Nuestros investigadores

Paula Rodríguez Otero

Publicaciones científicas más recientes (desde 2010)

Autores: Oriol, A.; Larocca, A. ; Leleu, X.; et al.
ISSN 1354-3784  Vol. 29  Nº 10  2020  págs. 1069 - 1078
Introduction: The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma. Areas covered: This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described. Expert opinion: Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.
Autores: Alegre, A.; de la Rubia, J. ; Balari, A. S.; et al.
ISSN 2572-9241  Vol. 4  Nº 3  2020  págs. e380
Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had ¿3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatment-emergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma. European Clinical Trials Database number: 2015-002993-19.
Autores: Garcés Latre, Juan José; Bretones, G. ; Burgos Rodríguez, Leire; et al.
ISSN 0887-6924  Vol. 34  Nº 11  2020  págs. 3007 - 3018
Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that similar to 22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (>= 95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, >= 82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.
Autores: Pérez Ruiz, Cristina; Botta, C.; Zabaleta, A.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 136  Nº 2  2020  págs. 199 - 209
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14-CD15+CD33+HLADR- cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC-related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
Autores: Morales Lozano, María Isabel; Viering, O.; Samnick, S. ; et al.
Revista: CANCERS
ISSN 2072-6694  Vol. 12  Nº 4  2020  págs. 1042
C-11-methionine (C-11-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than F-18-fluorodeoxyglucose (F-18-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of C-11-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to F-18-FDG. Twenty-two patients with newly diagnosed, treatment-naive symptomatic MM who had undergone C-11-MET and F-18-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion C-11-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), C-11-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in C-11-MET than in F-18-FDG (p < 0.05, respectively). C-11-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that C-11-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than F-18-FDG. Its implications for prognosis evaluation need further investigation.
Autores: Lonial, S. , (Autor de correspondencia); Lee, H. C.; Badros, A.; et al.
ISSN 1470-2045  Vol. 21  Nº 2  2020  págs. 207 - 221
Background Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study. Methods DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged >= 18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0-2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (<= 4 vs >4) and cytogenetic features to receive 2.5 mg/kg or 3.4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with, NCT03525678, and is ongoing. Findings Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2.5 mg/kg cohort and 99 in the 3.4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97.5% CI 20.8-42.6) of 97 patients in the 2.5 mg/kg cohort and 34 (34%; 23.9-46.0) of 99 patients in the 3.4 mg/kg cohort achieved an overall response. The most common grade 3-4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2.5 mg/kg cohort and 21 [21%] of 99 patients in the 3.4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2.5 mg/kg cohort and 47 (47%) of 99 in the 3.4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2.5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3.4 mg/kg cohort). Interpretation Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
Autores: Rodríguez Otero, Paula; Reis de Carvalho, Joana Sofía; Alfonso Piérola, Ana; et al.
ISSN 2687-8941  Vol. 6  2020  págs. 904 - 905
Autores: Goldschmidt, H.; Jagannath, S. ; Lin, Y. ; et al.
ISSN 2296-5270  Vol. 43  Nº SUPPL 4  2020  págs. 93 - 93
Autores: Richardson, P. ; Oriol, A.; Larocca, A.; et al.
ISSN 0361-8609  Vol. 95  2020  págs. S27 - S28
Autores: Weisel, K.; Rodríguez Otero, Paula; Davies, F. ; et al.
ISSN 2296-5270  Vol. 43  Nº SUPPL 4  2020  págs. 118 - 118
Autores: Kortum, M.; Lee, H. C.; Cohen, A. D.; et al.
ISSN 2296-5270  Vol. 43  Nº SUPPL 4  2020  págs. 102 - 102
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Martinez-Lopez, J.; et al.
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: Moreno Narro, Laura; Pérez Ruiz, Cristina; Zabaleta Azpiroz, Aintzane; et al.
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: Mateos, M. V. , (Autor de correspondencia); Blacklock, H. ; Schjesvold, F. ; et al.
ISSN 2352-3026  Vol. 6  Nº 9  2019  págs. e459 - e469
ackground: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). Methods: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at leas
Autores: Chari, A., (Autor de correspondencia); Martinez-Lopez, J.; Mateos, M. V.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 134  Nº 5  2019  págs. 421 - 431
Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomiderefractory patients were eligible. Carfilzomib- and daratumumab-naive patients (n 5 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m(2) initial dose, escalated to 70 mg/m(2) thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide.
