (15.9% versus 13.3%). The safety of pomalidomide plus low-dose dexamethasone was consistent with initial reports. In conclusion, pomalidomide plus low-dose dexamethasone is efficacious in patients with relapsed/refractory multiple myeloma and del(17p) and/or t(4;14).
Autores: Mateos, M. V.; Oriol, A.; Rosiñol, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 8  2015  págs. 1096 - 1102
Bendamustine is a bifunctional alkylating agent with proven activity in myeloma. In this study 60 newly diagnosed myeloma patients were given bendamustine plus bortezomib and prednisone in a regimen consisting of one cycle of bortezomib twice weekly for 6 weeks (1.3 mg/m(2) on days 1, 4, 8, 11, 22, 25, 29, and 32), plus bendamustine (90 mg/m(2) on days 1 and 4) and prednisone. The following cycles included bortezomib once weekly. Patients who were transplant candidates proceeded to stem cell collection after four cycles and the transplant was performed after six cycles. Patients who were not candidates for transplantation received up to nine cycles. Forty-two patients were transplant candidates and after six cycles, 50% achieved at least a very good partial response, with 24% having complete responses; 35 proceeded to a transplant, and the complete response rate was 54%. Seventeen patients continued up to nine cycles, and 57% achieved at least a very good partial response, including 26% with complete responses. The 2-year progression-free survival and overall survival rates were 62% and 86%, respectively. The safety profile was manageable, but stem cell mobilization was compromised in 35% of patients. In summary, this combination is effective in untreated patients, with an acceptable toxicity profile, but given the introduction of second-generation novel agents and monoclonal antibodies, the combination will probably be better reserved for relapsing patients, in whom stem cell collection is not needed, while cost-effective combinations with non-cross-resistant drugs continue to represent a medical need. This trial was registered with ClinicalTrials.gov, number NCT01376401.
Autores: Lonial, S.; Dimopoulos, M.; Palumbo, A.; et al.
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 1533-4406  Vol. 373  Nº 7  2015  págs. 621 - 631
BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death.
Autores: Paiva, Bruno; Corchete, L. A.; Vidriales, M. B.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 125  Nº 15  2015  págs. 2370 - 2380
Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n = 22), smoldering (n = 16), and symptomatic WM (n = 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25(-)CD22(+) B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25(+)CD22(+low)) B-cell counterpart. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P = .008), suggesting a multistep transformation of clonal B c
Autores: Giralt, S.; Garderet, L.; Durie, B.; et al.
Revista: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
ISSN 1523-6536  Vol. 21  Nº 12  2015  págs. 2039 - 2051
In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous Ha consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to "best non-HCT therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic Ha, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic Ha maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.
Autores: Andersen, J. P.; Bogsted, M.; Dybkaer, K.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 10  Nº 1  2015  págs. e0116966
BACKGROUND: International collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases. METHODS AND FINDINGS: We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (>90% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013. CONCLUSION AND PERSPECTIVE: Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care.
Autores: Palumbo, A.; Avet-Loiseau, H.; Oliva, S.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 33  Nº 26  2015  págs. 2863 - 2869
PURPOSE: The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). PATIENTS AND METHODS: Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. RESULTS: ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum ß2-microglobulin level < 3.5 mg/L and serum albumin level ¿ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum ß2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. CONCLUSION: The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.
Autores: San Miguel Izquierdo, Jesús; Weisel, K. C.; Song, K. W.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 10  2015  págs. 1334 - 1339
Pomalidomide is a distinct oral IMiD (R) immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (<= or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment.
Autores: Sanchez-Abarca, L. I.; Hernandez-Galilea, E.; Lorenzo, R.; et al.
Revista: CELL TRANSPLANTATION
ISSN 1555-3892  Vol. 24  Nº 12  2015  págs. 2423 - 2433
Clinical trials have assessed the use of human bone marrow stromal cells (hBMSCs) for the treatment of immune-related disorders such as graft-versus-host disease (GVHD). In the current study, we show that GFP(+)-transduced hBMSCs generated from bone marrow migrate and differentiate into corneal tissue after subconjunctival injection in mice. Interestingly, these hBMSCs display morphological features of epithelial, stromal, and endothelial cells and appear at different layers and with different morphologies depending on their position within the epithelium. Furthermore, these cells display ultrastructural properties, such as bundles of intermediate filaments, interdigitations, and desmosomes with GFP(-) cells, which confirms their differentiation into corneal tissues. GFP(+)-transduced hBMSCs were injected at different time points into the right eye of lethally irradiated mice undergoing bone marrow transplantation, which developed ocular GVHD (oGVHD). Remarkably, hBMSCs massively migrate to corneal tissues after subconjunctival injection. Both macroscopic and histopathological examination showed minimal or no evidence of GVHD in the right eye, while the left eye, where no hBMSCs were injected, displayed features of GVHD. Thus, in the current study, we confirm that hBMSCs may induce their therapeutic effect at least in part by differentiation and regeneration of damaged tissues in the host. Our results provide experimental evidence that hBMSCs represent a potential cellular therapy to attenuate oGVHD.
Autores: Herrero, A. B.; San Miguel Izquierdo, Jesús; Gutierrez, N. C.;
Revista: PLOS ONE
ISSN 1932-6203  Vol. 10  Nº 3  2015  págs. e0121581
Multiple myeloma (MM) is a hematological malignancy characterized by frequent chromosome abnormalities. However, the molecular basis for this genome instability remains unknown. Since both impaired and hyperactive double strand break (DSB) repair pathways can result in DNA rearrangements, we investigated the functionality of DSB repair in MM cells. Repair kinetics of ionizing-radiation (IR)-induced DSBs was similar in MM and normal control lymphoblastoid cell lines, as revealed by the comet assay. However, four out of seven MM cell lines analyzed exhibited a subset of persistent DSBs, marked by gamma-H2AX and Rad51 foci that elicited a prolonged G2/M DNA damage checkpoint activation and hypersensitivity to IR, especially in the presence of checkpoint inhibitors. An analysis of the proteins involved in DSB repair in MM cells revealed upregulation of DNA-PKcs, Artemis and XRCC4, that participate in non-homologous end joining (NHEJ), and Rad51, involved in homologous recombination (HR). Accordingly, activity of both NHEJ and HR were elevated in MM cells compared to controls, as determined by in vivo functional assays. Interestingly, levels of proteins involved in a highly mutagenic, translocation-promoting, alternative NHEJ subpathway (Alt-NHEJ) were also increased in all MM cell lines, with the Alt-NHEJ protein DNA ligase III alpha, also overexpressed in several plasma cell samples isolated from MM patients. Overactivation of the Alt-NHEJ pathway was revealed in MM cells by larger deletions and higher sequence microhomology at repair junctions, which were reduced by chemical inhibition of the pathway. Taken together, our results uncover a deregulated DSB repair in MM that might underlie the characteristic genome instability of the disease, and could be therapeutically exploited.
Autores: Martínez-López, J.; Paiva, Bruno; Lopez-Anglada, L.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 7  2015  págs. 858 - 862
Stringent complete response (sCR) criteria are used in multiple myeloma as a deeper response category compared with CR, but prospective validation is lacking, it is not always clear how evaluation of clonality is performed, and is it not known what the relative clinical influence is of the serum free light chain ratio (sFLCr) and bone marrow (BM) clonality to define more sCR. To clarify this controversy, we focused on 94 patients that reached CR, of which 69 (73%) also fulfilled the sCR criteria. Patients with sCR displayed slightly longer time to progression (median, 62 vs 53 months, respectively; P = .31). On analyzing this contribution to the prognosis of sFLCr or clonality, it was found that the sFLCr does not identify patients in CR at distinct risk; by contrast, low-sensitive multiparametric flow cytometry (MFC) immunophenotyping (2 colors), which is equivalent to immunohistochemistry, identifies a small number of patients (5 cases) with high residual tumor burden and dismal outcome; nevertheless, using traditional 4-color MFC, persistent clonal BM disease was detectable in 36% of patients, who, compared with minimal residual disease-negative cases, had a significantly inferior outcome. These results show that the current definition of sCR should be revised.
Autores: Cibeira, M. T.; Oriol, A.; Lahuerta, J. J.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 1365-2141  Vol. 170  Nº 6  2015  págs. 804 - 813
Immunomodulatory drugs have been shown to be of benefit in relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. We designed a prospective, multicentre phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with AL amyloidosis not eligible for autologous stem-cell transplantation. Twenty-eight patients were included in the study. Cardiac involvement was present in 23 patients; 14 of them had cardiac stage III. The overall haematological response rate was 46%, including complete and very good partial responses in 25% and 18% of patients respectively. Haematological response was mainly associated with absence of cardiac stage III and lower tumour burden. Organ response was observed in 46% of patients. After a median follow-up of 24months, median progression-free and overall survival have not been reached, both being significantly longer in responders (P<0001 and P=0001 respectively). Seventeen patients have discontinued treatment, mostly due to amyloid-related death, disease progression or lack of response. Only 14% of the patients discontinued treatment due to therapy-related adverse events. Our results support the efficacy of this regimen, with high quality responses and prolonged survival, as well as its tolerability, in patients with AL amyloidosis not eligible for stem cell transplant and without advanced cardiac involvement (clinicaltrials.gov identifier: NCT01194791).
Autores: Ocio, E. M.; Herrera, P.; Olave, M. T.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 10  2015  págs. 1294 - 1300
This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodysplastic syndrome were excluded and 38 evaluable patients were included in the study (median age: 71 years; range: 65-83). Study patients received an induction with idarubicin (8 mg/m(2) iv days 1-3) plus cytarabine (100 mg/m2 iv days 1-7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19) that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. Complete remission rate was 64% with a time to relapse of 17.0 months (12.8-21.1). Median overall survival for the whole series was 17 months (5.5-28.4). Moreover, in 4 of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated. The most frequent adverse events were thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia (mainly grades 1/2). Five patients required dose reduction during this phase, but only one discontinued therapy due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and suggest further investigation is warranted, particularly in the context of maintenance therapy.
Autores: Stewart, A Keith; Rajkumar, S Vincent; Dimopoulos, Meletios A; et al.
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 0028-4793  Vol. 372  Nº 2  2015  págs. 142-152
In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.
Autores: Weisel, K.; Dimopoulos, M.; Song, K. W.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
ISSN 2152-2669  Vol. 15  Nº 9  2015  págs. 519 - 530
As part of study MM-003 (A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone vs. High-Dose Dexamethasone in Patients With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study [NIMBUS]), we examined changes in health-related quality of life (HRQoL) in 433 patients with relapsed/refractory multiple myeloma (RRMM) randomized to pomalidomide plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX). POM + LoDEX offers improved clinical outcomes that lead to improved and prolonged HRQoL compared with HiDEX in patients with RRMM and end-stage disease. Background: Health-related quality of life (HRQoL) is an important element for consideration in treatment decisions in patients with relapsed/refractory multiple myeloma (RRMM). The pivotal MM-003 (A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone vs. High-Dose Dexamethasone in Patients With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study [ NIMBUS]) randomized, open-label, multicenter, phase III trial demonstrated improved progression-free survival (PFS) and prolonged overall survival (OS) with pomalidomide (POM) plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in patients with RRMM in whom lenalidomide (LEN) and bortezomib (BORT) had failed. MM-003 also investigated HRQoL as a predefined secondary end point. Patients and Methods: Recruited patients (n = 455) were refractory to their last treatment and had failed LEN and BORT after >= 2 consecutive cycles of each (alone or in combination). Eight clinically relevant and validated HRQoL domains from the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-MY20, and EQ-5D questionnaires were selected for analysis. Time to symptom worsening based on minimally important differences (MIDs) was calculated. Results: Clinically meaningful improvements in HRQoL as determined by MIDs, regression analyses, and best response analyses were observed more frequently in patients receiving POM + LoDEX than in those receiving HiDEX. POM + LoDEX significantly extended median time to clinically meaningful worsening in HRQoL versus HiDEX in 4 HRQoL domains and demonstrated a trend in an additional 3 domains. Patients in the HiDEX arm experienced earlier HRQoL deterioration compared with those in the POM + LoDEX arm in each domain analyzed. Conclusion: POM + LoDEX offer good clinical outcomes that lead to improved and prolonged HRQoL compared with HiDEX in patients with RRMM and end-stage disease.
Autores: Rajkumar, S. V. , (Autor de correspondencia); Richardson, P. ; San Miguel Izquierdo, Jesús
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 7  2015  págs. 921 - 922
Autores: Ocio, E. M., (Autor de correspondencia); Davila, J.; Caballero, J. C.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 7  2015  págs. E289 - E291
Autores: Paiva, Bruno (Autor de correspondencia); Azpilicueta Lusarreta, Arantza; Puig, N.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 29  Nº 10  2015  págs. 2110 - 2113
Autores: Puig, N., (Autor de correspondencia); Conde, I.; Jimenez, C.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 29  Nº 6  2015  págs. 1435 - 1437
Autores: Song, K. W. , (Autor de correspondencia); Dimopoulos, M. A. ; Weisel, K. C. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 2  2015  págs. E63 - E67
Autores: Paiva, Bruno; Chandia, M. ; Puig, N. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº 2  2015  págs. E53 - E55
Autores: Mateos, M. V., (Autor de correspondencia); Shi, H. L.; San Miguel Izquierdo, Jesús
Revista: AMERICAN JOURNAL OF HEMATOLOGY
ISSN 0361-8609  Vol. 90  Nº 8  2015  págs. 146 - 146
Autores: Sanoja-Flores, L. ; Paiva, Bruno; Flores-Montero, J. A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 23  2015 
Autores: Segura-Jimenez, R.; Rosinol-Dachs, L.; Oriol-Rocafiguera, A.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl. 4  2015  págs. 47 - 48
Autores: Lecumberri Villamediana, Ramón; Sola, I. ; Corrales Izquierdo, Fernando José; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl 4  2015  págs. 99
Autores: Sanoja Flores, L.; Paiva, Bruno; Flores Montero, J. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl 1  2015  págs. 40 - 41
Autores: Mishima, Y. ; Paiva, Bruno; Shi, J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 23  2015 
Autores: Aguirre Ena, Xabier; Castellano, G.; Pascual De Pedro, Marién; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl. 4  2015  págs. 41 - 42
Autores: Paiva, Bruno; Mateos, M. V. ; Sanchez-Abarca, L. I.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 23  2015 
Autores: San José Enériz, Edurne; Aguirre Ena, Xabier; Rabal Gracia, María Obdulia; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  2015  págs. 27
Autores: San José Enériz, Edurne; Aguirre Ena, Xabier; Rabal, O.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl. 4  2015  págs. 60 - 61
Autores: San Miguel Izquierdo, Jesús; Blade, J. ; Shpilberg, O.;
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 7  2014  págs. 1201
Autores: Rajkumar, S. V., (Autor de correspondencia); Dimopoulos, M. A. ; Palumbo, A.; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 15  Nº 12  2014  págs. E538 - E548
This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.
Autores: Mateos, M. V., (Autor de correspondencia); Leleu, X.; Palumbo, A. ; et al.
Revista: EXPERT REVIEW OF HEMATOLOGY
ISSN 1747-4086  Vol. 7  Nº 1  2014  págs. 67 - 77
Over two-thirds of newly diagnosed multiple myeloma are over 65 years. The treatment goals for the non-transplant-eligible patients should be to prolong survival by achieving the best response, while ensuring quality of life. New upfront treatment combinations based on first generation of novel proteasome inhibitors and immunomodulatory drugs plus alkylating agents, the historical platform, have significantly improved outcomes in the past 10 years. Other non-alkylator induction regimens, essentially lenalidomide plus low-dose dexamethasone are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Data indicate that prolonged treatment extends the progression-free survival. In summary, this group requires individualized and dose-modified regimens to improve tolerability and efficacy, while maintaining their quality of life.
Autores: San Miguel Izquierdo, Jesús
Revista: HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM
ISSN 1520-4383  Vol. 2014  Nº 1  2014  págs. 1 - 7
Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second- and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia)
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 99  Nº 1  2014  págs. 5 - 6
Autores: Palumbo, A.; Rajkumar, S. V.; San Miguel Izquierdo, Jesús; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 32  Nº 6  2014  págs. 587 - 600
Purpose: To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods: A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results: Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion: These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.
Autores: San Miguel Izquierdo, Jesús; Bladè, J.; Shpilberg, O.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 123  Nº 26  2014  págs. 4136 - 4142
Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27% on siltuximab plus VMP (S+VMP) and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10%. Overall response rate was 88% on S+VMP and 80% on VMP, and at least very good partial response rates were 71% and 51% (P = .0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the 2 arms. Grade ¿3 adverse-event incidence was 92% on S+VMP and 81% on VMP (P = .09), with trends toward more hematologic events and infections on S+VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve the CR rate or long-term outcomes. This study was registered at http://clinicaltrials.gov as #NCT00911859.
