Nuestros investigadores

Jesús San Miguel Izquierdo

Departamento
Director Médico de la CUN y Director de Medicina Clínica y Traslacional de la UN.
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
105, (WoS, 13/01/2020)

Publicaciones científicas más recientes (desde 2010)

Autores: Rodriguez, 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: Garcés, Juan-José; Simicek, M.; Vicari, M.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  2019 
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: 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: 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: Lahuerta, J. J., (Autor de correspondencia); Jimenez-Ubieto, A. ; Lourenco, Bruno David; 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. ; Lourenco, Bruno David, (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: Moreno, Laura; Zabaleta, 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: 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: Rodriguez, 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: 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: 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: 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: Garcés, Juan-José; Simicek, M.; Growkova, K.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  Nº s3  2019  págs. 13 - 14
Autores: Botta, C.; Zabaleta, Aintzane; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 149 - 149
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, Jesús Fernando; 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: Martínez, Nicolás, (Autor de correspondencia); Rodriguez, Paula; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº 7  2018  págs. E318 - E321
Autores: Arana P.; Lourenco, Bruno David; 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: Dimopoulos, M. A., (Autor de correspondencia); San Miguel, Jesús Fernando; 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: 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: 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: García, María José; Sarasquete, M. E.; Panizo, 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: San Miguel, Jesús Fernando, (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: 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: Sanoja-Flores, L.; Flores-Montero, J. ; Garcés, 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: Rodriguez, 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: 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: Mateos, M. V. , (Autor de correspondencia); Goldschmidt, H.; San Miguel, Jesús Fernando; 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: 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: 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: 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: 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: San Miguel, Jesús Fernando, (Autor de correspondencia); Lourenco, Bruno David;
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: 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, Jesús Fernando; 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, Jesús Fernando; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Ubieto, A. J. ; Lourenco, Bruno David; 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: Cavo, M. ; Dimopoulos, M. A.; San Miguel, Jesús Fernando; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 41  2018  págs. 182 - 183
Autores: Puig, N.; Lourenco, Bruno David; Lasa, M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Cavo, M. ; Iida, S.; Blade, J.; et al.
Revista: ONCOLOGY RESEARCH AND TREATMENT
ISSN 2296-5270  Vol. 41  2018  págs. 182
Autores: Rodriguez, Paula; Mateos, M. V.; Lopez, J. M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 4503
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: Tamariz-Amador, L.E; Hernández-Santamaría, T. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 118 - 118
Autores: Ruiz, C. P.; Zabaleta, 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, Jesús Fernando; Mateos, M. V. ; Goldschmidt, H.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
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: Lourenco, Bruno David; 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: Cuenca, I.; Sanchez-Vega, B. ; Lourenco, Bruno David; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 91 - 91
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, Ibai; Puig, N. ; Cedena, M. T. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 112
Autores: Vicari, M. ; Lara-Astiaso, D.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 188
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: Rodriguez, Paula; Lourenco, Bruno David; 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, Jesús Fernando; 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: Lahuerta, J. J.; Lourenco, Bruno David; 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: Flores-Montero, J.; Sanoja-Flores, L.; Lourenco, Bruno David; 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: Moreau, P.; San Miguel, Jesús Fernando; Sonneveld, P.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Suppl. 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: 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: 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: Lourenco, Bruno David; 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: Martinez-Lopez, J.; Sanchez-Vega, B.; Barrio, S.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 31  Nº 6  2017  págs. 1446 - 1449
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: 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: 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: Lapa, C. ; Garcia-Velloso, Maria Jose; 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. ; 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: 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: 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: Mishima, Y.; Lourenco, Bruno David; 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: 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: Seckinger A; Delgado, JA; 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: 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: San Miguel, Jesús Fernando, (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: Mateos, M. V.; San Miguel, Jesús Fernando;
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: 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, María Isabel; García, Berta; 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: Rodriguez, Paula; Mateos, M. V.; Orlowski, R. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 319
Autores: Rodriguez, Paula; Mateos, M. V.; Joaquin, M. L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 274 - 275
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, Jesús Fernando; 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, Jesús Fernando; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl 2  2017  págs. 779
Autores: San Miguel, Jesús Fernando; Weisel, K.; Cook, G.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 1 - 2
Autores: Carrasco, A.; Ezponda, 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: Kulis, M.; Russinol, N.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 102  Nº Supl. 4  2017  págs. 11 - 12
Autores: Ezponda, 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.; Lourenco, Bruno David; 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, Jesús Fernando; 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: Lourenco, Bruno David, (Autor de correspondencia); Merino, J; San Miguel, Jesús Fernando;