Autores: Rodríguez Otero, Paula; Mateos, M. V. ; Martinez-Lopez, J.; et al.
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: Mateos, M. V. , (Autor de correspondencia); Orlowski, R. Z.; Ocio, E. M.; et al.
ISSN 0007-1048  Vol. 186  Nº 5  2019  págs. e117 - e121
Autores: Richardson, P. G. ; Oriol, A.; Larocca, A. ; et al.
ISSN 2152-2650  Vol. 19  Nº Supl. 1  2019  págs. S329 - S330
Autores: Richardson, P. G.; Oriol, A.; Larocca, A.; et al.
ISSN 0361-8609  Vol. 94  Nº Supl. 2  2019  págs. S24 - S25
Autores: Caballero-Velazquez, T.; Quijano-Ruiz, B.; Lopez-Corral, L.; et al.
ISSN 1043-0342  Vol. 30  Nº 11  2019  págs. A88 - A88
Autores: Cedena, M. T. ; Puig, N.; Paiva, B.; et al.
ISSN 0390-6078  Vol. 104  2019  págs. 15 - 15
Autores: Richardson, P. G.; Oriol, A. ; Larocca, A. ; et al.
ISSN 0008-5472  Vol. 79  Nº 13  2019 
Autores: Richardson, P. G. ; Mateos, M. V.; Rodríguez Otero, Paula; et al.
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E352 - E353
Autores: Garcés Latre, Juan José; Bretones, G. ; Burgos Rodríguez, Leire; et al.
ISSN 2152-2650  Vol. 19  Nº 10  2019  págs. E351
Autores: Martínez Calle, Nicolás (Autor de correspondencia); Rodríguez Otero, Paula; Villar Fernández, Sara; et al.
ISSN 0390-6078  Vol. 103  Nº 7  2018  págs. E318 - E321
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Martinez-Lopez, J.; et al.
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: Sanoja-Flores, L.; Flores-Montero, J. ; Garcés Latre, Juan José; et al.
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: Tamariz Amador, Luis Esteban; Riesgo García, Álvaro; Hernández-Santamaría, T. ; et al.
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 118 - 118
Autores: Ocio, E. M.; Rodríguez Otero, Paula; Bringhen, S. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Rodríguez Otero, Paula (Autor de correspondencia)
ISSN 0390-6078  Vol. 103  Nº Supl. 1  2018  págs. 8 - 8
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Lopez, J. M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 4503
Autores: Richardson, P. ; Ocio, E.; Oriol, A. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Mateos, M. V. ; Rocafiguera, A. O. ; Rodríguez Otero, Paula; et al.
ISSN 0390-6078  Vol. 103  Nº Supl. 1  2018  págs. 32 - 32
Autores: Rodríguez Otero, Paula; Paiva, Bruno; Engelhardt, M. ; et al.
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: Lapa, C. ; García Velloso, María José; Lückerath, K.; et al.
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: Kumar, S. K., (Autor de correspondencia); Dimopoulos, M. A.; Kastritis, E.; et al.
ISSN 0887-6924  Vol. 31  Nº 11  2017  págs. 2443 - 2448
Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T-0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T-0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T-0 was 3.1 years. The median number of lines of therapy before T-0 was 4 (range 3-13). The median overall survival (OS) from T-0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T-0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T-0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Orlowski, R. ; et al.
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 319
Autores: Rodríguez Otero, Paula; Mateos, M. V.; Joaquin, M. L.; et al.
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 274 - 275
Autores: Morales Lozano, María Isabel; García García, Berta; Villar Fernández, Sara; et al.
ISSN 2253-654X  Vol. 36  Nº Supl 1  2017  págs. 10
n pacientes con mieloma múltiple el FDG-PET/CT es una herramienta sensible en la valoración de respuesta, permite la detección de enfermedad extramedular y complementa la valoración de la enfermedad mínima residual. La persistencia de captación de FDG en pacientes en RC puede predecir la recaída
Autores: Mateos, M. V. ; Martinez-Lopez, J.; Hernandez, M.; et al.
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 143
Autores: Garcia-Sanz, R.; Jimenez, C.; Puig, N.; et al.
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: Moreno, L.; Zabaleta Azpiroz, Aintzane; Alignani, Diego Oscar; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Burgos Rodríguez, Leire; Alignani, Diego Oscar; Garcés Latre, Juan José; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Figueroa Mora, María del Rocío; Marcos Jubilar, María; García García, Berta; et al.