Autores: Lopez-Corral, L.; Antonio Corchete, L.; Eugenia Sarasquete, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 99  Nº 8  2014  págs. 1365 - 1372
A multistep model has been proposed of disease progression starting in monoclonal gammopathy of undetermined significance continuing through multiple myeloma, sometimes with an intermediate entity called smoldering myeloma, and ending in extramedullary disease. To gain further insights into the role of the transcriptome deregulation in the transition from a normal plasma cell to a clonal plasma cell, and from an indolent clonal plasma cell to a malignant plasma cell, we performed gene expression profiling in 20 patients with monoclonal gammopathy of undetermined significance, 33 with high-risk smoldering myeloma and 41 with multiple myeloma. The analysis showed that 126 genes were differentially expressed in monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma as compared to normal plasma cell. Interestingly, 17 and 9 out of the 126 significant differentially expressed genes were small nucleolar RNA molecules and zinc finger proteins. Several proapoptotic genes (AKT1 and AKT2) were down-regulated and antiapoptotic genes (APAF1 and BCL2L1) were up-regulated in multiple myeloma, both symptomatic and asymptomatic, compared to monoclonal gammopathy of undetermined significance. When we looked for those genes progressively modulated through the evolving stages of monoclonal gammopathies, eight snoRNA showed a progressive increase while APAF1, VCAN and MEGF9 exhibited a progressive downregulation. In conclusion, our data show that although monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma are not clearly distinguishable groups according to their gene expression profiling, several signaling pathways and genes were significantly deregulated at different steps of the transformation process.
Autores: Garcia-Gomez, A.; De Las Rivas, J.; Ocio, E. M.; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 5  Nº 18  2014  págs. 8284 - 8305
Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment crosstalk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.
Autores: Roccaro, A. M.; Sacco, A.; Jimenez, C.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 123  Nº 26  2014  págs. 4120 - 4131
The C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in modulating cell trafficking in hematopoietic stem cells and clonal B cells. We screened 418 patients with B-cell lymphoproliferative disorders and described the presence of the C1013G/CXCR4 warts, hypogammaglobulinemia, infections, and myelokathexis-associated mutation in 28.2% (37/131) of patients with lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia [WM]), being either absent or present in only 7% of other B-cell lymphomas. In vivo functional characterization demonstrates its activating role in WM cells, as demonstrated by significant tumor proliferation and dissemination to extramedullary organs, leading to disease progression and decreased survival. The use of a monoclonal antibody anti-CXCR4 led to significant tumor reduction in a C1013G/CXCR4 WM model, whereas drug resistance was observed in mutated WM cells exposed to Bruton's tyrosine kinase, mammalian target of rapamycin, and phosphatidylinositol 3-kinase inhibitors, but not proteasome inhibitors. These findings demonstrate that C1013G/CXCR4 is an activating mutation in WM and support its role as a critical regulator of WM molecular pathogenesis and as an important therapeutic target.
Autores: Moreau, P.; Cavo, M.; Sonneveld, P.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 32  Nº 20  2014  págs. 2173 - 2180
Purpose: To construct and validate among patients with multiple myeloma (MM) who were treated with intensive therapy a prognostic index of early MM progression-related death. Patients and methods: Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial (N = 482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from three other trials: the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) 26866138-MMY-3006 trial (N = 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)-GEMMENOS65 trial (N = 390), and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) -65/German-Speaking Myeloma Multicenter Group (GMMG) -HD4 trial (N = 827). Results: The risk of early MM progression-related death was related to three independent prognostic variables: lactate dehydrogenase (LDH) higher than than normal, International Staging System 3 (ISS3), and adverse cytogenetics [t(4;14) and/or del(17p)]. These three variables enabled the definition of an ordinal prognostic classification composed of four scores (0 to 3). Patients with a score of 3, defined by the presence of t(4;14) and/or del(17p) in addition to ISS3 and/or high LDH, comprised 5% (20 of 387 patients) to 8% (94 of 1,139 patients) of the patients in the learning and validation samples, respectively, and they had a very poor prognosis. When applied to the population of 855 patients who had received bortezomib-based induction therapy in the four trials, the prognostic classification was also able to segregate patients into four categories, with a very poor prognosis attributed to patients with a score of 3. Conclusion: Our model allows the simple definition of a subgroup of MM patients at high risk of early MM progression-related death despite the use of the most modern and effective strategies.
Autores: Morabito, F.; Bringhen, S.; Larocca, A.; et al.
Revista: AMERICAN JOURNAL OF HEMATOLOGY
ISSN 1096-8652  Vol. 89  Nº 4  2014  págs. 355 - 362
Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ¿ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.
Autores: Paiva, Bruno; Chandia, M.; Vidriales, M. B.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 8  2014  págs. 1300 - 1303
Solitary plasmacytoma represents a heterogeneous group of patients; approximately half develop multiple myeloma (MM) in 2 or 3 years, whereas others remain disease-free at 10 years. By definition, these patients do not have morphologic bone marrow (BM) plasma cell (PC) infiltration. Here, we investigated whether sensitive BM evaluation of patients with solitary bone plasmacytoma(SBP; n = 35) and extramedullary plasmacytoma (EMP; n = 29) through multiparameter flow cytometry (MFC) would unravel the presence of clonal PCs in otherwise disease-free BM, and whether BMclonality predicted higher risk of progression. BM clonal PCs were detected in 17 of 35 SBP (49%) and 11 of 29 EMP (38%) patients. Seventy-one percent of flow-positive vs only 8% of flow-negative SBP patients evolved to MM (median time to progression of 26 months vs not reached; hazard ratio, 17.4; P < .001). No significant differences were observed among EMP cases. Our results highlight the importance of MFC for sensitive BM evaluation of SBP patients, to predict risk of developing treatment-requiring MM and to plan disease monitoring.
Autores: Jimenez, C.; del Carmen Chillon, M.; Balanzategui, A.; et al.
Revista: APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
ISSN 1533-4058  Vol. 22  Nº 10  2014  págs. 768 - 773
MYD88 L265P mutation has been reported in ~90% of Waldenström's Macroglobulinemia (WM) patients and immunoglobulin M (IgM) monoclonal gammopathies of uncertain significance (MGUS), as well as in some cases of lymphoma and chronic lymphocytic leukemia. The present study aimed to develop a real-time allele-specific oligonucleotide PCR (ASO-RQ-PCR) to detect the MYD88 L265P mutation. We first evaluated the reproducibility and sensitivity of the technique with a diluting experiment of a previously known positive sample. Then, we evaluated the applicability of the methodology by analyzing 30 selected patients (10 asymptomatic WM, 10 symptomatic WM, and 10 IgM MGUS) as well as 10 healthy donors. The quantitative ASO-PCR assay could detect the MYD88 L265P mutation at a dilution of 0.25%, showing an inverse correlation between the tumor cell percentage and the cycle threshold (CT) value, thus allowing for tumor burden quantitation. In addition, mutated cases were distinguished from the unmutated by >10 cycles of difference between CTs. To sum up, ASO-RQ-PCR is an inexpensive, robust, and optimized method for the detection of MYD88 L265P mutation, which could be considered as a useful molecular tool during the diagnostic work-up of B-cell lymphoproliferative disorders.
Autores: Mulligan, G.; Lichter, D. I.; Di Bacco, A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 123  Nº 5  2014  págs. 632 - 639
Various translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as RAS genes were mutated in a large proportion of cases (45.9%) and these mutations were mutually exclusive. New recurrent mutations were also identified, including in the PDGFRA and JAK3 genes. NRAS mutations were associated with a significantly lower response rate to single-agent bortezomib (7% vs 53% in patients with mutant vs wildtype NRAS, P = .00116, Bonferroni-corrected P = .016), as well as shorter time to progression in bortezomib-treated patients (P = .0058, Bonferroni-corrected P = .012). However, NRAS mutation did not impact outcome in patients treated with high-dose dexamethasone. KRAS mutation did not reduce sensitivity to bortezomib or dexamethasone. These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes.
Autores: Walker, B. A.; Wardell, C. P.; Melchor, L.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 28  Nº 2  2014  págs. 384 - 390
The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n = 4), high-risk (HR) SMM (n = 4), MM (n = 26) and PCL (n = 2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
Autores: Paino, T.; Sarasquete, M.E.; Paiva, Bruno; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9  Nº 3  2014  págs. e92378
Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138(++) (95-99%) and CD138(low) (1-5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138(low) subpopulation is morphologically identical to the CD138(++) fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138(++) and CD138(low) subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138(++) as well as CD138(low) cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.
Autores: Mateos, M. V.; Oriol, A.; Martínez-López, J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 12  2014  págs. 1887 - 1893
Melphalan (M), in combination with prednisone (MP), has been the backbone of new combinations, including bortezomib plus MP (VMP). However, new alkylator-free schemes, such as lenalidomide plus low-dose dexamethasone, are challenging the role of alkylators in myeloma treatment of elderly patients. Here we have updated, after a long follow-up (median 6 years), the results of the GEM2005 study that addressed this question by comparing VMP with bortezomib plus thalidomide and prednisone (VTP) as induction. Between April 2005 and October 2008, 260 patients were randomized to receive 6 cycles of VMP or VTP as induction. The median progression-free survival was 32 months for the VMP and 23 months for the VTP arms (p = .09). VMP significantly prolonged the overall survival (OS) compared with VTP (median of 63 and 43 months, respectively; hazard ratio [HR]: 0.67, p = .01). Achieving immunophenotypic complete response was associated with a significantly longer OS, especially in the VMP arm (66% remain alive after 8 years). Melphalan, plus bortezomib, should be maintained as standard care for the treatment of elderly multiple myeloma patients.
Autores: Thiago, L. S.; Perez-Andres, M.; Balanzategui, A.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 99  Nº 1  2014  págs. 155 - 162
The B-cell compartment in which multiple myeloma stem cells reside remains unclear. We investigated the potential presence of mature, surface-membrane immunoglobulin-positive B lymphocytes clonally related to the tumor bone marrow plasma cells among different subsets of peripheral blood B cells from ten patients (7 with multiple myeloma and 3 with monoclonal gammopathies of undetermined significance). The presence of clonotypic immunoglobulin heavy chain gene rearrangements was determined in multiple highly-purified fractions of peripheral blood B-lymphocytes including surface-membrane IgM(+) CD27(-) naive B-lymphocytes, plus surface-membrane IgG(+), IgA(+) and IgM(+) memory CD27(+) B cells, and normal circulating plasma cells, in addition to (mono) clonal plasma cells, by a highly-specific and sensitive allele-specific oligonucleotide polymerase chain reaction directed to the CDR3 sequence of the rearranged IGH gene of tumor plasma cells from individual patients. Our results showed systematic absence of clonotypic rearrangements in all the different B-cell subsets analyzed, including M-component isotype-matched memory B-lymphocytes, at frequencies <0.03 cells/mu L (range: 0.0003-0.08 cells/mu L); the only exception were the myeloma plasma cells detected and purified from the peripheral blood of four of the seven myeloma patients. These results indicate that circulating B cells from patients with multiple myeloma and monoclonal gammopathies of undetermined significance are usually devoid of clonotypic B cells while the presence of immunophenotypically aberrant myeloma plasma cells in peripheral blood of myeloma patients is a relatively frequent finding.
Autores: Garcia-Gomez, A. ; Quwaider, D. ; Canavese, M. ; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 20  Nº 6  2014  págs. 1542 - 1554
PURPOSE: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models. EXPERIMENTAL DESIGN: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. RESULTS: Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-¿B ligand)-induced NF-¿B activation, F-actin ring disruption, and diminished expression of ¿Vß3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/ß-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow-disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). CONCLUSION: Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma.
Autores: Paiva, Bruno; Montes, M. C.; Garcia-Sanz, R.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 28  Nº 1  2014  págs. 166 - 173
Although multiparameter flow cytometry (MFC) has demonstrated clinical relevance in monoclonal gammopathy of undetermined significance (MGUS)/myeloma, immunophenotypic studies on the full spectrum of Waldenstrom's Macroglobulinemia (WM) remain scanty. Herein, a comprehensive MFC analysis on bone marrow samples from 244 newly diagnosed patients with an immunoglobulin M (IgM) monoclonal protein was performed, including 67 IgM-MGUS, 77 smoldering and 100 symptomatic WM. Our results show a progressive increase on the number and light-chain-isotype-positive B-cells from IgM-MGUS to smoldering and symptomatic WM (P<.001), with only 1% of IgM-MGUS patients showing > 10% B cells or 100% light-chain-isotype-positive B-cells (P<.001). Complete light-chain restriction of the B-cell compartment was an independent prognostic factor for time-to progression in smoldering WM (median 26 months; HR: 19.8, P = 0.001) and overall survival in symptomatic WM (median 44 months; HR: 2.6, P = 0.004). The progressive accumulation of light-chain-isotype-positive B-cells accompanied the emergence of a characteristic Waldenstrom's phenotype (CD22(+dim)/CD25(+)/CD27(+)/IgM(+)) that differed from other B-NHL by negative expression of CD5, CD10, CD11c or CD103. In contrast to myeloma, light-chain-isotype-positive plasma cells in IgM monoclonal gammopathies show otherwise normal antigenic expression. Our results highlight the potential value of MFC immunophenotyping for the characterization of the Waldenstrom's clone, as well as for the differential diagnosis, risk of progression and survival in WM.
Autores: Mateos, M. V.; Bringhen, S.; Richardson, P. G.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 99  Nº 6  2014  págs. 1114 - 1122
Substantial efficacy has been demonstrated with bortezomib-melphalan-prednisone in phase III studies in transplant-ineligible myeloma patients using various twice-weekly and once-weekly bortezomib dosing schedules. In VISTA, the regimen comprised four 6-week twice-weekly cycles, plus five 6-week once-weekly cycles. In the GIMEMA MM-03-05 study, the bortezomib-melphalan-prednisone regimen was either per VISTA ('GIMEMA twice-weekly'), or comprised nine 5-week once-weekly cycles ('GIMEMA once-weekly'). In the GEM2005MAS65 study, the regimen comprised one 6-week twice-weekly cycle, plus five 5-week once-weekly cycles. We evaluated the cumulative bortezomib dose administered during bortezomib-melphalan-prednisone, as well as efficacy and tolerability, using patient-level study data. Over all bortezomib-melphalan-prednisone cycles (nine in VISTA/GIMEMA; six in GEM2005MAS65), the median cumulative bortezomib dose administered was 38.5, 42.1, 40.3, and 32.9 mg/m(2) in VISTA, GIMEMA twice-weekly, GIMEMA once-weekly, and GEM2005MAS65, respectively, and the respective proportions of planned bortezomib dose actually delivered were 57.0%, 62.3%, 86.1%, and 90.4%. Response rates following bortezomib-melphalan-prednisone were 74-87% and appeared generally similar between studies. Three-year survival rates were 67.9-75.7% across studies. Grade 3/4 peripheral neuropathy rates were 13% in VISTA and 14% in GIMEMA twice-weekly, but were lower at 2% in GIMEMA once-weekly and 7% in GEM2005MAS65. Discontinuations and bortezomib dose reductions due to peripheral neuropathy were reduced in GIMEMA once-weekly versus VISTA and GIMEMA twice-weekly. Exclusive or predominant use of once-weekly bortezomib dosing in GIMEMA once-weekly and GEM2005MAS65 resulted in high efficacy, comparable with that demonstrated in VISTA, and similar cumulative bortezomib dose with reduced toxicity. Trials are registered with ClinicalTrials.gov: VISTA (Identifier:00111319), GIMEMA MM-03-05 (Identifier:01063179), and GEM2005MAS65 (Identifier:00443235).
Autores: Sanchez-Sanchez, B.; Gutierrez-Herrero, S.; Lopez-Ruano, G.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1557-3265  Vol. 20  Nº 15  2014  págs. 4014 - 4025
Purpose: Cancer cells show higher levels of reactive oxygen species (ROS) than normal cells and increasing intracellular ROS levels are becoming a recognized strategy against tumor cells. Thus, diminishing ROS levels could be also detrimental to cancer cells. We surmise that avoiding ROS generation would be a better option than quenching ROS with antioxidants. Chronic myelogenous leukemia (CML) is triggered by the expression of BCR-ABL kinase, whose activity leads to increased ROS production, partly through NADPH oxidases. Here, we assessed NADPH oxidases as therapeutic targets in CML. Experimental Design: We have analyzed the effect of different NADPH oxidase inhibitors, either alone or in combination with BCR-ABL inhibitors, in CML cells and in two different animal models for CML. Results: NADPH oxidase inhibition dramatically impaired the proliferation and viability of BCR-ABL-expressing cells due to the attenuation of BCR-ABL signaling and a pronounced cell-cycle arrest. Moreover, the combination of NADPH oxidase inhibitors with BCR-ABL inhibitors was highly synergistic. Two different animal models underscore the effectiveness of NADPH oxidase inhibitors and their combination with BCR-ABL inhibitors for CML targeting in vivo. Conclusion: Our results offer further therapeutic opportunities for CML, by targeting NADPH oxidases. In the future, it would be worthwhile conducting further experiments to ascertain the feasibility of translating such therapies to clinical practice.
Autores: San Miguel Izquierdo, Jesús; Hungria, V. T. M.; Yoon, S. S.; et al.
Revista: LANCET ONCOLOGY
ISSN 1474-5488  Vol. 15  Nº 11  2014  págs. 1195 - 1206
Background: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Methods: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. Findings: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). Interpretation: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. Funding: Novartis Pharmaceuticals.
Autores: San Miguel Izquierdo, Jesús
Revista: REVISTA CLINICA ESPANOLA
ISSN 1578-1860  Vol. 214  Nº 8  2014  págs. 466 - 469
Autores: Martínez-López, J.; Lahuerta, J. J.; Pepin, F.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 123  Nº 20  2014  págs. 3073 - 3079
We assessed the prognostic value of minimal residual disease(MRD) detection in multiple myeloma(MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJ(H), IGH-DJ(H), and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD- by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD+. When stratifying patients by different levels of MRD, the respective TTP medians were: MRD >= 10(-3) 27 months, MRD 10(-3) to 10(-5) 48 months, and MRD <10(-5) 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD+. In complete response patients, the TTP remained significantly longer for MRD- compared with MRD+ patients (131 vs 35 months; P = .0009).
