Ocio, E.M. (Enrique M.)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
12 results
Search Results
Now showing 1 - 10 of 12
- Response to novel drugs before and after allogeneic stem cell transplantation in patients with relapsed multiple myeloma(Elsevier BV, 2019) Pérez-Vicente, S. (Sabina); Morgades, M. (Mireia); Krsnik, I. (Isabel); Martinez, C. (Carmen); Perez-Simon, J.A. (José Antonio); Heras, I. (Inmaculada); Martin, J. (Jesus); Ocio, E.M. (Enrique M.); Vázquez, A. (Alejandro); Sampol, A. (Antonia); Cabero, M. (Martin); Rifon, J. J. (Jose J.); Mateos, M.V. (María Victoria); Torres-Juan, M. (Marta); Rovira, M. (Montserrat); Rosiñol, L. (Laura); Gutierrez, G. (Gonzalo); Castilla-Llorente, C. (Cristina); Caballero, D. (Dolores); Fernandez-Aviles, F. (Francesc); Ribera, J.M. (José María); Lopez-Godino, O. (Oriana); Iniesta, F. (Francisca); Caballero-Velázquez, T. (Teresa); Morillo, D. (Daniel); Moraleda, J. M. (José M.); Lopez-Corral, L. (Lucia); San-Miguel, J.F. (Jesús F.)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.
- Minimal residual disease monitoring and immune profiling using second generation flow cytometry in elderly multiple myeloma(American Society of Hematology, 2016) Cedena, M.T. (María Teresa); Montero, J. (Juan); Martínez-López, J. (Joaquín); Gironella, M. (Mercedes); Martin, J. (Jesus); Bladé, J. (Joan); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Ocio, E.M. (Enrique M.); Gonzalez, Y. (Yolanda); Martin-Ramos, M.L. (Maria Luisa); Mateos, M.V. (María Victoria); Encinas, C. (Cristina); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Arana, P. (Paula); Cabrera, C. (Carmen); Cordón, L. (Lourdes); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Dongen, J.J.M. (Jacques J. M.) van; Teruel, A.I. (Ana Isabel); Paiva, B. (Bruno); Oriol, A. (Albert); Bargay, J. (Joan); Martínez, R. (Rafael); San-Miguel, J.F. (Jesús F.); Echeveste, M.A. (Maria Asuncion)The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible than elderly patients. Since an optimal balance between treatment efficacy and toxicity is of utmost importance in elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used 2nd generation 8-color multiparameter-flow-cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study, The transition from 1st to 2nd generation MFC resulted in increased sensitivity, and allowed to identify three patient groups according to MRD levels: MRD-negative (<10-5; n=54, 34%), MRD-positive between <10-4 and ≥10-5 (n=20, 12%), and MRD-positive ≥10-4 (n=88, 54%). MRD status was an independent prognostic factor for time-to progression (-TTP- HR:2.7; P=.007) and overall survival (-OS- HR:3.1; P=.04) with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3-years), and similar poorer outcomes for cases with MRD levels between <10-4 and ≥10-5 vs ≥10-4 (both median TTP of 15 months; 63% and 55% OS at 3-years). Furthermore, MRD-negativity significantly improved TTP of patients >75-years (HR:4.8; P<.001), and those with high-risk cytogenetics (HR:12.6; P=.01). Using 2nd generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate and favorable outcome (25%, 61% and 100% OS at 3-years; P=.01); the later patients being characterized by an increased compartment of mature B-cells. Our results show that similarly to transplant-candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM, irrespectively of patients’ age and cytogenetic risk.
- Pembrolizumab as consolidation strategy in patients with multiple myeloma: Results of the GEM-Pembresid clinical trial(MDPI AG, 2020) Paino, T. (Teresa); Gonzalez-Calle, V. (Veronica); Blanchard, M.J. (María Jesús); Pérez-Morán, J. (José); Bladé, J. (Joan); García-Sanz, R. (Ramón); Ocio, E.M. (Enrique M.); Mateos, M.V. (María Victoria); Dávila, J. (Julio); Arriba, F. (Felipe) de; Puig, N. (Noemí); Lahuerta, J.J. (Juan José); Paiva, B. (Bruno); Corchete-Sánchez, L.A. (Luis A.); Oriol, A. (Albert); Rubia, J. (Javier) de la; Martín-Sánchez, J. (Jesús); San-Miguel, J.F. (Jesús F.)PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43, p = 0.007; 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly lower expression of PD1 in CD8+ effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23.
- A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma(Springer Nature, 2020) Lendvai, N. (Nikoletta); Gasparetto, C. (Cristina); Hari, P. (Parameswaran); Kaufman, J.L. (Jonathan L.); Ocio, E.M. (Enrique M.); Chiron, M. (Marielle); Kumar, S. (Shaji); Mikhael, J. (Joseph); Bensinger, W. (William); Martin, T. (Thomas); Vij, R. (Ravi); Oprea, C. (Corina); Zonder, J. (Jeffrey); Richter, J. (Joshua); Brillac, C. (Claire); Cole, C. (Craig); Dimopoulos, M.A. (Meletios A.); San-Miguel, J.F. (Jesús F.); Charpentier, E. (Eric)A Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ≥3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38–85), 5 (2–14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ≥10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common nonhematologic adverse events (typically grade ≤2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ≤2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ≥10 mg/kg.
- Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis(Nature, 2019) González, M.E. (María Esther); Cedena, M.T. (María Teresa); Verde, J. (Javier); Pérez, J.J. (José J.); Martínez-López, J. (Joaquín); Krsnik, I. (Isabel); Gironella, M. (Mercedes); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Ocio, E.M. (Enrique M.); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Puerta, J.E. (José Enrique) de la; Puig, N. (Noemí); Labrador, J. (Jorge); Burgos, L. (Leire); Lasa, M. (Marta); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Pérez-Montaña, A. (Albert); Gómez-Toboso, D. (Dolores); Paiva, B. (Bruno); Lecumberri, R. (Ramón); Oriol, A. (Albert); Rubia, J. (Javier) de la; Prosper-Cardoso, F. (Felipe); Casanova, M. (María); Lecrevisse, Q. (Quentin); Merino, J. (Juana); San-Miguel, J.F. (Jesús F.); Moreno, C. (Cristina); Cabañas, V. (Valentín); García-de-Coca, A. (Alfonso)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 = 94), 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 MFC-based automated risk classification ready for implementation in clinical practice.
- Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance(American Society of Hematology, 2016) Gironella, M. (Mercedes); Bladé, J. (Joan); Barlogie, B. (Bart); García-Sanz, R. (Ramón); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Sanchez, M.L. (Maria Luz); Ocio, E.M. (Enrique M.); Gonzalez, Y. (Yolanda); Mateos, M.V. (María Victoria); Maiso, P. (Patricia); Arriba, F. (Felipe) de; Epstein, J. (Joshua); Rodriguez, I. (Idoia); Hernandez, M.T. (Miguel Teodoro); Puig, N. (Noemí); Burgos, L. (Leire); Alignani, D. (Diego); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Paiva, B. (Bruno); Oriol, A. (Albert); Corchete, L.A. (Luis A.); Barcena, P. (Paloma); San-Miguel, J.F. (Jesús F.); Johnson, S.K. (Sarah K.); Echeveste, M.A. (Maria Asuncion)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 as ALCAM that 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 the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered at www.clinicaltrials.gov as #NCT01237249.
- Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 1b study from GELTAMO group(2016) López-Guillermo, A. (Armando); González-Barca, E. (Eva); Ocio, E.M. (Enrique M.); Montes-Moreno, S. (Santiago); Martin, A. (Alejandro); Caballero, D. (Dolores); Canales-Albendea, M. A. (Miguel Ángel); Redondo, A. M. (Alba M.); Salar, A. (Antonio); Dlohuy, I. (Iván)Diffuse large B-cell lymphoma (DLBCL) patients failing rituximab-containing therapy have a poor outcome with the current salvage regimens. We conducted a phase 1b trial to determine the maximum tolerated dose (MTD) of lenalidomide in combination with R-ESHAP (rituximab, etoposide, cisplatin, cytarabine, methylprednisolone) (LR-ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were collected as a secondary objective. Subjects received 3 cycles of lenalidomide at escalating doses (5, 10 or 15 mg) given on days 1–14 of every 21-day cycle, in combination with R-ESHAP. Responding patients received BEAM (carmustine, etoposide, cytarabine, melphalan) followed by autologous stem-cell transplantation. Lenalidomide 10 mg/d was identified as the MTD because, in the 15 mg cohort, one patient experienced dose-limiting toxicity (grade 3 angioedema) and two patients had mobilization failure. A total of 19 patients (3, 12 and 4 in the 5, 10 and 15 mg cohorts, respectively) were evaluable. All toxicities occurring during LR-ESHAP cycles resolved appropriately and no grade 4–5 non-haematological toxicities were observed. The complete remission and overall response rates were 47·4% and 78·9%, respectively. With a median follow-up of 24·6 (17·4–38·2) months, the 2-year progression-free survival and overall survival were 44% and 63%, respectively. In conclusion, the LR-ESHAP regimen is feasible and yields encouraging outcomes.
- Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation(2023) Moreau, P. (Philippe); Martínez-López, J. (Joaquín); Perrot, A. (Aurore); Fitzmaurice, T. (Thomas); Le-Roux, N. (Nadia); Ocio, E.M. (Enrique M.); Gassiot, M. (Matthieu); Marcatti, M. (Magda); Nogai, A. (Axel); Mateos, M.V. (María Victoria); Karlin, L. (Lionel); Oliva, S. (Stefania); Dong, L. (Liyan); Bringhen, S. (Sara); Oprea, C. (Corina); Rodriguez-Otero, P. (Paula); Wang, S.Y. (Song Yau); Blau, I.W. (Igor W.); Mace, S. (Sandrine); San-Miguel, J.F. (Jesús F.); Bories, P. (Pierre)Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10(-5) sensitivity). Grade >= 3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).
- Phenotypic, genomic and functional characterization reveals no differences between CD138++ and CD138low subpopulations in multiple myeloma cell lines(Public Library of Science, 2014) Paino, T. (Teresa); Krzeminski, P. (Patryk); Garayoa, M. (Mercedes); Sarasquete, M.E. (María E.); García-Sanz, R. (Ramón); Ocio, E.M. (Enrique M.); San-Segundo, L. (Laura); Gutierrez, N.C. (Norma C.); Paiva, B. (Bruno); Redondo, A. M. (Alba M.); Corchete, L.A. (Luis A.); San-Miguel, J.F. (Jesús F.)Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations--CD138++ (95-99%) and CD138low (1-5%)--in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.
- Phase 1b Study of Isatuximab in combination with bortezomib, cyclophosphamide, and dexamethasone in newly diagnosed, transplant-ineligible multiple myeloma patients(2023) Martínez-López, J. (Joaquín); Le-Roux, N. (Nadia); Ocio, E.M. (Enrique M.); Mateos, M.V. (María Victoria); Oliva, S. (Stefania); Bringhen, S. (Sara); Dong, Y. (Yvonne); Rodriguez-Otero, P. (Paula); Mace, S. (Sandrine); San-Miguel, J.F. (Jesús F.); Doroumian, S. (Severine)