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: Lourenco, Bruno David; García-Sanz, R.; San Miguel, Jesús Fernando;
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, Jesús Fernando, (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: Herrero-Sánchez MC; Rodríguez-Serrano C; Almeida J; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 173  Nº 5  2016  págs. 754-68
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: 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: Lourenco, Bruno David; Mateos, MV.; Sanchez Abarca, LI.; 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: 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: Lourenco, Bruno David; 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: Herrero-Sanchez MC; Rodríguez-Serrano; Almeida J; 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: Lourenco, Bruno David; 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: 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: Dimopoulos, M. A.; Oriol, A.; San Miguel, Jesús Fernando; 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: 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: 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: 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: 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: 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: 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: García, Berta; Morales, María Isabel; Guillen Valderrama, E; et al.
Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070  Vol. 43  Nº Supl.1.  2016  págs. S127 - S127
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, Laura; Delgado, JA; 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: 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, Jesús Fernando; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl. 6  2016  págs. 940TiP
Autores: Seckinger, A.; Delgado, JA; 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: Moreno, L.; Zabaleta, Aintzane; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
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, Jesús Fernando; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl.4  2016  págs. 27 - 28
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: Figueroa, Rocío; Marcos-Jubilar, María; García, Berta; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl. 1  2016  págs. 524
Autores: Lourenco, Bruno David; Puig, N. ; Cedena, M. T.; 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: Burgos, Leire; Garcés, Juan-José; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Bretones, G.; Lourenco, Bruno David; Valdes-Mas, R.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Arana P.; Zabaleta, A.; Lasa, M. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Carrasco, A.; Ezponda, Teresa; Meydan, C.; 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, Jesús Fernando; 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, Jesús Fernando; 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. ; Lourenco, Bruno David; 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, Jesús Fernando;
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, Jesús Fernando;
Revista: HEMATOLOGICAL ONCOLOGY
ISSN 1099-1069  Vol. 33  Nº Supl. 1  2015  págs. 33 - 37
Autores: San Miguel, Jesús Fernando; Lourenco, Bruno David; Lasarte, Juan José;
Revista: CANCER CELL
ISSN 1535-6108  Vol. 28  Nº 3  2015  págs. 281-3
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: 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: Lourenco, Bruno David; 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, Jesús Fernando, (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, Jesús Fernando, (Autor de correspondencia); Lourenco, Bruno David; Lasarte, 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, Jesús Fernando, (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: 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: 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: 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: 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: 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: Stewart, AK.; Rajkumar, SV.; Dimopoulos, MA.; 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: 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: Herrero, A. B.; San Miguel, Jesús Fernando; 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: Agirre, X; 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: Rajkumar, S. V. , (Autor de correspondencia); Richardson, P. ; San Miguel, Jesús Fernando;
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: Lourenco, Bruno David, (Autor de correspondencia); Azpilicueta, 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: Lourenco, Bruno David; 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, Jesús Fernando;
Revista: AMERICAN JOURNAL OF HEMATOLOGY
ISSN 0361-8609  Vol. 90  Nº 8  2015  págs. 146 - 146
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, Ramón; Sola, I. ; Corrales, Fernando José; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl 4  2015  págs. 99
Autores: Agirre, X; Castellano, G.; Heath, S.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl. 4  2015  págs. 41 - 42
Autores: Sanoja Flores, L.; Lourenco, Bruno David; Flores Montero, J. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl 1  2015  págs. 40 - 41
Autores: Mishima, Y. ; Lourenco, Bruno David; Shi, J.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 23  2015 
Autores: Lourenco, Bruno David; Mateos, M. V. ; Sanchez-Abarca, L. I.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 23  2015 
Autores: San José, Edurne; Agirre, X; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  2015  págs. 27
Autores: Sanoja-Flores, L. ; Lourenco, Bruno David; Flores-Montero, J. A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 126  Nº 23  2015 
Autores: San José, Edurne; Agirre, X; Rabal, O.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl. 4  2015  págs. 60 - 61
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: 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: 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: Matarraz, S., (Autor de correspondencia); Lourenco, Bruno David; Diez-Campelo, M.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 28  Nº 8  2014  págs. 1747 - 1750
Autores: Agirre, X; Castellano, G.; Health, S.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 21  2014 
Autores: San José, Edurne; Agirre, X; Roa, Sergio; 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: Lourenco, Bruno David; Mateos, M. V. ; Lopez-Corral, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 99  Nº Supl 1  2014  págs. 95
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: Lonial, S.; San Miguel, Jesús Fernando;
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: Puchades Carrasco, L.; Lecumberri, 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: Puchades-Carrasco, L. ; Lecumberri, Ramón; Martinez-Lopez, J; et al.
Revista: EUROPEAN JOURNAL OF CANCER
ISSN 0959-8049  Vol. 49  Nº Supl 4  2013  págs. S14
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: 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: 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: 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. Clin Cancer Res; 16( 12); 3260-9. (C)2010 AACR.