Autores: Ludwig, H.; Sonneveld, P.; Davies, F.; et al.
Revista: ONCOLOGIST
ISSN 1549-490X  Vol. 19  Nº 8  2014  págs. 829 - 844
The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on "fitness," with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results.
Autores: Matarraz, S., (Autor de correspondencia); Paiva, Bruno; Diez-Campelo, M.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 28  Nº 8  2014  págs. 1747 - 1750
Autores: San José Enériz, Edurne; Aguirre Ena, Xabier; Rabal Gracia, María Obdulia; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 21  2014 
Autores: Mateos, M. V.; Hernandez, M. T. ; Giraldo, P.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 21  2014 
Autores: Paiva, Bruno; Mateos, M. V. ; Lopez-Corral, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 99  Nº Supl 1  2014  págs. 95
Autores: Thilakarathne, P. ; Palumbo, A. ; Diels, J. ; et al.
Revista: VALUE IN HEALTH
ISSN 1098-3015  Vol. 17  Nº 7  2014  págs. A546 - A546
Autores: Aguirre Ena, Xabier; Castellano, G.; Pascual De Pedro, Marién; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 21  2014 
Autores: de Larrea, C. F. , (Autor de correspondencia); Kyle, R. A.; Durie, B. G. M. ; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 27  Nº 4  2013  págs. 780 - 791
Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (>= 20%) and absolute number (>= 2 x 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.
Autores: Mateos, M. V., (Autor de correspondencia); Ocio, E. M. ; San Miguel Izquierdo, Jesús
Revista: SEMINARS IN ONCOLOGY
ISSN 0093-7754  Vol. 40  Nº 5  2013  págs. 618 - 633
The activity observed with proteasome inhibitors and immunomodulatory drugs (IMIDs) in multiple myeloma (MM) has prompted the development of second- and third-generation agents with similar, but not exactly the smile, mechanisms of action as their predecessors. This review summarizes the mechanism of action and the available data on the clinical activity of novel proteasome inhibitors (carfilzomib, oprozomib, ixazomib, and marizomib) and novel IMIDs (pomalidomide), stressing the similarities and differences with bortezomib, and with thalidomide and lenalidomide, respectively. In summary, these novel agents have shown clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their parental drugs; moreover, they may even overcome resistance, indicating that there are some differences in their mechanisms of action and resistance. These data indicate that both the inhibition of the proteasome and the modulation of the immune system are good strategies to target MM tumor cells and this, along with the absence of complete cross-resistance observed among these drugs, open new avenues to optimize their use through the most appropriate sequencing and combinations.
Autores: San Miguel Izquierdo, Jesús; Paiva, Bruno; Gutierrez, N. C.;
Revista: AMERICAN SOCIETY OF CLINICAL ONCOLOGY EDUCATIONAL BOOK. AMERICAN SOCIETY OF CLINICAL ONCOLOGY. ANNUAL MEETING
ISSN 1548-8756  2013 
This article reviews the most relevant techniques currently used for the evaluation of patients with multiple myeloma. Although bone marrow morphologic examination and electrophoretic analysis of the monoclonal paraprotein and conventional x-rays remain the "gold standard" techniques for fast, accurate, and cost-effective diagnosis, other assays such as molecular cytogenetics, immunophenotyping, MRI, and PET-CT may contribute to a better assessment of patients with myeloma. Here, we will discuss not only the contribution of each technique to differential diagnosis of monoclonal gammopathies, but also the value of each parameter for determining prognosis and for monitoring treatment efficacy. In addition, possible technical pitfalls inherent to each technique will be analyzed.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: CURRENT HEMATOLOGIC MALIGNANCY REPORTS
ISSN 1558-822X  Vol. 8  Nº 4  2013  págs. 270 - 276
Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of one or both features of serum M-protein >= 30 g/L and bone marrow plasma cell infiltration >= 10 %. However, myeloma-related symptomatology is absent from this condition. The risk of progression to active MM is not uniform, and several markers are useful for identifying SMM patients at high risk of progression to active MM. These include the size of the M-protein and the infiltration in the bone marrow, the serum-free light-chain ratio, the presence of immunoparesis and percentage of plasma cell with aberrant phenotype by flow cytometry, or the presence of focal lesions in magnetic resonance imaging. Overall, the presence of these factors identifies patients who have a 50 % probability of progression at 2 years, and the forthcoming challenge will be to identify ultra-high-risk patients who have an 80 % risk of progression at 2 years. The current standard of care is not to treat until progression to symptomatic disease occurs. Several trials of melphalan, thalidomide and bisphosphonates have been conducted in the overall SMM patient population to examine the delay in time to progression (TTP) to symptomatic disease, but these have shown no significant benefit. However, a randomized trial that focused on high-risk SMM patients allocated to receive early treatment with lenalidomide plus dexamethasone versus observation did report a significant benefit with respect to TTP and overall survival. In summary, high-risk SMM patients should be targetted for early treatment, and more so efforts should be made to identify the ultra-high-risk subgroup within the high-risk SMM patient population which may be considered as early MM and thereby candidates for receiving therapy before they develop myeloma-related symptomatology.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia)
Revista: BLOOD
ISSN 0006-4971  Vol. 122  Nº 18  2013  págs. 3092 - 3093
Autores: Lonial, S.; San Miguel Izquierdo, Jesús
Revista: JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
ISSN 1540-1405  Vol. 11  Nº 1  2013  págs. 19 - 28
Treatment options for patients with newly diagnosed myeloma have evolved significantly over the past 10 years. Although response rates after induction for older or younger patients were limited, with few patients achieving complete remission, more recent combinations have cleared the way for major response and even complete remissions after induction therapy. As a consequence of these changes, patients are now achieving more durable and longer remissions, which have ultimately improved overall survival for patients with myeloma. The age-appropriate use of induction therapy, autologous transplant, and maintenance therapy, all keeping in mind the specific genetic risk group of a given patient, requires a long-term treatment plan for each patient defined early in the treatment course.
Autores: Alcoceba, M.; Sebastian, E.; Marin, L.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 122  Nº 8  2013  págs. 1448 - 1454
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P=.0008, Pc=.0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P=.019) and 5-year overall (71% vs 92%, P=.001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.
Autores: Mateos, M. V.; Hernandez, M. T.; Giraldo, P.; et al.
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 0028-4793  Vol. 369  Nº 5  2013  págs. 438 - 447
Background For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention. Methods In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety. Results After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. Conclusions Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival.
Autores: Schmidt-Hieber, M.; Laura Gutierrez, M.; Perez-Andres, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 98  Nº 2  2013  págs. 279 - 287
Cytogenetic studies in clonal plasma cell disorders have mainly been done in whole bone marrow or CD138(+) microbead-enriched plasma cells and suggest that recurrent immunoglobulin heavy chain translocations - e.g. t(4; 14) are primary oncogenetic events. The aim of this study was to determine cytogenetic patterns of highly purified aberrant plasma cells (median purity >= 98%) in different clonal plasma cell disorders. We analyzed aberrant plasma cells from 208 patients with multiple myeloma (n=148) and monoclonal gammopathy of undetermined significance (n=60) for the presence of del(13q14), del(17p13) and t(14q32) using multicolor interphase fluorescence in situ hybridization. Additionally, immunoglobulin heavy chain gene arrangements were analyzed and complementarity determining region 3 was sequenced in a subset of patients and combined multicolor interphase fluorescence in situ hybridization/immunofluorescent protein staining analyses were performed in selected cases to confirm clonality and cytogenetic findings. At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy. The cytogenetic heterogeneity of individual cases reflected coexistence of cytogenetically-defined aberrant plasma cell clones, and led to the assumption that karyotypic alterations were acquired stepwise. Cases of multiple myeloma and monoclonal gammopathy of undetermined significance frequently showed different but related cytogenetic profiles when other cytogenetic alterations such as deletions/gains of the immunoglobulin heavy chain or the fibroblast growth factor receptor 3 were additionally considered. Interestingly, in 24% of multiple myeloma versus 62% of monoclonal gammopathy of undetermined significance patients with an immunoglobulin heavy chain translocation, aberrant plasma cells with and without t(14q32) coexisted in the same patient. Our data suggest that recurrent immunoglobulin heavy chain translocations might be absent in the primordial plasma cell clone in a significant proportion of patients with clonal plasma cell disorders carrying these cytogenetic alterations.
Autores: San Miguel Izquierdo, Jesús; Richardson, P. G.; Guenther, A.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 31  Nº 29  2013  págs. 3696 - 3703
Purpose: Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM. Patients and methods: In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria. Results: The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ¿ minimal response. Conclusion: The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.
Autores: Puig, N.; Sarasquete, M. E.; Alcoceba, M.; et al.
Revista: ANNALS OF HEMATOLOGY
ISSN 0939-5555  Vol. 92  Nº 1  2013  págs. 97 - 100
We have evaluated the use of CD138+ positively selected bone marrow samples to identify a molecular target for minimal residual disease assessment by polymerase chain reaction (PCR) in 25 untreated patients with multiple myeloma. A fraction of each sample was used for CD138+ selection, and the rest served as a reference control. VDJH, DJH, and Kde gene rearrangements were tested for amplification according to the BIOMED-2 Concerted Action. PCR products were directly sequenced in an automated ABI 3130 DNA sequencer using Big-Dye terminators. Within the CD138+ selected group, VDJH rearrangements were detected in all cases (100 %), DJH in 16 (64 %), and Kde in 18 (72 %) cases; whereas in the control samples, VDJH, DJH, and Kde rearrangements were detected in 19 (76 %), 11 (44 %), and 12 (48 %) cases, respectively. After sequencing, 24 (96 %) cases within the CD138+ group had a PCR target for MRD detection compared with 15 (60 %) cases in the control group. We conclude that the use of CD138+ positively selected bone marrow samples increases the applicability of minimal residual disease studies by PCR in patients with multiple myeloma.
Autores: Bergsagel, P. L.; Mateos, M. V.; Gutierrez, N. C.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 121  Nº 6  2013  págs. 884 - 892
Multiple myeloma (MM) is a heterogeneous disease with certain genetic features [eg, t(4;14), del17p] associated with worse outcome. The introduction of thalidomide, lenalidomide, and bortezomib has dramatically improved the outlook for patients with MM, but their relative benefit (or harm) for different genetic patient subgroups remains unclear. Unfortunately, the small number of patients in each subgroup frequently limits the analysis of high-risk patients enrolled in clinical trials. Strategies that result in survival of high-risk genetic subgroups approximating that of patients lacking high-risk features are said to overcome the poor prognostic impact of these high-risk features. This outcome has been difficult to achieve, and studies in this regard have so far been limited by inadequate sample size. In contrast, strategies that compare the survival of high-risk genetic subgroups randomized to different treatment arms can identify approaches that improve survival. This type of analysis is clinically useful, even if the absolute gains do not improve outcomes to levels seen in patients without high-risk cytogenetics. Reviewing available data in high-risk MM from this perspective, it appears that bortezomib has frequently been associated with improved survival, whereas thalidomide maintenance has sometimes been associated with a shorter survival
Autores: Labrador, J.; Lopez-Anglada, L.; Perez-Lopez, E.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 98  Nº 3  2013  págs. 437 - 443
Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.
Autores: Bringhen, S.; Victoria Mateos, M.; Zweegman, S.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 98  Nº 6  2013  págs. 980 - 987
Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95% CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95% CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95% CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95% CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95% CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95% CI; 1.12-2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.
Autores: San Miguel Izquierdo, Jesús; Schlag, R.; Khuageva, N. K.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 31  Nº 4  2013  págs. 448 - 455
Purpose: This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies. Patients and methods: In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients. Results: After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ¿ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates. Conclusion: VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP. Trial registration: ClinicalTrials.gov NCT00111319.
Autores: Jimenez, C.; Sebastian, E.; Chillon, M. C.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 27  Nº 8  2013  págs. 1722 - 1728
We evaluated the MYD88 L265P mutation in Waldenstrom's macroglobulinemia (WM) and B-cell lymphoproliferative disorders by specific polymerase chain reaction (PCR) (sensitivity similar to 10(-3)). No mutation was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas and 9/48 (19%) non-germinal center (GC) diffuse large B-cell lymphomas (DLBCLs). The mutation was absent in all 28 GC-DLBCLs, 13 DLBCLs not subclassified, 35 hairy cell leukemias, 39 chronic lymphocytic leukemias (16 with M-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas and 1 IgM-related neuropathy. Among WM and IgM-MGUS, MYD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P = 0.022), more lymphocytosis (24 vs 5%, P = 0.006), higher lactate dehydrogenase level (371 vs 265 UI/L, P = 0.002), atypical immunophenotype (CD23 - CD27 ++ FMC7++), less Immunoglobulin Heavy Chain Variable gene (IGHV) somatic hypermutation (57 vs 97%, P = 0.012) and less IGHV3-23 gene selection (9 vs 27%, P = 0.014). These small differences did not lead to different time to first therapy, response to treatment or progression-free or overall survival.
Autores: Paiva, Bruno; Paino, T.; Sayagues, J. M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 122  Nº 22  2013  págs. 3591 - 3598
Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter-sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34 1 cells, and opposite to stromal cell-derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period.
Autores: Carrancio, S.; Romo, C.; Ramos, T.; et al.
Revista: CELL TRANSPLANTATION
ISSN 1555-3892  Vol. 22  Nº 7  2013  págs. 1171 - 1183
Hematopoietic stem cell transplantation (HSCT) using umbilical cord blood (UCB) progenitors is increasingly being used. One of the problems that may arise after UCB transplantation is an impaired engraftment. Either intrabone (IB) injection of hematopoietic progenitors or mesenchymal stem cell (MSC) coadministration has been proposed among the strategies to improve engraftment. In the current study, we have assessed the effects of both approaches. Thus, NOD/SCID recipients were transplanted with human UCB CD34+ cells administered either intravenously (IV) or IB, receiving or not bone marrow (BM)-derived MSCs also IV or IB (in the right femur). Human HSC engraftment was measured 3 and 6 weeks after transplantation. Injected MSCs were tracked weekly by bioluminescence. Also, lodgment within the BM niche was assessed at the latter time point by immuno-fluorescence. Our study shows regarding HSC engraftment that the number of BM human CD45+ cells detected 3 weeks after transplantation was significantly higher in mice cotransplanted with human MSCs. Moreover, these mice had a higher myeloid (CD13+) engraftment and a faster B-cell (CD19+) chimerism. At the late time point evaluated (6 weeks), human engraftment was higher in the group in which both strategies were employed (IB injection of HSC and MSC coadministration). When assessing human MSC administration route, we were able to track MSCs only in the injected femurs, whereas they lost their signal in the contralateral bones. These human MSCs were mainly located around blood vessels in the subendosteal region. In summary, our study shows that MSC coadministration can enhance HSC engraftment in our xenogenic transplantation model, as well as IB administration of the CD34+ cells does. The combination of both strategies seems to be synergistic. Interestingly, MSCs were detected only where they were IB injected contributing to the vascular niche.
Autores: Alvarez-Fernandez, S.; Ortiz-Ruiz, M. J.; Parrott, T.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 19  Nº 10  2013  págs. 2677 - 2687
Purpose: To analyze the antimyeloma potential of TG02, an ERK5/CDK inhibitory drug. Experimental design: Utilizing different multiple myeloma cell lines we determined the effect of TG02 over viability by MTT assays. The apoptotic effect over multiple myeloma patient samples was studied ex vivo by cytometry. The mechanism of action of TG02 was analyzed in the cell line MM1S, studying its effect on the cell cycle, the induction of apoptosis, and the loss of mitochondrial membrane potential by cytometry and Western blot. Two models of multiple myeloma xenograft were utilized to study the in vivo action of TG02. Results: TG02 potently inhibited proliferation and survival of multiple myeloma cell lines, even under protective bone marrow niche conditions, and selectively induced apoptosis of primary patient-derived malignant plasma cells. TG02 displayed significant single-agent activity in two multiple myeloma xenograft models, and enhanced the in vivo activity of bortezomib and lenalidomide. Signaling analyses revealed that the drug simultaneously blocked the activity of CDKs 1, 2, and 9 as well as the MAP kinase ERK5 in MM1S cells, leading to cell-cycle arrest and rapid commitment to apoptosis. TG02 induced robust activation of both the intrinsic and extrinsic pathways of apoptosis, and depletion of XIAP and the key multiple myeloma survival protein Mcl-1. Conclusions: TG02 is a promising new antimyeloma agent that is currently in phase I clinical trials in leukemia and multiple myeloma patients.
Autores: San Miguel Izquierdo, Jesús; Weisel, K.; Moreau, P.; et al.
Revista: LANCET ONCOLOGY
ISSN 1474-5488  Vol. 14  Nº 11  2013  págs. 1055 - 1066
Background Few eff ective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients. Methods This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2: 1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1-21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (<= 75 years vs > 75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30. Findings The accrual for the study has been completed and the analyses are presented.302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10.0 months (IQR 7.2-13.2), median PFS with pomalidomide plus low-dose dexamethasone was 4.0 months (95% CI 3.6-4.7) versus 1.9 months (1.9-2.2) with high-dose dexamethasone (hazard ratio 0.48 [95% CI 0.39-0.60]; p<0.0001).The most common grade 3-4 haematological adverse events in the pomalidomide plus lowdose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3-4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group. Interpretation Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma.