ISSN 0390-6078  Vol. 101  Nº Supl. 1  2016  págs. 524
Autores: San José Enériz, Edurne; Aguirre Ena, Xabier; Rodríguez Otero, Paula; et al.
ISSN 1750-1911  Vol. 5  Nº 5  2013  págs. 525 - 538
Acute lymphoblastic leukemia (ALL) is a heterogeneous cancer that is characterized by rapid and uncontrolled proliferation of immature B- or T-lymphoid precursors. Although ALL has been regarded as a genetic disease for many years, the crucial importance of epigenetic alterations in leukemogenesis has become increasingly evident. Epigenetic mechanisms, which include DNA methylation and histone modifications, are critical for gene regulation during many key biological processes. Here, we review the cell signaling pathways that are regulated by DNA methylation or histone modifications in ALL. Recent studies have highlighted the fundamental role of these modifications in ALL development, and suggested that future investigation into the specific genes and pathways that are altered by epigenetic mechanisms can contribute to the development of novel drug-based therapies for ALL.
Autores: Vilas Zornoza, Amaia; Aguirre Ena, Xabier; Martín-Palanco, V.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 6  Nº 2  2011  págs. e17012
Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n¿=¿48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2'-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p¿=¿0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p¿=¿0.006) and overall survival (OS) (p¿=¿0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.
Autores: Rodríguez Otero, Paula; Román-Gómez, J.; Vilas Zornoza, Amaia; et al.
ISSN 0007-1048  Vol. 155  Nº 1  2011  págs. 73 - 83
The role of epigenetic mechanisms in the regulation of microRNAs (miRNAs) with a tumour-suppressor function in human neoplasms has recently been established. Several miRNAs have been found to be inappropriately regulated by DNA methylation in patients with acute lymphoblastic leukaemia (ALL). We analysed the methylation status of the three members of the MIR9 family (MIR9-1, MIR9-2 and MIR9-3) in a uniformly treated cohort of 200 newly diagnosed ALLs. MIR9 was methylated in 54% of the patients and was associated with downregulation of MIR9 (P < 0.01). Hypermethylation of MIR9 was an independent prognostic factor for disease-free survival, overall survival and event-free survival in a multivariate analysis (P < 0 01). Epigenetic downregulation of MIR9 induced upregulation of its targets, FGFR1 and CDK6, while treatment of ALL cells with FGFR1 (PD-173074) and CDK6 (PD-0332991) inhibitors induced a decrease in cell proliferation and an increase in apoptosis of ALL cells. Our results indicate that the MIR9 family is involved in the pathogenesis and clinical behaviour of ALL and provide the basis for new therapeutic strategies in the treatment of ALL, targeting the epigenetic regulation of miRNAs and/or the FGFR1 or CDK6-RB pathway directly
Autores: Gállego Pérez de Larraya, Jaime; Palma Carazo, José Alberto; Carmona Iragui, María; et al.
ISSN 0167-594X  Vol. 103  Nº 3  2011  págs. 603 - 609
Central nervous system (CNS) prophylaxis is required during initial treatment of non-Hodgkin lymphoma (NHL) subtypes that carry a high risk of CNS involvement. Intrathecal (IT) liposomal cytarabine, a formulation with prolonged half-life, has been shown to be safe and effective in the treatment of meningeal disease in patients with high-grade lymphoma. We retrospectively reviewed all adult patients with high-grade NHL that received prophylactic therapy with IT liposomal cytarabine and developed neurologic complications in our institution between April 2007 and May 2009. We recorded information on hospital admission, chemotherapy regimens, clinical features, neuroimaging, cerebrospinal fluid, neurophysiology data, and outcome. Neurotoxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Four of fourteen patients (28%) developed moderate or severe neurotoxicity (grades 2 and 3 of the NCI-CTC), manifested as conus medullaris/cauda equine syndrome or pseudotumour cerebri-like syndrome, after a median of 3.5 IT courses of liposomal cytarabine. All patients had received corticosteroids to prevent arachnoiditis. Liposomal cytarabine given via the IT route, even with concomitant corticosteroid administration, can result in significant neurotoxicity in some patients. We discuss the potential pathogenesis of these effects and suggest hypothetical therapeutic measures to prevent these complications. Specialists should be aware of these possible complications when administering prophylactic IT liposomal cytarabine in high-grade NHL patients, and additional prospective studies should be conducted to more clearly delineate the frequency and characteristics of these complications.