  OTROS MÉRITOS RELEVANTES

El Prof. Jesús San-Miguel, es Director de Medicina Clínica y Traslacional de la Universidad de Navarra. Catedrático de Hematología, trabajó con anterioridad como Profesor y Jefe de Servicio de Hematología del Hospital Universitario de Salamanca y Director Científico del Instituto de Investigación Biomédica de Salamanca (IBSAL). Entre sus áreas de especialización destacan: el mieloma múltiple, Inmunofenotipo y factores pronósticos en leucemias y enfermedad mínima residual.
Jesús San-Miguel, MD, PhD, is a professor of medicine-hematology and Director of Clinical and Translational Medicine at the University of Navarra in Spain. He served as director of the Hematology Department of the University Hospital of Salamanca in Spain for more than 2 decades; also was President of the International Myeloma Society since from 2012 until 2019. Dr. San-Miguel has published over 879 original papers (803 in international journals). He has made important contributions to myeloma cell biology in areas such as immunephenotyping, risk of progression from monoclonal gammopathy of undetermined significance or smouldering MM into active MM, and minimal residual disease, as well as, making important contributions in the area of therapeutics, including studies for new antimyeloma drugs at the preclinical and clinical levels, including proteasome inhibitors, immunomodulatory drugs, and histone deacetylases. He is member of the Advisory Board of the International Myeloma Foundation and the Multiple Myeloma Research Foundation. He has served as board councillor for the European Association, chairman of the Scientific Committee for the IXth Congress (2004), and president of the 15th European Hematology Association (EHA) Congress. He has been associate editor for Blood and Hematologica. He has received numerous awards, including the Waldenstöm Award, EBMT Lecture, Celgene Career Achievement Award, Kyle Lifetime Achievement Award, Jose Carreras EHA Award, Ham-Wasserman Lecture Award, Michaeli Award, Rey Jaime I Award in Clinical Medicine, and the Spanish Prizes in both oncology and translational research.
H index: 105. Sum of times cited: 50.296. Average citations last five years: 4928. Articles in WoS: 882. Last updated: Jan 13th, 2020.
Titles of five relevant publications -Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. San Miguel JF et al. N Engl J. Med. 359 (9):906-17, 2008. -Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. Mateos MV et al. ( San Miguel JF). N Engl J Med. 1;369(5):438-47, 2013. -Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. Mateos MV et al. (San-Miguel J); N Engl J Med. 378(6):518-528, 2018. -Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. Dimopoulos MA, at al. ( San-Miguel J). N Engl J Med. 379(19):1811-1822, 2018. -Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial . San Miguel J et al. Lancet Oncol. 14(11):1055-66, 2013.