Autores: Paiva, Bruno; Vidriales, M. B.; Rosinol, L.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 27  Nº 10  2013  págs. 2056 - 2061
Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N = 698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N = 497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; similar to 60% at 10 years; P < 0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P = 0.81) and OS (P = 0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P = 0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM
ISSN 1520-4383  2013  págs. 488 - 495
Multiple myeloma (MM) is the second most frequent hematological disease. Two-thirds of newly diagnosed MM patients are more than 65 years of age. Elsewhere in this issue, McCarthy et al discuss the treatment of transplantation candidates; this chapter focuses on the data available concerning therapy for non-transplantation-eligible MM patients. Treatment goals for these non-transplantation-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. Until recently, treatment options were limited to alkylators, but new up-front treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) plus alkylating agents have significantly improved outcomes. Other nonalkylator induction regimens are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Phase 3 data indicate that maintenance therapy or prolonged treatment in elderly patients also improves the quality and duration of clinical responses, extending time to progression and progression-free survival; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. The potential for novel treatment regimens to improve the adverse prognosis associated with high-risk cytogenetic profiles also requires further research. In summary, although we have probably doubled the survival of elderly patients, this group requires close monitoring and individualized, dose-modified regimens to improve tolerability and treatment efficacy while maintaining their quality of life.
Autores: Garcia-Gomez, A.; Ocio, E. M. ; Pandiella, A.; et al.
Revista: INVESTIGATIONAL NEW DRUGS
ISSN 0167-6997  Vol. 31  Nº 1  2013  págs. 200 - 205
Introduction The RAS/RAF/MEK/ERK signaling pathway plays an important role in osteoclast (OC) differentiation and survival mediated by macrophage-colony stimulating factor (M-CSF). Also, vascular endothelial growth factor (VEGF) may greatly influence OC formation and resorption through VEGFR1 and VEGFR2. RAF265 is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2. Methods Effect of RAF265 on osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) and OC resorption on calcium-coated wells was assessed by appropriate in vitro assays. Immunoblotting, real-time RT-PCR and flow cytometry were used to evaluate RAF265 mechanism of action. Results RAF265 significantly impaired in vitro differentiation of PBMCs to OCs induced by receptor activator of NF-kB ligand (RANKL) and M-CSF (IC50 a parts per thousand...aEuro parts per thousand 160 nM). In parallel, RAF265 exerted a potent inhibition of OC resorptive capacity (IC50 a parts per thousand...aEuro parts per thousand 20 nM). RAF265 treatment led to ERK inhibition and diminished expression of c-fos and NFATc1 (nuclear factor of activated T cells, calcineurin-dependent 1), which would likely account for inhibition of osteoclastogenesis. The reduced gene expression of aVb3 integrin, CCR1, cathepsin K, carbonic anhydrase II, matrix metalloproteinase 9, urokinase and tissue-type plasminogen activators, vacuolar H+-ATPase subunit (ATP6V1A) and Rab7 GTPase would probably mediate RAF265 hindered resorption. RAF265 inhibitory effect on VEGFR2 (noticeable at 10-50 nM) was also found to be implicated in the potent inhibition of this agent on OC function. Conclusions We have found a new therapeutic application for RAF265 as an inhibitory agent of osteoclastogenesis and OC function, which might be useful for the treatment of skeletal disorders associated with increased bone resorption.
Autores: Hurchla, M. A.; Garcia-Gomez, A.; Hornick, M. C.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 27  Nº 2  2013  págs. 430 - 440
Proteasome inhibitors (Pis), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzonnib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the nunnber and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozonnib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzonnib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.
Autores: Misiewicz-Krzeminska, I.; Sarasquete, M. E.; Quwaider, D.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 98  Nº 4  2013  págs. 640 - 648
MicroRNA have been demonstrated to be deregulated in multiple myeloma. We have previously reported that miR-214 is down-regulated in multiple myeloma compared to in normal plasma cells. The functional role of miR-214 in myeloma pathogenesis was explored by transfecting myeloma cell lines with synthetic microRNA followed by gene expression profiling. Putative miR-214 targets were validated by luciferase reporter assay. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this microRNA, gene expression profiling of the H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. miR-214 directly down-regulated the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-untranslated regions. In addition, gankyrin inhibition induced an increase of P53 mRNA levels and subsequent up-regulation of CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. In conclusion, MiR-214 functions as a tumor suppressor in myeloma by positive regulation of p53 and inhibition of DNA replication.
Autores: Sanchez-Abarca, L. I.; Alvarez-Laderas, I.; Diez Campelo, M.; et al.
Revista: CYTOTHERAPY
ISSN 1465-3249  Vol. 15  Nº 6  2013  págs. 673 - 678
Background aims. Mesenchymal stromal cells (MSCs) are multipotent stem cells with immunosuppressive properties. Nevertheless, it has been previously reported that MSCs might also trigger the immune response. We studied whether MSCs may act as carriers, capturing antigens that can be endocytosed by antigen-presenting cells later on. Methods. We measured the cellular uptake of mannose receptor-mediated fluid phase macropinocytosis, assessed as cellular uptake of fluorescein isothiocyanate-dextran, and PKH-67-labeled cell lysates as a surrogate marker for antigen capture among dendritic cells (DCs, positive control), T lymphocytes (negative control) and MSCs. Results. All experiments confirmed that MCSs displayed pinocytic and endocytic capacities, which were lower than those observed for DCs but significantly higher than those observed for T cells. We also demonstrated that MSCs release previously endocytosed antigens, which subsequently can be captured by DCs. Conclusions. MSCs have the ability to capture and release antigens.
Autores: Fraile, P.; Vazquez, L.; Caballero, D.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 91  Nº 2  2013  págs. 129 - 134
IntroductionAllogenic hematopoietic stem cell transplant (allo-HSCT) is the treatment of choice for several hematological diseases. Although rare, patients could present nephrotic syndrome as a clinical feature of chronic graft-versus-host disease (cGVHD). The objective of our study is to screen patients with allo-HSCT to determine who developed a glomerular pathology in the context of cGVHD. Patients and methodsWe studied patients who underwent allo-HSCT treatment in our center between October 1995 and October 2012 and who developed glomerular pathology. cGVHD was defined as a pathology when it appeared after 100d post-allo-HSCT. ResultsFive hundred eighty-three allo-HSCT were performed. The prevalence of cGVHD of the kidney was 1.03%. All patients with cGVHD of the kidney were hosts who received peripheral blood from an identical HLA match donor. GVHD prophylaxis with calcineurin inhibitors plus methotrexate was administered in five cases, and prophylaxis with sirolimus was used in another case. cGVHD of the kidney was seen to appear after the removal of the prophylaxis for GVHD, within 33 +/- 11.54months intervals after allo-HSCT in five patients and in another patient, it appeared despite immunosuppressive therapy being administered. All patients had proteinuria, within 11.82 +/- 9.03g/d ranges. The kidney biopsies revealed membranous glomerulonephritis (four patients), focal segmental glomerulonephritis (one patient) and lupus nephropathy class III (one patient). It seems, immunosuppressive therapy achieved complete remission, within the first year of treatment in four patients. Although in three of them, the proteinuria recurred when we tried to remove the therapy; two patients have recently started treatment, being in partial remission now. ConclusionscGVHD of the kidney is a rare complication after allo-HSCT, related with the removal of the immunosuppression. Monitoring proteinuria in these patients may be useful. In our patients, a complete remission was achieved; although the removal of the immunosuppression may lead to the appearance of outbreaks. We must reconsider the treatment of glomerular pathology secondary to cGVHD.
Autores: Moreau, P.; San Miguel Izquierdo, Jesús; Ludwig, H.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 1569-8041  Vol. 24  Nº Supl. 6  2013  págs. 133 - 137
Autores: Martínez-López, J.; Fernandez-Redondo, E.; Garcia-Sanz, R.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 1365-2141  Vol. 163  Nº 5  2013  págs. 581 - 589
Minimal residual disease monitoring is becoming increasingly important in multiple myeloma (MM), but multiparameter flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) techniques are not routinely available. This study investigated the prognostic influence of achieving molecular response assessed by fluorescent-PCR (F-PCR) in 130 newly diagnosed MM patients from Grupo Espanol Multidisciplinar de Melanoma (GEM)2000/GEM05 trials (NCT00560053, NCT00443235, NCT00464217) who achieved almost very good partial response after induction therapy. As a reference, we used the results observed with simultaneous MFC. F-PCR at diagnosis was performed on DNA using three different multiplex PCRs: IGH D-J, IGK V-J and KDE rearrangements. The applicability of F-PCR was 915%. After induction therapy, 64 patients achieved molecular response and 66 non-molecular response; median progression-free survival (PFS) was 61 versus 36months, respectively (P=0001). Median overall survival (OS) was not reached (NR) in molecular response patients (5-year survival: 75%) versus 66months in the non-molecular response group (P=003). The corresponding PFS and OS values for patients with immunophenotypic versus non-immunophenotypic response were 67 versus 42months (P=0005) and NR (5-year survival: 95%) versus 69months (P=0004), respectively. F-PCR analysis is a rapid, affordable, and easily performable technique that, in some circumstances, may be a valid approach for minimal residual disease investigations in MM.
Autores: Pessoa de Magalhaes, R. J.; Vidriales, M. B.; Paiva, Bruno; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 98  Nº 1  2013  págs. 79 - 86
Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8(+) T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting improved immune surveillance.
Autores: Blanes, M.; Lahuerta, J. J.; Gonzalez, J. D.; et al.
Revista: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
ISSN 1523-6536  Vol. 19  Nº 1  2013  págs. 69 - 74
Melphalan 200 mg/m(2) (MEL200) is the standard conditioning regimen administered to newly diagnosed patients with multiple myeloma (MM) undergoing autologous stern cell transplantation (ASCT). Few alternatives have been explored in order to improve the antimyeloma activity of this conditioning. We compare i.v. busulfan (BU) 9.6 mg/kg and MEL 140 mg/m(2) (MEL140) versus MEL200 mg/m(2) as a conditioning regimen before ASCT for newly diagnosed patients with MM. For this purpose, 51 patients receiving i.v. BU plus MEL were compared to 102 patients receiving MEL200 mg/m(2) in a 1: 2 matched control analysis. Matching criteria included age, clinical stage at diagnosis, and response to induction therapy. No differences in the overall and complete response (CR) rates were observed after ASCT between both groups. After a median follow-up of 63 and 50 months in control and BU plus MEL groups, progression-free survival (PFS) was 24 and 33 months, respectively (P = .10). Most frequent toxicities included mucositis and febrile neutropenia in both groups. No case of sinusoidal obstruction syndrome was observed. Transplant-related mortality was 4% and 2% in BU plus MEL and control groups, respectively. ASCf conditioned with i.v. BU plus MEL may be considered an effective and well-tolerated alternative to a MEL-only approach as a conditioning regimen for patients with MM who are candidates for ASCT. (Clinicaltrials.gov identifier: NCT00560053 and NCT00804947.)
Autores: Caballero-Velazquez, T.; Lopez-Corral, L.; Encinas, C.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 1365-2141  Vol. 162  Nº 4  2013  págs. 474 - 482
The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma.
Autores: Sarasquete, M. E.; Martínez-López, J.; Chillon, M. C.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 1365-2141  Vol. 163  Nº 2  2013  págs. 223 - 234
The gene expression profiles (GEPs) of 96 selected genes were analysed by real-time quantitative polymerase chain reaction (qPCR) with a TaqMan low-density array card in isolated tumour plasma cells (PCs) from 157 newly diagnosed multiple myeloma (MM) patients. This qPCR-based GEP correctly classified cases following the Translocation-cyclin D classification. Classic prognostic parameters and qPCR-based GEP predicted MM patient outcome and, although multivariate analyses revealed that cytogenetic risk (standard vs. high risk) was the variable that most strongly predicted prognosis, GEP added significant information for risk stratification. Considering only the standard risk cytogenetic patients, multivariate analyses revealed that high beta 2-microglobulin, low CDKN1A and high SLC19A1 gene expression levels independently predicted a short time-to-progression (TTP), while high International Staging System stage, low CDKN2B and high TBRG4 gene expression predicted poor overall survival (OS). A gene expression risk score enabled the division of standard risk patients into two groups with different TTPs (83% vs. 38% at 3years, P<0 center dot 0001) and OS rates (88% vs. 61% at 5years; P=0 center dot 003). This study demonstrates that quantitative PCR is a robust, accurate and feasible technique for implementing in the daily routine as a surrogate for GEP-arrays.
Autores: Puchades Carrasco, L.; Lecumberri Villamediana, Ramón; Martinez Lopez, J.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 19  Nº 17  2013  págs. 4770 - 4779
Purpose: Multiple myeloma remains an incurable disease. New approaches to develop better tools for improving patient prognostication and monitoring treatment efficacy are very much needed. In this study, we aimed to evaluate the potential of metabolomics by H-1-NMR to provide information on metabolic profiles that could be useful in the management of multiple myeloma. Experimental Design: Serum samples were collected from multiple myeloma patients at the time of diagnosis and after achieving complete remission. A matched control set of samples was also included in the study. The H-1-NMR measurements used to obtain the metabolic profile for each patient were followed by the application of univariate and multivariate statistical analyses to determine significant differences. Results: Metabolic profiles of multiple myeloma patients at diagnosis exhibited higher levels of isoleucine, arginine, acetate, phenylalanine, and tyrosine, and decreased levels of 3-hydroxybutyrate, lysine, glutamine, and some lipids compared with the control set. A similar analysis conducted in multiple myeloma patients after achieving complete remission indicated that some of the metabolic changes (i.e., glutamine, cholesterol, lysine) observed at diagnosis displayed a variation in the opposite direction upon responding to treatment, thus contributing to multiple myeloma patients having a closer metabolic profile to those of healthy individuals after the disappearance of major disease manifestations. Conclusions: The results highlight the potential of metabolic profiles obtained by H-1-NMR in identifying multiple myeloma biomarkers that may be useful to objectively discriminate individuals with and without multiple myeloma, and monitor response to treatment. (C)2013 AACR.
Autores: Mateos, M. V. , (Autor de correspondencia); San Miguel Izquierdo, Jesús
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 0028-4793  Vol. 369  Nº 18  2013  págs. 1764 - 1765
Autores: Paino, T. ; Paiva, Bruno; San Miguel Izquierdo, Jesús (Autor de correspondencia)
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 98  Nº 1  2013  págs. e10
Autores: Puchades-Carrasco, L. ; Lecumberri Villamediana, Ramón; Martinez-Lopez, J; et al.
Revista: EUROPEAN JOURNAL OF CANCER
ISSN 0959-8049  Vol. 49  Nº Supl 4  2013  págs. S14
Autores: Richardson, P. G., (Autor de correspondencia); Delforge, M.; Beksac, M. ; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 26  Nº 4  2012  págs. 595 - 608
Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.
Autores: Chanan-Khan, A. A., (Autor de correspondencia); San Miguel Izquierdo, Jesús; Jagannath, S.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 18  Nº 8  2012  págs. 2145 - 2163
Renal impairment is a major complication of multiple myeloma. Patients presenting with severe renal impairment represent a greater therapeutic challenge and generally have poorer outcome. However, once patients with renal impairment achieve remission, their outcomes are comparable with those of patients without renal impairment. Therapies that offer substantial activity in this setting are needed. Bortezomib, thalidomide, and lenalidomide have substantially improved the survival of patients with multiple myeloma. Here we review the pharmacokinetics, activity, and safety of these agents in patients with renal impairment. Bortezomib can be administered at the full approved dose and schedule in renally impaired patients; similarly, no dose reductions are required with thalidomide. The pharmacokinetics of lenalidomide is affected by its renal route of excretion, and dose adjustments are recommended for moderate/severe impairment. Substantial evidence has emerged showing that these novel agents improve outcomes of patients with renal impairment, including impairment reversal. Bortezomib, thalidomide, and lenalidomide (at the recommended doses) are active options for patients with mild to moderate impairment, although limited data are available for thalidomide. Information on lenalidomide-based combinations is still emerging, but the available data indicate considerable activity. Substantial evidence indicates that bortezomib-high-dose dexamethasone with or without a third drug (e. g., cyclophosphamide, thalidomide, or doxorubicin) is an appropriate option for patients with any degree of renal impairment.
Autores: Ocio, E. M., (Autor de correspondencia); Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: EXPERT OPINION ON INVESTIGATIONAL DRUGS
ISSN 1354-3784  Vol. 21  Nº 8  2012  págs. 1075 - 1087
Introduction: Several novel proteasome inhibitors (PIs) and immunomodulatory agents (IMIDs) with similar, but not exactly the same, mechanisms of action than their predecessors have been developed in the last years with three different aims: to increase the efficacy; to overcome the resistance and to exhibit a better toxicity profile. Areas covered: This review summarizes the mechanism of action of novel PIs (carfilzomib, ONX-0912, MLN-9708, marizomib and CEP-18770) and IMIDs (pomalidomide), stressing the similarities and differences with their parental drugs. It also reviews their most updated clinical results. A search of the recent literature in published papers and abstracts from the most important oncology scientific meetings (ASCO and ASH) has been performed. Expert opinion: Novel PIs and IMIDs show clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their predecessors; moreover, they may even overcome resistance to their parental drugs, indicating that there are some differences in their mechanisms of action and resistance. The investigation of these mechanisms of resistance and ways to overcome it would allow the optimization of the sequential use of these agents, and the design of novel therapeutic strategies and more appropriate scientifically based combinations.
Autores: Ludwig, H.; Avet-Loiseau, H.; Bladè, J.; et al.
Revista: ONCOLOGIST
ISSN 1549-490X  Vol. 17  Nº 5  2012  págs. 592 - 606
The management of multiple myeloma has undergone profound changes over the recent past as a result of advances in our understanding of the disease biology as well as improvements in treatment and supportive care strategies. Notably, recent years have seen a surge in studies incorporating the novel agents thalidomide, bortezomib, and lenalidomide into treatment for different disease stages and across different patient groups. This article presents an update to a previous review of European treatment practices and is based on discussions during an expert meeting that was convened to review novel agent data published or presented at medical meetings until the end of 2011 and to assess their impact on treatment strategies.
Autores: Palumbo, A. , (Autor de correspondencia); Blade, J.; Boccadoro, M.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 12  Nº 1  2012  págs. 5 - 11
Neutropenia is a hematologic adverse event characterized by an absolute neutrophil count (ANC) lower than 1500 cells/mL. This reduction may be due to decreased neutrophil production, accelerated use, a shift in compartments of neutrophils, or a combination of these factors. Neutropenia is often associated with infections, which are major causes of morbidity and mortality in patients with cancer. In patients with multiple myeloma, the novel agents thalidomide, lenalidomide, and bortezomib have improved outcome, but chemotherapy-related neutropenia should be carefully considered. Chemotherapy-related high-risk factors for severe neutropenia include regimens with an expected neutropenia rate of > 50%, such as the 3-drug combinations including lenalidomide plus alkylating agents or doxorubicin, whereas low-risk regimens include combinations of the novel agents with dexamethasone alone. Patient characteristics, disease stage, type of current and previous treatment, and ANC < 1000 cells/mL at baseline are additional factors that define the risk of severe neutropenia. Granulocyte-colony stimulating factor (G-CSF) should be used to manage chemotherapy-related neutropenia so that patients may stay on treatment for a longer time and benefit from it. Primary G-CSF prophylaxis should be used when high-risk regimens are administered or when low/intermediate-risk regimens are used and additional risk factors are present. Reactive G-CSF treatment is indicated when patients undergoing low-risk chemotherapy experience grade 3/4 neutropenia. If ANC restores to > 1000 cells/mL, therapy can be resumed with no dose modifications. In case of persistence of severe neutropenia, treatment should be delayed until ANC reaches > 1000 cells/mL, and dose reductions are necessary.
Autores: Moreau, P., (Autor de correspondencia); Richardson, P. G.; Cavo, M. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 120  Nº 5  2012  págs. 947 - 959
Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these "second-generation" PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.
Autores: Ludwig, H. , (Autor de correspondencia); Durie, B. G. M.; McCarthy, P.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 119  Nº 13  2012  págs. 3003 - 3015
Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.
Autores: Rajkumar, S. V., (Autor de correspondencia); Merlini, G.; San Miguel Izquierdo, Jesús
Revista: NATURE REVIEWS CLINICAL ONCOLOGY
ISSN 1759-4774  Vol. 9  Nº 9  2012  págs. 494 - 496
The current definition of multiple myeloma is outdated. The diagnosis requires evidence of overt end-organ damage, preventing initiation of early therapy when the malignancy is at its most susceptible stage. We propose an evidence-based approach using more-sensitive and highly specific biomarkers to update the definition of this disease.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia)
Revista: BLOOD
ISSN 0006-4971  Vol. 120  Nº 1  2012  págs. 2 - 3
The use of a short consolidation treatment after autologous transplantation increases the complete response rate and relapse-free survival.
Autores: Gutierrez-Cosio, S.; de la Rica, L.; Ballestar, E.; et al.
Revista: LEUKEMIA RESEARCH
ISSN 0145-2126  Vol. 36  Nº 7  2012  págs. 895 - 899
PRAME is a tumor associated antigen (TAA) of particular interest since it is widely expressed by lymphoid and myeloid malignancies. Several studies have associated high PRAME RNA levels with good prognosis in acute myeloid leukemia (AML). PRAME expression is regulated at the epigenetic level. For this reason inhibitors of DNA methylation, such as 5-azacytidine, can modulate the expression of this TAAs. In the current study we analyzed the effect of 5-azaC on the expression of PRAME in blasts versus CD34+ cells from healthy donors in an attempt to increase its expression, thus inducing a potential target for therapeutic strategies.
Autores: Sánchez-Guijo, F. M.; Lopez-Villar, O.; Lopez-Anglada, L.; et al.
Revista: TRANSFUSION
ISSN 1537-2995  Vol. 52  Nº 5  2012  págs. 1086 - 1091
BACKGROUND: Posttransplant cytopenias are a severe complication after allogeneic stem cell transplantation (allo-SCT) and their origin is often multifactorial or unknown. They are frequently refractory to standard therapy, which may include steroids and/or immunoglobulins. Mesenchymal stem cells (MSCs) are an attractive therapeutic tool in the allo-SCT setting for the ability to enhance engraftment as well as acting as immunosuppressants for graft-versus-host disease. There is no prior experience in the literature of the use of MSCs to treat cytopenias after allo-SCT. CASE REPORTS: In this work we report for the first time four cases of refractory posttransplant cytopenias (three patients with thrombocytopenia and one with neutropenia) that were treated with MSCs from a third-party donor. MSCs were expanded from 100 mL of marrow obtained under standard good manufacturing practice conditions. Most patients received more than one cell dose, and median dose of MSCs administered was 1 x 106/kg. RESULTS: All patients recovered normal blood counts, with a mean follow-up of 12.5 months. There were no adverse events related to MSC administration. CONCLUSION: MSC therapy may contribute to the recovery of refractory posttransplant peripheral cytopenias in patients undergoing allo-SCT.
Autores: Delforge, M.; Dhawan, R.; Robinson, D. Jr.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 89  Nº 1  2012  págs. 16 - 27
Objectives The phase 3 VISTA study ( NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The phase 3 VISTA study ( NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). Methods EORTC QLQ-C30 was administered at screening, on day 1 of each cycle, at the end-of-treatment visit, and every 8 wk until progression. EORTC QLQ-C30 scores were evaluated among patients with a valid baseline and at least one post-baseline HRQoL assessment. Results At baseline, domain scores were similar between arms. By cycle 4, mean differences were clinically meaningful for most domains, indicating poorer health status with VMP. From cycle 5 onwards, improvements relative to baseline/MP were observed for all domains with VMP. Mean scores were generally improved by the end-of-treatment assessment vs. baseline in both arms. Among responding patients, mean scores generally improved from time of response to end-of-treatment assessment, substantially driven by patients achieving complete response (CR). Multivariate analysis showed a significant impact of duration of response/CR on improving global health status, pain, and appetite loss scores. Analyses by bortezomib dose intensity indicated better HRQoL in patients receiving lower dose intensity. Conclusions These findings demonstrate clinically meaningful, transitory HRQoL decrements with VMP and relatively lower HRQoL vs. MP during early treatment cycles, associated with the expected additional toxicities. However, HRQoL is not compromised in the long term, recovering by the end-of-treatment visit to be comparable vs. MP.
Autores: Santamaria, C.; Muntion, S.; Roson, B.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 97  Nº 8  2012  págs. 1218 - 1224
Background Recent findings suggest that a specific deletion of Dicer1 in mesenchymal stromal cell-derived osteoprogenitors triggers several features of myelodysplastic syndrome in a murine model. Our aim was to analyze DICER1 and DROSHA gene and protein expression in mesenchymal stromal cells (the osteoblastic progenitors) obtained from bone marrow of myelodysplastic syndrome patients, in addition to microRNA expression profile and other target genes such as SBDS, a DICER1-related gene that promotes bone marrow dysfunction and myelodysplasia when repressed in a murine model. Design and methods: Mesenchymal stromal cells from 33 bone marrow samples were evaluated. DICER, DROSHA and SBDS gene expression levels were assessed by real-time PCR and protein expression by Western blot. MicroRNA expresion profile was analyzed by commercial low-density arrays and some of these results were confirmed by individual real-time PCR. Results: Mesenchymal stromal cells from myelodysplastic syndrome patients showed lower DICER1 (0.65±0.08 vs. 1.91±0.57; P=0.011) and DROSHA (0.62±0.06 vs. 1.38±0.29; P=0.009) gene expression levels, two relevant endonucleases associated to microRNA biogenesis, in comparison to normal myelodysplastic syndrome. These findings were confirmed at protein levels by Western blot. Strikingly, no differences were observed between paired mononuclear cells from myelodysplastic syndrome and controls. In addition, mesenchymal stromal cells from myelodysplastic syndrome patients showed significant lower SBDS (0.63±0.06 vs. 1.15±0.28; P=0.021) gene expression levels than mesenchymal stromal cells from healthy controls. Furthermore, mesenchymal stromal cells from myelodysplastic syndrome patients showed an underlying microRNA repression compared to healthy controls. Real-time PCR approach confirmed that mir-155, miR-181a and miR-222 were down-expressed in mesenchymal stromal cells from myelodysplastic syndrome patients. Conclusions This is the first description of an impaired microRNA biogenesis in human mesenchymal stromal cells from myelodysplastic syndrome patients, where DICER1 and DROSHA gene and protein downregulation correlated to a gene and microRNA abnormal expression profile, validating the animal model results previously described.
Autores: Kumar, S. K.; Lee, J. H.; Lahuerta, J. J.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 26  Nº 1  2012  págs. 149 - 157
Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T-0). The median age at diagnosis was 58 years, and time from diagnosis to T-0 was 3.3 years. Following T-0, 213 (74%) patients had a treatment recorded with one or more regimens (median = 1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including >= partial response in 69 (32%). The median overall survival and event-free survival from T-0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.
Autores: Garcia-Gomez, A.; Ocio, E. M.; Crusoe, E.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 7  Nº 4  2012  págs. e34914
Background: Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function. Methods: For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model. Results: Dasatinib inhibited the platelet derived growth factor receptor-beta (PDGFR-beta), c-Src and c-Kit phosphorylation in hMSC-TERT and MG-63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2-5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1-2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, alpha V beta 3 integrin and CCR1 expression. Conclusions: Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease.
Autores: Lopez-Corral, L.; Mateos, M. V.; Corchete, L. A.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 97  Nº 9  2012  págs. 1439 - 1443
Smoldering myeloma is an asymptomatic plasma cell dyscrasia with a heterogeneous propensity to progress to active myeloma. In order to investigate the biology of smoldering myeloma patients with high risk of progression, we analyzed the genomic characteristics by FISH, SNP-arrays and gene expression profile of a group of patients with high-risk smoldering myeloma included in a multicenter randomized trial. Chromosomal abnormalities detected by FISH and SNP-arrays at diagnosis were not associated to risk of progression to symptomatic myeloma. However, the overexpression of four SNORD genes (SNORD25, SNORD27, SNORD30 and SNORD31) was correlated with shorter time to progression (P<0.03). When plasma cells from high-risk smoldering patients who progressed to symptomatic myeloma were sequentially analyzed, newly acquired lesions together with an increase in the proportion of plasma cells carrying a given abnormality were observed. These findings suggest that gene expression profiling is a valuable technique to identify smoldering myeloma patients with high risk of progression. (Clinical Trials NCT00443235)
Autores: Mateos, M. V.; Oriol, A.; Martínez-López, J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 120  Nº 13  2012  págs. 2581 - 2588
Maintenance therapy has become a hot field in myeloma, and it may be particularly relevant in elderly patients because the major benefit results from the initial therapy. We report the results of a randomized comparison of maintenance with bortezomib plus thalidomide (VT) or prednisone (VP) in 178 elderly untreated myeloma patients who had received 6 induction cycles with bortezomib plus either melphalan and prednisone or thalidomide and prednisone. The complete response (CR) rate increased from 24% after induction up to 42%, higher for VT versus VP (46% vs 39%). Median progression-free survival (PFS) was superior for VT (39 months) compared with VP (32 months) and overall survival (OS) was also longer in VT patients compared with VP (5-year OS of 69% and 50%, respectively) but the differences did not reach statistical significance. CR achievement was associated with a significantly longer PFS (P < .001) and 5-year OS (P < .001). The incidence of G3-4 peripheral neuropathy was 9% for VT and 3% for VP. Unfortunately, this approach was not able to overcome the adverse prognosis of cytogenetic abnormalities. In summary, these maintenance regimens result in a significant increase in CR rate, remarkably long PFS, and acceptable toxicity profile. The trial is registered at www.clinicaltrials.gov as NCT00443235.
Autores: Matarraz, S.; Paiva, Bruno; Diez-Campelo, M.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 97  Nº 10  2012  págs. 1608 - 1611
Increased risk of acute myeloid leukemia/myelodysplastic syndromes following treatment has been reported in multiple myeloma, but whether dysplastic features are already present at diagnosis remains to be investigated. Using multiparameter flow cytometry, we analyzed the distribution and phenotype of bone marrow hematopoietic cells from 47 multiple myeloma patients (15 symptomatic and 32 high-risk smoldering). From the 32 smoldering myeloma patients, 18 were studied at baseline and 22 after nine cycles of lenalidomide/dexamethasone treatment following the QUIREDEX trial (including 8 from baseline). Phenotypic alterations of bone marrow cells of 7 (47%) symptomatic and 6 (33%) smoldering myeloma patients were detected at baseline; there was no difference in the frequency and extent of phenotypic alterations between symptomatic versus smoldering cases. Likewise, no difference was seen between smoldering myeloma patients studied at baseline versus after lenalidomide/dexamethasone treatment. Our results suggest that phenotypic alterations of bone marrow hematopoietic cells are often present in newly diagnosed symptomatic and smoldering multiple myeloma patients. QUIREDEX trial (NCT00480363)
Autores: Muntion, S.; Sánchez-Guijo, F. M.; Carrancio, S.; et al.
Revista: TRANSFUSION MEDICINE
ISSN 0958-7578  Vol. 22  Nº 2  2012  págs. 122 - 127
Purpose: The aim of this study was to optimise the yield of metaphases in mesenchymal stromal cells (MSC) in vitro cultures and to study the karyotype of MSC expanded in good manufacturing practice (GMP) conditions for clinical use. Background: MSC are being increasingly used in clinical trials for a number of diseases. Biosafety demonstration in all cases is mandatory. Unfortunately, current standard karyotyping methods fail to obtain enough number of evaluable metaphases. Methods and materials: In the present work, to optimise the yield of metaphases in MSC expanded in vitro, we have tested several conditions by modifying colcemid concentration (we have tested 0.01, 0.05 and 0.1 mu g mL(-1)) and exposure time (during 5, 15 and 24 h). We further applied these optimised conditions to 61 MSC expansions in GMP conditions for clinical use. Results: Our results show that the highest number of metaphases was obtained when MSC were incubated with 0.05 mu g mL(-1) of colcemid overnight (15 h), compared to the remaining experimental conditions. In most cases (59/61 cases) enough number of metaphases was obtained. And what is more relevant, only in one case a karyotypic abnormality was found (trisomy of chromosome 10), and cells were subsequently discarded for clinical use. Conclusion: We describe here an optimal method to obtain enough number of metaphases for karyotype analysis of in vitro expanded MSCs, what is essential for their clinical use in cell therapy programmes.
Autores: Lapusan, S.; Vidriales, M. B.; Thomas, X.; et al.
Revista: INVESTIGATIONAL NEW DRUGS
ISSN 0167-6997  Vol. 30  Nº 3  2012  págs. 1121 - 1131
The efficacy of anti-CD33 immunoconjugates had been previously demonstrated for gemtuzumab-ozogamicin. AVE9633 is an anti-CD33-maytansine conjugate created by ImmunoGen Inc. Phase I trials of AVE9633 were performed in patients with AML to evaluate tolerability, pharmacokinetics and pharmacodynamics. Three phase I studies of AVE9633 were performed in 54 patients with refractory/relapsed AML, evaluating drug infusion on day 1 of a 21-day cycle (Day 1 study), day 1 and 8 (Day 1/8 study) and day 1, 4 and 7 (Day 1/4/7 study) of a 28-day cycle. Toxicity was mainly allergic reaction during infusion (3 grade 3 bronchospasms). DLT was reached for the D1-D7 schedule at 150 mg/sqm (1 keratitis, 1 liver toxicity), and the MTD was set at 130 mg/sqm for this schedule. In the two other phases I, the DLT was not reached. In the Day 1/8 study, CD33 on peripheral blasts was saturated and down-modulated for doses of 75 mg/m(2) x 2 or higher, which was correlated with WBC kinetics and plasma levels of AVE9633. Decrease of DM4/CD33 ratio on the blasts surface between day 1 and 8 was the rational for evaluating day 1/4/7 schedule. This induced relatively constant DM4/CD33 levels over the first 8 days, however no activity was noted. One CRp, one PR and biological activity in five other patients were observed in this study. The Day 1 and Day 1/4/7 studies were early discontinued because of drug inactivity at doses significantly higher than CD33 -saturating doses. No myelossuppression was observed at any trial of AVE9633. The pharmacokinetics/pharmacodynamics data obtained in these studies will provide very useful information for the design of the next generation of immunoconjugates.
Autores: Santamaria, C.; Ramos, F.; Puig, N.; et al.
Revista: ANNALS OF HEMATOLOGY
ISSN 0939-5555  Vol. 91  Nº 12  2012  págs. 1887 - 1895
Several studies have evaluated the prognostic value of the individual expression of certain genes in patients with myelodysplastic syndromes (MDS). However, none of them includes their simultaneous analysis by quantitative polymerase chain reaction (PCR). We evaluated relative expression levels of 14 molecular markers in 193 peripheral blood samples from untreated MDS patients using real-time PCR. Detectable WT1 expression levels, low TET2, and low IER3 gene expression were the only markers showing in univariate analysis a poor prognostic value for all treatment-free (TFS), progression-free (PFS), and overall survival (OS). In multivariate analysis, molecular parameters associated with a shorter TFS were: WT1 detection (p = 0.014), low TET2 (p = 0.002), and low IER3 expression (p = 0.025). WT1 detection (p = 0.006) and low TET2 (p = 0.006) expression were associated with a shorter PFS when multivariate analysis was carried out by including only molecular markers. Molecular values with an independent value in OS were: WT1 detection (p = 0.003), high EVI1 expression (p = 0.001), and undetectatable p15-CDKN2B (p = 0.037). WT1 expressers were associated with adverse clinical-biological features, high IPSS and WPSS scoring, and unfavorable molecular expression profile. In summary, detectable WT1 expression levels, and low TET2 and low IER3 expression in peripheral blood showed a strong association with adverse prognosis in MDS patients at diagnosis. However, WT1 was the only molecular marker displaying an independent prognostic value in both OS and TFS.
Autores: Sebastian, E.; Alcoceba, M.; Balanzategui, A.; et al.
Revista: AMERICAN JOURNAL OF PATHOLOGY
ISSN 0002-9440  Vol. 181  Nº 5  2012  págs. 1879 - 1888
The pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains partially unknown. The analysis of the B-cell receptor of the malignant cells could contribute to a better understanding of the DLBCL biology. We studied the molecular features of the immunoglobulin heavy chain (IGH) rearrangements in 165 patients diagnosed with DLBCL not otherwise specified. Clonal IGH rearrangements were amplified according to the BIOMED-2 protocol and PCR products were sequenced directly. We also analyzed the criteria for stereotyped patterns in all complete IGHV-IGHD-IGHJ (V-D.J) sequences. Complete V-D-J rearrangements were identified in 130 of 165 patients. Most cases (89%) were highly mutated, but 12 sequences were truly unmutated or minimally mutated. Three genes, IGHV4-34, IGHV3-23, and IGHV4-39, accounted for one third of the whole cohort, including an over-representation of IGHV4-34 (15.5% overall). Interestingly, all IGHV4-34 rearrangements and all unmutated sequences belonged to the nongerminal center B-cell like (non-GCB) subtype. Overall, we found three cases following the current criteria for stereotyped heavy chain VH CDR3 sequences, two of them belonging to subsets previously described in CLL. IGHV gene repertoire is remarkably biased, implying an antigen-driven origin in DLBCL The particular features in the sequence of the immunoglobulins suggest the existence of particular subgroups within the non-GCB subtype.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: THERAPEUTIC ADVANCES IN HEMATOLOGY
ISSN 2040-6207  Vol. 3  Nº 2  2012  págs. 117 - 124
The discovery of the ubiquitin-proteasome pathway first, and the proteasome inhibitors thereafter were not made in the hope of improving the treatment of malignant diseases. However, bortezomib, the first in class proteasome inhibitor introduced in the clinical practice has contributed to improve the outcome of patients with multiple myeloma, at relapse or disease progression as well as upfront. The results observed in a large randomized trial (APEX) comparing bortezomib and high-dose dexamethasone demonstrated a significant benefit for bortezomib in terms of response rate, progression-free and overall survival. These results led to bortezomib being approved for use in relapsed and/or refractory myeloma patients. Subsequent studies demonstrated that its activity could be enhanced in combination with other drugs; and the next step was to move to the newly diagnosed patient population; in fact, bortezomib-melphalan-prednisone (VMP) is approved as a standard of care for newly diagnosed elderly patients. However, toxicity, especially peripheral neuropathy, as well as the intravenous route required for its administration are the two most significant bortezomib-related issues. To try to reduce the peripheral neuropathy, new guidelines for its management and the introduction of weekly schedules of administration have contributed to significantly decrease its incidence and the subcutaneous administration has been recently introduce to avoid the intravenous (IV) route. Results obtained in phase I/II and III studies have confirmed that subcutaneous administration is feasible and represents an additional step towards the optimization of bortezomib use, resulting in a probably more convenient method than the IV route that is at least as effective.
Autores: Paiva, Bruno; Vidriales, M. B.; Montalban, M. A.; et al.
Revista: AMERICAN JOURNAL OF PATHOLOGY
ISSN 0002-9440  Vol. 181  Nº 5  2012  págs. 1870 - 1878
The incorporation of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) and novel agents has significantly improved survival in patients with multiple myeloma (MM), but whether this improvement also benefits patients harboring poor prognostic features, such as nonhyperdiploid MM (NH-MM) and a high proliferation index, remains largely unknown. We analyzed the DNA content and proliferation index of bone marrow plasma cells (PCs) by multiparameter flow cytometry in 595 newly diagnosed transplant-eligible patients with MM included in two consecutive PETHEMA/GEM trials: GEM2000 [VBMCP/VBAD (vincristine, carmustine, melphalan, cyclophosphamide, prednisone/vincristine, bischloroethylnitrosourea, adriamycin, and dexamethasone) followed by HDT/ASCT; n = 319] and GEM2005<65y (randomized induction with VBMCP/VBAD/bortezomib or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT: n = 276). Of the 595 patients, 295 were classified as NH-MM (49.6%) and 336 (56.5%) as high-proliferative MM (>= 1% PCs in S-phase). Detection of NH-MM DNA content and >= 1% PCs in S-phase were of independent prognostic value for overall survival. Treatment with bortezomib-based regimens abrogated the inferior overall survival of patients with >= 1% PCs in S-phase but not of patients with NH-MM. Finally, a comparative analysis of PC proliferation index at diagnosis versus disease progression showed a two-fold increase at relapse in 44 of 52 patients (85%) analyzed at both time points. NH-MM and a high proliferation index assessed by multiparameter flow cytometry remain as independent prognostic factors in MM, but the latter may be overcome by incorporating novel agents in the HDT/ASCT setting.
Autores: Lopez-Corral, L.; Sarasquete, M. E.; Bea, S.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 26  Nº 12  2012  págs. 2521 - 2529
Genetic events mediating transformation from premalignant monoclonal gammopathies (MG) to multiple myeloma (MM) are unknown. To obtain a comprehensive genomic profile of MG from the early to late stages, we performed high-resolution analysis of purified plasma cells from 20 MGUS, 20 smoldering MM (SMM) and 34 MM by high-density 6.0 SNP array. A progressive increase in the incidence of copy number abnormalities (CNA) from MGUS to SMM and to MM (median 5, 7.5 and 12 per case, respectively) was observed (P = 0.006). Gains on 1q, 3p, 6p, 9p, 11q, 19p, 19q and 21q along with 1p, 16q and 22q deletions were significantly less frequent in MGUS than in MM. Although 11q and 21q gains together with 16q and 22q deletions were apparently exclusive of MM status, we observed that these abnormalities were also present in minor subclones in MGUS. Overall, a total of 65 copy number-neutral LOH (CNN-LOH) were detected. Their frequency was higher in active MM than in the asymptomatic entities (P = 0.047). A strong association between genetic lesions and fragile sites was also detected. In summary, our study shows an increasing genomic complexity from MGUS to MM and identifies new chromosomal regions involved in CNA and CNN-LOH.
Autores: Paiva, Bruno; Gutierrez, N. C.; Rosiñol, L.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 119  Nº 3  2012  págs. 687 - 691
The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.
Autores: San Miguel Izquierdo, Jesús; Mateos, M. V.; Ocio, E.; et al.
Revista: HEMATOLOGY
ISSN 1024-5332  Vol. 17  Nº Supl. 1  2012  págs. S3 - S6
Melphalan-prednisone (MP) was introduced for the treatment of MM in late 1960s. In the subsequent 30 years, the treatment improvements remained stagnant, since more complex chemotherapy combinations, such as vincristine, doxorubicin, and dexamethasone (VAD), or with the addition of BCNU (VBAD) or melphalan and cyclophosphamide (VCMP), only led to small increases in the overall response rate but without differences in survival, as assessed in a large meta-analysis that included over 6000 patients. The next step forward was the use of high-dose melphalan followed by stem cell support (autologous stem cell transplant - ASCT) for young myeloma patients, which resulted in a significant improvement in disease free survival and overall survival. However, for elderly patients MP remained as the standard of care. From year 2000, a revolution in the treatment armamentarium of MM has emerged with the availability of new agents with singular mechanism of action such as thalidomide and lenalidomide (Revlimid®), both immunomodulatory drugs and the proteasome inhibitor bortezomib (Velcade®).
Autores: Paino, T.; Ocio, E. M.; Paiva, Bruno; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 1592-8721  Vol. 97  Nº 7  2012  págs. 1110 - 1114
Although new therapies have doubled the survival of multiple myeloma patients, this remains an incurable disease. It has been postulated that the so-called myeloma cancer stem cells would be responsible for tumor initiation and relapse but their unequivocal identification remains unclear. Here, we investigated in a panel of myeloma cell lines the presence of CD20(+) cells harboring a stem-cell phenotype. Thus, only a small population of CD20(dim+) cells (0.3%) in the RPMI-8226 cell line was found. CD20(dim+) RPMI-8226 cells expressed the plasma cell markers CD38 and CD138 and were CD19(-)CD27(-). Additionally, CD20(dim+) RPMI-8226 cells did not exhibit stem-cell markers as shown by gene expression profiling and the aldehyde dehydrogenase assay. Furthermore, we demonstrated that CD20(dim+) RPMI-8226 cells are not essential for CB17-SCID mice engraftment and show lower self-renewal potential than the CD20(-) RPMI-8226 cells. These results do not support CD20 expression for the identification of myeloma cancer stem cells.
Autores: Paiva, Bruno; Gutierrez, N. C.; Chen, X.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 26  Nº 8  2012  págs. 1862 - 1869
he presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.
Autores: Rosiñol, L.; Garcia-Sanz, R.; Jose Lahuerta, J.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 97  Nº 4  2012  págs. 616 - 621
Background: Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. Design and methods: In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (¿ 25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. Results: There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Conclusions: Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease.
Autores: Perez-Simon, J. A.; Afram, G.; Martino, R.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 97  Nº 8  2012  págs. 1187 - 1195
Background: Chronic graft-versus-host disease (cGVHD) is a major complication after allogeneic stem cell transplantation with an adverse effect on both mortality and morbidity. In 2005, the National Institute of Health proposed new criteria for diagnosis and classification of chronic graft-versus-host disease for clinical trials. New sub-categories were recognized such as late onset acute graft-versus-host disease and overlap syndrome. Design and methods: We evaluated the prognostic impact of the new sub-categories as well as the clinical scoring system proposed by the National Institute of Health in a retrospective, multicenter study of 820 patients undergoing allogeneic stem cell transplantation between 2000 and 2006 at 3 different institutions. Patients were retrospectively categorized according to the National Institute of Health criteria from patients' medical histories. Results: As far as the new sub-categories are concerned, in univariate analysis diagnosis of overlap syndrome adversely affected the outcome. Also, the number of organs involved for a cut-off value of 4 significantly influenced both cGVHD related mortality and survival. In multivariate analysis, in addition to NIH score, platelet count and performance score at the time of cGVHD diagnosis, plus gut involvement, significantly influenced outcome. These 3 variables allowed us to develop a simple score system which identifies 4 subgroups of patients with 84%, 64%, 43% and 0% overall survival at five years after cGVHD diagnosis (score 0: HR=15.96 (95% CI: 6.85-37.17), P<0.001; score 1: HR=5.47 (95% CI: 2.6-11.5), P<0.001; score 2: HR=2.8 (95% CI: 1.32-5.93), P=0.007). Conclusions: In summary, we have identified a powerful and simple tool to discriminate different subgroups of patients in terms of chronic graft-versus-host disease related mortality and survival.
Autores: Caballero-Velazquez, T.; Sanchez-Abarca, L. I.; Gutierrez-Cosio, S.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 1592-8721  Vol. 97  Nº 9  2012  págs. 1329 - 1337
Background: We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. Design and methods: We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. Results: The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN ¿, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. Conclusions: The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.
Autores: Puig, N.; Sarasquete, M. E.; Alcoceba, M.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 89  Nº 4  2012  págs. 328 - 335
Background and Objectives Minimal residual disease (MRD) assessment by PCR in multiple myeloma (MM) has several shortcomings, including the lack of a suitable target. Kappa deleting element (KDE) rearrangements occur in virtually all Ig-lambda B-cell malignancies and in 1/3 of Ig-kappa are not affected by somatic hypermutation and, as in ALL, could be used as PCR targets. Methods We have first investigated the incidence, gene segment usage, and CDR3 composition of IGK-KDE rearrangements in 96 untreated myeloma patients. Second, we tested 16 KDE gene rearrangements as molecular targets for MRD assessment by RQ-PCR using a germline reverse primer and a germline Taqman probe in combination with allele-specific oligonucleotides (ASO) as forward primers. Results Monoclonal KDE rearrangements were amplified in 45% (43/96) of cases, monoallelic in 2/3 of them (29 cases), and biallellic in the remaining 14 cases. Overall, 88% of cases were successfully sequenced, KDE being equally frequently rearranged with VK and with intron-Recombination signal sequence (RSS). Median numbers of inserted and deleted nucleotides in the junctional region were one and five, respectively. Conclusions Using KDE rearrangements as additional PCR target for MRD assessment in MM improves the applicability of these studies in 9% of cases overall and in 20% of lambda cases. Its use in the latter subset could represent a significant advance.
Autores: Porras, S. R.; Guijo, A. R.; Lopez, A. M.; et al.
Revista: BONE MARROW TRANSPLANTATION
ISSN 0268-3369  Vol. 47  Nº Supl. 1  2012  págs. S139 - S140
Autores: Palumbo, A. , (Autor de correspondencia); Mateos, M. V.; Bringhen, S. ; et al.
Revista: BLOOD REVIEWS
ISSN 0268-960X  Vol. 25  Nº 4  2011  págs. 181 - 191
The current standard of care for elderly patients with newly diagnosed multiple myeloma is melphalan and prednisone (MP) in combination with either bortezomib (VMP) or thalidomide (MPT), with lenalidomide plus dexamethasone increasingly being employed. The addition of bortezomib or thalidomide to the established MP regimen significantly improves outcomes and prolongs survival in elderly and transplant-ineligible patients. However, these benefits are accompanied by increases in treatment-related adverse events (AEs), which may be particularly pronounced in older individuals. Patients receiving bortezomib as part of a VMP regimen commonly experience transient and cyclical thrombocytopenia and neutropenia, along with gastrointestinal AEs. Fortunately, these AEs can be managed with appropriate supportive care and, when necessary, adjustments in dose. Peripheral neuropathy (PN) is the most important side effect of bortezomib, and although it is reversible in a high proportion of patients, it affects their quality of life. Furthermore, PN can require temporary or permanent withholding of bortezomib, which will reduce treatment efficacy. PN is also a common adverse effect of thalidomide; thromboembolic events are also a key concern, requiring thromboprophylaxis in patients receiving thalidomide in combination. For lenalidomide in combination with dexamethasone, the most clinically important adverse effects are hematologic toxicity (particularly neutropenia) and thromboembolic events. Recent phase III studies in newly diagnosed elderly patients are providing further insight into the most appropriate treatment regimens to maximize outcomes and minimize toxicity in individual patients. Of note, once-weekly bortezomib dosing (in combination with MP±T) was shown to reduce the incidence of peripheral neuropathy and gastrointestinal events compared with twice-weekly dosing, while maintaining efficacy. Elderly patients may be less able to withstand the AEs associated with newer treatment regimens and combinations of multiple drugs, and may experience greater declines in quality of life and, subsequently, reduced treatment adherence. It is therefore critical that these patients are closely monitored and any emergent AEs promptly and appropriately managed. For very elderly, frail patients, tailored therapy, reduced intensity regimens, and adverse event management are necessary to encourage treatment adherence and reduce discontinuation. This article will provide practical guidance on the management of bortezomib-, thalidomide-, and lenalidomide-associated AEs, to maximize treatment feasibility and active drug delivered, and thus help minimize toxicity and maximize outcomes.
Autores: van de Donk, N. W. C. J., (Autor de correspondencia); Lokhorst, H. M.; Dimopoulos, M.; et al.
Revista: CANCER TREATMENT REVIEWS
ISSN 0305-7372  Vol. 37  Nº 4  2011  págs. 266 - 283
The introduction of the Immunomodulatory drugs (IMiDs) and proteasome inhibitors, used either as a single-agent or combined with classic anti-myeloma therapies, has improved the outcome for patients with relapsed myeloma. However, there is currently no generally accepted standard treatment for relapsed/refractory myeloma patients, partly because of the absence of trials comparing the efficacy of the novel agents in relapsed/refractory myeloma. Choice of a new treatment regimen depends on both patient and disease-specific characteristics. A lenalidomide-based regimen is the first choice in patients with neuropathy, while bortezomib has the highest efficacy in patients with renal insufficiency and is not associated with increased risk of thromboembolism. A second autologous stem cell transplantation (auto-SCT) can be applied in patients with a progression-free period of >= 18-24 months after the first auto-SCT. In high-risk relapse such as occurring early after auto-SCT consolidation with allogeneic SCT can be considered. In this review we provide an overview of the various salvage regimens and give recommendations for treatment of patients with relapsed/refractory myeloma in different clinical settings.
Autores: Dimopoulos, M. A. , (Autor de correspondencia); Palumbo, A.; Attal, M. ; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 25  Nº 5  2011  págs. 749 - 760
An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelo-suppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma. Leukemia (2011) 25, 749-760; doi: 10.1038/leu.2011.3; published online 4 February 2011
Autores: Ludwig, H.; Beksac, M.; Bladè, J.; et al.
Revista: ONCOLOGIST
ISSN 1083-7159  Vol. 16  Nº 4  2011  págs. 388 - 403
The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.
Autores: Dimopoulos, M. A., (Autor de correspondencia); San Miguel Izquierdo, Jesús; Anderson, K. C.;
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 86  Nº 1  2011  págs. 1 - 15
Encouraging progress has been made in the treatment of patients with relapsed/refractory multiple myeloma (MM). The rapidly evolving understanding of key pathways responsible for tumor growth and survival has led to the development of novel agents (including immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and other targeted agents) with the potential to provide significant improvements in response and survival, and influence treatment guidelines. This review summarizes recent advances in understanding of the biology of relapsed/refractory MM and clinical trials with novel targeted agents that are currently under investigation for patients with this disease.
Autores: Mitsiades, C. S. , (Autor de correspondencia); Davies, F. E.; Laubach, J. P.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 29  Nº 14  2011  págs. 1916 - 1923
Despite tangible progress in recent years, substantial therapeutic challenges remain in multiple myeloma (MM), particularly for patients at high risk for early relapse or death and for those with advanced multi-drug resistant disease and refractoriness to currently available combination regimens. Addressing these challenges requires identification of novel classes of anti-MM agents, their incorporation into safe and more effective combination regimens, and development of efficient algorithms to select the most appropriate therapeutic options for the clinical and molecular features of individual patients at a given time during their disease. Ideally, these goals can be facilitated by preclinical identification of the "driver" molecular lesions on which different myeloma subtypes exquisitely depend, and by informative preclinical models simulating the clinical setting(s) in which trials will be conducted. Large prospective studies of patients treated uniformly with contemporary clinical regimens are essential, but there is also a major need for flexibility in studying new regimens in the future. Long-term patient follow-up and integrated annotation of clinical (safety and efficacy) and correlative (molecular, biochemical, etc) data are also critical. Novel molecular profiling techniques will likely identify more clinically and biologically discrete subsets of patients with recurrent, even if infrequent, lesions. This molecular heterogeneity, combined with the increasing numbers of candidate therapeutic targets and respective investigational agents, may pose formidable challenges for the development and implementation of personalized medicine in MM. This review discusses these challenges, as well as potential strategies to address them, with the aim of making significant improvement in the clinical outcome of patients with MM.
Autores: Palumbo, A., (Autor de correspondencia); Bringhen, S. ; Ludwig, H.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 118  Nº 17  2011  págs. 4519 - 4529
Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients with MM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age > 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Mateos, M. V.;
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 96  Nº 9  2011  págs. 1246 - 1248
Autores: San Miguel Izquierdo, Jesús; Dimopoulos, M. A.; Stadtmauer, E. A.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
ISSN 2152-2669  Vol. 11  Nº 1  2011  págs. 38 - 43
Background: In two randomized phase III trials (MM-009 and MM-010), lenalidomide plus dexamethasone significantly prolonged time to progression and overall survival (OS) in patients with relapsed/refractory multiple myeloma compared with dexamethasone alone. In both trials the treatment was continued until disease progression or unacceptable toxicity. We conducted a subanalysis to determine if continuing therapy after achieving partial response (PR) improved survival. Patients and Methods: Data were collected on 212 patients who were treated with lenalidomide plus dexamethasone and achieved >= PR. Kaplan-Meier survival estimates were compared between patients on continued treatment versus patients discontinuing therapy because of adverse events, withdrawal of consent, or other reasons. Time-dependent multivariate regression analyses were used to determine the benefit of continuing treatment with lenalidomide. Results: A total of 174 patients received continued treatment until disease progression or death, and 38 patients discontinued therapy without progression. There was a trend toward longer median OS in patients who continued therapy (50.9 months vs. 35.0 months; P = .0594). When controlling for the number of previous antimyeloma therapies, beta(2)-microglobulin levels, and Dune-Salmon stage (which adversely affected survival in these patients), continued lenalidomide treatment (HR, 0.137; 95% CI, 0.045-0.417; P = .0005) or each additional cycle of lenalidomide (HR, 0.921; 95% CI, 0.886-0.957; P < .0001) were both associated with longer survival. Conclusion: Continued lenalidomide treatment until disease progression after achievement of PR is associated with a significant survival advantage when controlling for patient characteristics. These findings should be confirmed in a prospectively designed trial.
Autores: Lopez-Corral, L.; Gutierrez, N. C.; Vidriales, M. B.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1557-3265  Vol. 17  Nº 7  2011  págs. 1692 - 1700
Purpose: Genetic aberrations detected in multiple myeloma (MM) have also been reported in the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Our aim was to investigate in depth the level of clonal heterogeneity of recurrent genetic abnormalities in these conditions. Experimental design: Immunoglobulin heavy chain (IGH) translocations, 13q14 and 17p13 deletions, and 1q21 gains using FISH were evaluated in 90 MGUS, 102 high-risk SMM, and 373 MM. To this end, we not only purified plasma cells (PC) for the FISH analysis (purity > 90%), but subsequently, we examined the correlation between the proportion of PC with cytogenetic changes and the number of clonal PC present in the same sample, as measured by multiparametric flow cytometry. Results: We observed a significant difference between the proportion of clonal PC with specific genetic abnormalities in MGUS compared with SMM and in SMM compared with MM. Thus, the median proportion of PC with IGH translocations globally considered, t(11;14) and 13q deletions was significantly lower in MGUS than in SMM, and in SMM than in MM [IGH translocations: 34% vs. 57% vs. 76%; t(11;14): 38% vs. 61% vs. 81%; and 13q deletion: 37% vs. 61% vs. 74% in MGUS, SMM, and MM, respectively]. For t(4;14), the difference was significant in the comparison between MGUS/SMM and MM and for 1q between MGUS and SMM/MM. Conclusions: This study demonstrates that the progression from MGUS to SMM, and eventually to MM, involves a clonal expansion of genetically abnormal PC.
Autores: Rajkumar, S. V.; Harousseau, J. L.; Durie, B.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 117  Nº 18  2011  págs. 4691 - 4695
It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript.
Autores: Puente, X. S.; Pinyol, M.; Quesada, V.; et al.
Revista: NATURE
ISSN 0028-0836  Vol. 475  Nº 7354  2011  págs. 101 - 105
Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.
Autores: Alcoceba, M.; Marin, L.; Balanzategui, A.; et al.
Revista: TISSUE ANTIGENS
ISSN 1399-0039  Vol. 78  Nº 4  2011  págs. 249 - 255
The frequencies of human leukocyte antigen (HLA) class I and class II specificities and haplotypic associations were determined in 1940 unrelated donors from Castilla y León and compared with other Iberian, Mediterranean and European populations. Specificities were determined using polymerase chain reaction reverse sequence-specific oligonucleotide or polymerase chain reaction sequence-specific primer techniques. In the analysis, 19, 29 and 13 specificities were found for HLA-A, -B and -DRB1, respectively, with HLA-A*02 (26%), -A*01 (11%), -B*44 (16%), -B*35 (10%), -DRB1*07 (16%) and -DRB1*13 (14%) showing the highest frequencies. In addition, 10 common HLA-A-B-DRB1 haplotypic associations were observed, A*01-B*08-DRB1*03 (3%) and A*29-B*44-DRB1*07 (3%) being the most frequent ones. These findings indicate that the population of Castilla y León is genetically equidistant from the Portuguese and other Spanish populations and shares a common origin with other Iberian populations, in which European, Mediterranean and North African genetic components are present; this is in agreement with the historical and genetic background of the population. These data contribute to a better understanding of the genetic structure of the Iberian Peninsula and provide a healthy control population from our region that should be useful for the study of disease associations.
Autores: Mateos, M. V.; Gutierrez, N. C.; Martin-Ramos, M. L.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 118  Nº 17  2011  págs. 4547 - 4553
Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.
Autores: Schmidt-Hieber, M.; Perez-Andres, M.; Paiva, Bruno; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 1592-8721  Vol. 96  Nº 2  2011  págs. 328 - 332
Aberrant CD117 expression is associated with a favorable outcome in multiple myeloma. We analyzed 106 patients with symptomatic multiple myeloma (n=50), smoldering multiple myeloma (n=38) and monoclonal gammopathy of undetermined significance (n=18) to elucidate biological features of CD117(+) versus CD117(-) monoclonal garnmopathies. CD117(+) (mono)clonal plasma cells were detected in 30% symptomatic multiple myeloma, 45% smoldering multiple myeloma and 72% monoclonal garnmopathy of undetermined significance patients. CD117 expression was associated with higher percentages of normal bone marrow plasma cells, CD117(+) myeloid precursors and CD38(+) B lymphocytes in all monoclonal gammopathies. Conversely, the number of bone marrow CD34(+) myeloid cells and peripheral blood neutrophils was reduced among CD117 multiple myeloma but not monoclonal gammopathy of undetermined significance patients. CD117 expression by (mono)clonal plasma cells is associated with uniquely altered patterns of production of hematopoietic bone marrow cells with decreased peripheral blood neutrophil counts and persistence of normal residual bone marrow plasma cells.
Autores: Colado, E.; Paino, T.; Maiso, P.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 1592-8721  Vol. 96  Nº 5  2011  págs. 687 - 695
Background: Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid of marine origin. Design and methods: The activity of zalypsis was studied in four acute myeloid leukemia cell lines and in freshly isolated blasts taken from patients with acute myeloid leukemia before they started therapy. Zalypsis-induced apoptosis of both malignant and normal cells was measured using flow cytometry techniques. Gene expression profiling and western blot studies were performed to assess the mechanism of action of the alkaloid. Results: Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells. Zalypsis-induced apoptosis was the result of an important deregulation of genes involved in the recognition of double-strand DNA breaks, such as Fanconi anemia genes and BRCA1, but also genes implicated in the repair of double-strand DNA breaks, such as RAD51 and RAD54. These gene findings were confirmed by an increase in several proteins involved in the pathway (pCHK1, pCHK2 and pH2AX). Conclusions: The potent and selective antileukemic effect of zalypsis on DNA damage response mechanisms observed in acute myeloid leukemia cell lines and in patients' samples provides the rationale for the investigation of this compound in clinical trials.
Autores: Munshi, N. C.; Anderson, K. C.; Bergsagel, P. L.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 117  Nº 18  2011  págs. 4696 - 4700
A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum ß(2)-microglobulin level and International Staging System stages II and III, incorporating high ß(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.
Autores: Martínez-López, J.; Bladè, J.; Mateos, M. V.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 118  Nº 3  2011  págs. 529 - 534
For establishing the true effect of different response categories in patients with multiple myeloma (MM) treated with autologous stem cell transplantation, we evaluated, after a median follow-up of 153 months, 344 patients with MM who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10(-5)); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR+VGPR+PR group are alive at 17 years; 2 cases had relapsed in the nCR+VGPR+PR group. In conclusion, MM achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.
Autores: Diaz-Rodriguez, E.; Alvarez-Fernandez, S.; Chen, X.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 6  Nº 11  2011  págs. e27583
Multiple myeloma (MM) is a hematological disease characterized by an abnormal accumulation of plasma cells in the bone marrow. These cells have frequent cytogenetic abnormalities including translocations of the immunoglobulin heavy chain gene and chromosomal gains and losses. In fact, a singular characteristic differentiating MM from other hematological malignancies is the presence of a high degree of aneuploidies. As chromosomal abnormalities can be generated by alterations in the spindle assembly checkpoint (SAC), the functionality of such checkpoint was tested in MM. When SAC components were analyzed in MM cell lines, the RNA levels of most of them were conserved. Nevertheless, the protein content of some key constituents was very low in several cell lines, as was the case of MAD2 or CDC20 in RPMI-8226 or RPMI-LR5 cells. The recovery of their cellular content did not substantially affect cell growth, but improved their ability to segregate chromosomes. Finally, SAC functionality was tested by challenging cells with agents disrupting microtubule dynamics. Most of the cell lines analyzed exhibited functional defects in this checkpoint. Based on the data obtained, alterations both in SAC components and their functionality have been detected in MM, pointing to this pathway as a potential target in MM treatment.
Autores: Dimopoulos, M. A.; Mateos, M. V.; Richardson, P. G.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 86  Nº 1  2011  págs. 23 - 31
Objectives: This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib-associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high-dose therapy who received bortezomib plus melphalan-prednisone. Methods: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, and days 1, 8, 22, 29, cycles 5-9; melphalan 9 mg/m(2), days 1-4, cycles 1-9; and prednisone 60 mg/m(2), days 1-4, cycles 1-9). Results: Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ¿ 3 (<1% grade 4). The PN incidence was dose-related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m(2). Median time to PN onset was 2.3 months. Bortezomib-associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non-responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P=0.0065], grade ¿ 2 PN (HR 2.205, P=0.0032), and grade ¿ 3 PN (HR 2.438, P=0.023); age, pre-existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN. Conclusions: Rates of bortezomib-induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases. Trial registration: ClinicalTrials.gov NCT00111319.
Autores: Richardson, P.; Schlag, R.; Khuageva, N.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 1365-2141  Vol. 153  Nº 2  2011  págs. 212 - 221
P>Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis-stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade (R) as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n = 344) versus MP (n = 338) in previously untreated MM patients ineligible for high-dose therapy, and evaluates the impact of ESA use or red-blood-cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time-to progression (TTP) was similar between ESA/non-ESA [hazard ratio: 1 center dot 03 (95% confidence interval 0 center dot 76-1 center dot 39); P = 0 center dot 8478] in both arms (VMP: 19 center dot 9/not reached; MP: 15 center dot 0/17 center dot 5 months). Three-year overall survival (OS) rates were similar between ESA/non-ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (P < 0 center dot 0001) versus non-RBC-transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival.
Autores: Dimopoulos, M.; Kyle, R.; Fermand, J. P.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 117  Nº 18  2011  págs. 4701 - 4705
A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum ß(2)-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.
Autores: Paiva, Bruno; Vidriales, M. B.; Perez, J. J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 117  Nº 13  2011  págs. 3613 - 3616
The clinical value of multiparameter flow cytometry (MFC) immunophenotyping in primary or light chain amyloidosis (AL) remains unknown. We studied 44 consecutive bone marrow samples from newly diagnosed patients with amyloidosis; 35 patients with AL and 9 with other forms of amyloidosis. Monoclonal plasma cells (PCs) were identifiable by MFC immunophenotyping in 34 of 35 (97%) patients with AL, whereas it was absent from all but 1 of the 9 (11%) patients with other forms of amyloidosis. Quantification of bone marrow plasma cells (BMPCs) by MFC immunophenotyping was a significant prognostic factor for overall survival (OS) (¿ 1% vs > 1% BMPC cutoff; 2-year OS rates of 90% vs 44%, P = .02). Moreover, detecting persistent normal PCs at diagnosis identifies a subgroup of patients with AL with prolonged OS (> 5% vs ¿ 5% normal PC within all BMPC cutoff, 2-year rates of 88% vs 37%, P = .01). MFC immunophenotyping could be clinically useful for the demonstration of PC clonality in AL and for the prognostication of patients with AL.
Autores: Paiva, Bruno; Perez-Andres, M.; Vidriales, M. B.; et al.
Revista: LEUKEMIA
ISSN 1476-5551  Vol. 25  Nº 4  2011  págs. 697 - 706
Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34(+) hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged >60 years. Our results show that BM and peripheral blood (PB) clonal PC progressively increase from MGUS to MM, the latter showing a slightly more immature immunophenotype. Of note, such increased number of clonal PC is associated with progressive depletion of normal PC, B-cell precursors and CD34(+) HSC in the BM, also with a parallel increase in PB. In an ex vivo model, normal PC, B-cell precursors and CD34(+) HSC from MGUS and SMM, but not MM patients, were able to abrogate the migration of clonal PC into serial concentrations of SDF-1. Overall, our results show that progressive competition and replacement of normal BM cells by clonal PC is associated with more advanced disease in patients with MGUS, SMM and MM.
Autores: Garcia-Sanz, R. , (Autor de correspondencia); Ocio, E. M.; del Carpio, D.; et al.
Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
ISSN 2152-2650  Vol. 11  Nº 1  2011  págs. 168 - 171
To assess the value of bone marrow (BM) assessment by flow cytometry FCM after therapy in the clinical outcome of WM patients, we analyzed 42 WM patients who were evaluated before and after therapy. Patients were studied with a panel that always included the CD 19, CD22, CD25, and kappa/lambda light chain immunoglobulin monoclonal antibodies. The mean of abnormal B-cells in the pre-therapeutic BM was 17.8% +/- 12.1%, which decreased was after therapy to 5.4% +/- 0.7% (P = .049). A linear correlation was seen between the better quality of response and the reduction in the tumor B-lymphocyte counts at the BM, since the ratio of abnormal B cells between pre and posttherapy BM was 1172.17, 221.64, 3.37, 1.03, and 0.56 for responses complete, partial, minor, stable disease and progression, respectively (P < .001). Intensive and rituximab-containing therapies correlated with deeper tumor cell reductions. Finally, the B-cell decrease correlated with the better overall and progression-free survival.
Autores: Lorenzo Perez, R.; Perez-Simon, J. A.; Caballero-Velazquez, T.; et al.
Revista: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
ISSN 1083-8791  Vol. 17  Nº 2  2011  págs. 270 - 273
Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality among patients undergoing allogeneic hematopoietic stem cell transplantation. Although animal models have been clearly established for the study of skin, liver, and gut, currently there is no equivalent experiemental model for analyzing ocular involvement, which is rather common, especially among patients diagnosed with chronic GVHD. In the current study we have developed a murine model of ocular GVHD and, for the first time, we describe the histopathologic features involving cornea and limbus, which could play a role in the physiopathology of the disease at the ocular level. Our results represent a major finding that allows us to define a model for evaluating new therapeutic strategies for treating ocular GVHD prior to their use in clinical setting.
Autores: Carrancio, S.; Blanco, B.; Romo, C.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 6  Nº 10  2011  págs. e26241
The aim of the present study was to determine how mesenchymal stem cells (MSC) could improve bone marrow (BM) stroma function after damage, both in vitro and in vivo. Human MSC from 20 healthy donors were isolated and expanded. Mobilized selected CD34(+) progenitor cells were obtained from 20 HSCT donors. For in vitro study, long-term bone marrow cultures (LTBMC) were performed using a etoposide damaged stromal model to test MSC effect in stromal confluence, capability of MSC to lodge in stromal layer as well as some molecules (SDF1, osteopontin,) involved in hematopoietic niche maintenance were analyzed. For the in vivo model, 64 NOD/SCID recipients were transplanted with CD34(+) cells administered either by intravenous (IV) or intrabone (IB) route, with or without BM derived MSC. MSC lodgement within the BM niche was assessed by FISH analysis and the expression of SDF1 and osteopontin by immunohistochemistry. In vivo study showed that when the stromal damage was severe, TP-MSC could lodge in the etoposide-treated BM stroma, as shown by FISH analysis. Osteopontin and SDF1 were differently expressed in damaged stroma and their expression restored after TP-MSC addition. Human in vivo MSC lodgement was observed within BM niche by FISH, but MSC only were detected and not in the contralateral femurs. Human MSC were located around blood vessels in the subendoestal region of femurs and expressed SDF1 and osteopontin. In summary, our data show that MSC can restore BM stromal function and also engraft when a higher stromal damage was done. Interestingly, MSC were detected locally where they were administered but not in the contralateral femur.
Autores: Sarasquete, M. E.; Gutierrez, N. C.; Misiewicz-Krzeminska, I.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 1592-8721  Vol. 96  Nº 3  2011  págs. 468 - 471
Dicer and Drosha are key enzymes in the miRNA-processing pathway which is altered in many human cancers. We analyzed Dicer and Drosha expression levels by quantitative PCR in 151 patients with monoclonal gammopathies: 102 symptomatic myeloma patients, 23 smoldering myelomas and 26 monoclonal gammopathy of undetermined significance. We found that Dicer expression values were significantly higher in monoclonal gammopathy of undetermined significance than in smoldering myelomas and symptomatic myeloma (mean ± SD, 0.84 ± 0.36 vs. 0.60 ± 0.23 and 0.62 ± 0.51; P<0.01). Moreover, the median progression-free survival was significantly longer in symptomatic myeloma patients with high expression of Dicer (not reached vs. 23.6 months; P=0.02). By contrast, no differences in the expression of Drosha among these groups of patients were observed. Our data suggest that Dicer expression may play an important role in the progression and prognosis of monoclonal gammopathies.
Autores: Delforge, M.; Terpos, E.; Richardson, P. G.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 1600-0609  Vol. 86  Nº 5  2011  págs. 372 - 384
Objectives: Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. Methods: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338). Results: Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P¿0.0001) and CR/PR (P¿0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. Conclusions: These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.
Autores: Cavo, M.; Rajkumar, S. V.; Palumbo, A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 117  Nº 23  2011  págs. 6063 - 6073
The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.
Autores: Bladè, J.; Sonneveld, P.; San Miguel Izquierdo, Jesús; et al.
Revista: CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
ISSN 2152-2669  Vol. 11  Nº 1  2011  págs. 44 - 49
Introduction: Bortezomib with pegylated liposomal doxorubicin (PLD) is superior to bortezomib alone in the relapsed and/or refractory setting, based on the results of a randomized, parallel-group, open-label, multicenter phase III study. To identify patients who might most benefit from this new standard of care, we performed retrospective analyses evaluating the effects of clinically defined, high-risk features on the outcomes with this regimen. Patients and methods: Patients received either bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every-21-day cycle with PLD 30 mg/m2 on day 4 (n=324) or bortezomib alone (n=322). Four high- and low-risk subgroup categories were identified, including age¿65, ¿2 previous therapies, International Staging System stage II/III, and disease refractory to last previous therapy. Results: Compared with bortezomib alone, PLD plus bortezomib significantly prolonged the time to progression and duration of response in all of these subgroups. PLD plus bortezomib was well tolerated in all subgroups, and had a safety profile that was not affected by response to previous therapy. Conclusion: Treatment of relapsed/refractory myeloma with the combination of PLD plus bortezomib provides better outcomes over bortezomib alone, even in the presence of high-risk prognostic factors. These results suggest that PLD plus bortezomib may represent an additional standard of care for this population of patients with multiple myeloma.
Autores: Paiva, Bruno; Martínez-López, J.; Vidriales, M. B.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 29  Nº 12  2011  págs. 1627 - 1633
Purpose: To investigate the impact of immunophenotypic response (IR) versus complete response (CR) and CR plus normal serum free light chain (sFLC) ratio (stringent CR) in elderly patients with multiple myeloma (MM) treated with novel agents. Patients and methods: From a total of 260 elderly patients newly diagnosed with MM included in the GEM05>65y trial, 102 patients achieving at least a partial response with ¿ 70% reduction in M-component after the six planned induction cycles were simultaneously analyzed by immunofixation, sFLC, and multiparameter flow cytometry (MFC) immunophenotyping; this population is the focus of this study. Results: Forty-three percent of patients achieved CR, 30% achieved stringent CR, and 30% achieved IR. Patients in stringent CR showed no significant survival advantage compared with those in CR, whereas patients in IR showed significantly increased progression-free survival (PFS) and time to progression (TTP) compared with those in stringent CR or CR; this was confirmed by multivariate analysis (hazard ratio, 4.1; P = .01 for PFS). Discrepancies between the three techniques were relatively common. Notably, in all seven patients achieving IR but remaining immunofixation positive, the M-component disappeared in follow-up analysis. In contrast, MFC-positive patients who were immunofixation negative (n = 20) showed a tendency toward early reappearance of the M-component (median, 3 months). Similarly, in five of 11 stringent CR but MFC-positive patients, symptomatic disease progression was recorded at a median of 13 months after induction. Conclusion: Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM.
Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús
Revista: CURRENT HEMATOLOGIC MALIGNANCY REPORTS
ISSN 1558-8211  Vol. 6  Nº 2  2011  págs. 113 - 119
Melphalan plus prednisone (MP) has long been considered the gold-standard treatment for elderly patients with newly diagnosed myeloma, and it still forms the backbone for combinations based on novel agents. MP plus thalidomide (MPT), bortezomib (VMP), or lenalidomide (MPR), as induction plus maintenance, have proved to be superior to MP and are currently the treatment of choice for this population. Low-dose dexamethasone in combination with thalidomide and cyclophosphamide (CTDa) or with lenalidomide can be an alternative option for these patients. The benefit of these novel agents in terms of prolonged survival is accompanied by increases in treatment-related adverse events, however, which may be particularly pronounced in older individuals. In managing these patients, efficacy and toxicity should be balanced, and thus prophylactic measures to avoid adverse effects are mandatory. Moreover, reduced-intensity regimens are recommended for fragile or very elderly patients. Finally, the wide array of new treatment options will facilitate individualized treatment approaches, based on characteristics of the disease, patient comorbidities, and personal and social circumstances.
Autores: Gonzalez-Lopez, T. J.; Vazquez, L.; Flores, T.; et al.
Revista: CLINICS AND PRACTICE
ISSN 2039-7275  Vol. 1  Nº 4  2011  págs. e95
A 63-year-old woman presented with progressive renal insufficiency, until a glomerular filtration rate (GFR) of 12 mL/min. A renal biopsy demonstrated glomerular deposition of immunoglobulin ¿light chain. The presence of a small population of monoclonal plasmacytes producing an only light ¿monoclonal component was demonstrated and Bortezomib and Dexamethasone (BD) was provided as initial therapy. After seven courses of therapy, renal function improved without dialysis requirements up to a GFR 31 mL/min. Under hematological complete response (HCR) the patient underwent high dose of melphalan (HDM) and autologous peripheral blood stem cell transplant. Fifty-four months later the patient remains in HCR and the GFR has progressively improved up to 48 mL/min. This report describes a notably renal function improvement in a patient with Light Chain Deposition Disease after therapy with BD followed by HDM, which can support this treatment as a future option for these patients.
Autores: Silva, F., (Autor de correspondencia); Perez-Simon, J. A.; Caballero-Velazquez, T. ; et al.
Revista: BONE MARROW TRANSPLANTATION
ISSN 0268-3369  Vol. 46  Nº 10  2011  págs. 1395 - 1397
Autores: Lokhorst, H.; Einsele, H. ; Vesole, D.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 29  Nº 16  2011  págs. E484
Autores: Paiva, B.; Mateos, M. V. ; Lopez-Corral, L.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 118  Nº 21  2011  págs. 1686
Autores: Delforge, M., (Autor de correspondencia); Blade, J.; Dimopoulos, M. A. ; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 11  Nº 11  2010  págs. 1086 - 1095
Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.
Autores: Ludwig, H.; Beksac, M. ; Blade, J.; et al.
Revista: ONCOLOGIST
ISSN 1083-7159  Vol. 15  Nº 1  2010  págs. 6 - 25
The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.
Autores: Kyle, R. A., (Autor de correspondencia); Durie, B. G. M.; Rajkumar, S. V.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 24  Nº 6  2010  págs. 1121 - 1127
Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein < 15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months. Leukemia (2010) 24, 1121-1127; doi:10.1038/leu.2010.60; published online 22 April 2010
Autores: Lokhorst, H., (Autor de correspondencia); Einsele, H. ; Vesole, D.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 28  Nº 29  2010  págs. 4521 - 4530
Purpose To define consensus statement regarding allogeneic stem-cell transplantation (Allo-SCT) as a treatment option for multiple myeloma (MM) on behalf of International Myeloma Working Group. Patients and Methods In this review, results from prospective and retrospective studies of Allo-SCT in MM are summarized. Results Although the introduction of reduced-intensity conditioning (RIC) has lowered the high treatment-related mortality associated with myeloablative conditioning, convincing evidence is lacking that Allo-RIC improves the survival compared with autologous stem-cell transplantation. Conclusion New strategies are necessary to make Allo-SCT safer and more effective for patients with MM. Until this is achieved, Allo-RIC in myeloma should only be recommended in the context of clinical trials.
Autores: Dimopoulos, M. A., (Autor de correspondencia); Terpos, E.; Chanan-Khan, A. ; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 28  Nº 33  2010  págs. 4976 - 4984
Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease. J Clin Oncol 28:4976-4984. (C) 2010 by American Society of Clinical Oncology
Autores: Lopez-Corral, L., (Autor de correspondencia); Garcia-Sanz, R.; San Miguel Izquierdo, Jesús
Revista: MEDICINA CLINICA
ISSN 0025-7753  Vol. 135  Nº 8  2010  págs. 368 - 374
The identification and quantification of the monoclonal immunoglobulin in Plasma Cell Disorders (PCD) is based on electrophoresis, immunofixation (IFE) and on immunoglobulins nephelometric measurement. Even though the combination of these techniques is highly sensitive, there are two entities which pose a diagnostic challenge: Non-secretory Multiple Myeloma (MM) and Amyloidosis (AL) patients. Furthermore, when it comes to the results, these techniques have a degree of subjective interpretation and the IFE does not provide quantitative results. Within these limitations a new assay capable of quantifying free light chains (FLC) in serum has been developed. This is a great improvement in PCD and its major indication is the diagnosis and monitoring of patients with AL and non-secretory MM. In addition, its use has been recommended in the screening of all gammopathies; in the prognostic evaluation of MM and other PCD; and the definition of the stringent complete response for patients who achieve a complete remission (CR) with negative IFE and a normalized FLC ratio.
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia)
Revista: BLOOD REVIEWS
ISSN 0268-960X  Vol. 24  Nº Supl. 1  2010  págs. S33 - S34
Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia)
Revista: BLOOD REVIEWS
ISSN 0268-960X  Vol. 24  Nº Supl. 1  2010  págs. S1 - S3
Autores: Garcia-Sanz, R.; Gonzalez-Lopez, T. J.; Vazquez, L.; et al.
Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441  Vol. 84  Nº 3  2010  págs. 266 - 270
Few diseases have a prognosis worse than Hodgkin's lymphoma (HL), patients relapsing after autologous or allogeneic stem cell transplantation. Here, we report two highly refractory patients with HL who successfully responded to a combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex). Despite the use of a very large number of different drugs (>5 different schemes) including high-dose therapy and autologous and allogeneic stem cell transplantation, both patients proved to be suffering from a highly resistant disease. Fortunately, they finally responded to the ThaCyDex combination, achieving sustained complete remission that would support the running of a trial within this setting.
Autores: Mateos, M. V.; Oriol, A.; Martínez-López, J.; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 11  Nº 10  2010  págs. 934 - 941
Background: Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects. Methods: Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m² on days 1-4) or daily thalidomide (100 mg), and prednisone (60 mg/m² on days 1-4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m² on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m² on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235. Findings: In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 [31%] vs 20 [15%], p=0·01) and discontinuations (22 [17%] vs 15 [12%], p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine [7%] vs 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy. Interpretation: Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma.
Autores: Harousseau, J. L.; Palumbo, A.; Richardson, P. G.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 116  Nº 19  2010  págs. 3743 - 3750
The phase 3 Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study in newly diagnosed multiple myeloma patients ineligible for high-dose therapy demonstrated that bortezomib-melphalan-prednisone (VMP) was superior to melphalan-prednisone across all efficacy end points. We assessed the prognostic impact of response on time-to-event parameters in the intent-to-treat population. Patients received nine 6-week cycles of treatment. Time to progression, time to next therapy, and treatment-free interval were associated with quality of response. When European Group for Blood and Marrow Transplantation criteria were used, complete response (CR) was associated with significantly longer time to progression (hazard ratio [HR] = 0.45, P = .004), time to next therapy (HR = 0.46, P = .0004), and treatment-free interval (HR = 0.38, P < .0001) versus partial response, but there was no significant difference in overall survival (HR = 0.87, P = .54); similar differences were seen with CR versus very good partial response by uniform criteria. Quality of response improved with prolonged VMP treatment, with 28% of CRs achieved during cycles 5-9. CR duration appeared similar among patients with "early" (cycles 1-4) and "late" CRs (cycles 5-9) and among patients receiving 9 versus < 9 cycles of bortezomib within VMP. These results highlight that CR is an important treatment goal and support prolonged VMP therapy to achieve maximal response. This study is registered at http://www.clinicaltrials.gov as NCT00111319.
Autores: Mateos, M. V. ; Cibeira, M. T.; Richardson, P. G.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 16  Nº 12  2010  págs. 3260 - 3269
Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma. Experimental design: This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m(2) as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks. Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009). Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population.
Autores: Sanchez-Abarca, L. I.; Gutierrez-Cosio, S.; Santamaria, C.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 115  Nº 1  2010  págs. 107 - 121
Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferase inhibitor that induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in the G(0) to G(1) phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma. This effect was not attributable to a proapoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes that induce cell-growth arrest, such as DCUN1D2, U2AF2, GADD45B, or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, overexpression of FOXP3, and expansion of regulatory T cells. Finally, the administration of 5-azaC after transplantation prevented the development of graft-versus-host disease, leading to a significant increase in survival in a fully mismatched bone marrow transplantation mouse model. In conclusion, the current study shows the effect of 5-azaC in T lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways that must be explored to prevent graft-versus-host disease.
Autores: Ludwig, H.; Bolejack, V.; Crowley, J.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 1527-7755  Vol. 28  Nº 9  2010  págs. 1599 - 1605
Purpose: To assess the impact of age on outcome and to analyze the projected years of life lost in patients with multiple myeloma. Patients and methods: Ten thousand five hundred forty-nine patients were evaluated; 6,996 patients were treated with conventional chemotherapy, and 3,553 patients were treated with high-dose therapy with autologous stem-cell transplantation. Results: Mean observed and relative overall survival times in the entire cohort were 3.7 and 3.9 years, respectively. Observed survival decreased steadily from 6.4 years in patients younger than age 50 years to 2.5 years in patients > or = age 80 years. A similar decrease was noted for relative survival. Higher age correlated significantly with higher International Staging System (ISS) stage. Relative excess risk of death differed significantly between 10-year age cohorts beginning from age 40 years (P < .001 for age 50 to 59 v age 40 to 49, P < .001 for age 60 to 69 v age 50 to 59, P < .001 for age 70 to 79 v age 60 to 69, and P = .009 for age > or = 80 v 70 to 79). The average years of life lost per patient was 16.8 years in the entire patient cohort and decreased steadily from 36.1 years in patients younger than 40 years old to 4.6 years in patients > or = age 80 years. Conclusion: Age is associated with higher ISS stage and is an important risk factor for early mortality. Survival declined continuously by each decade from age 50 to age > or = 80 from more than 6 to less than 3 years. The average of years of life lost in patients with myeloma is higher than in many other cancers and amounts to more than 30 years in patients younger t