Arriba, F. (Felipe) de

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    Prognostic value of serum paraprotein response kinetics in patients with newly diagnosed multiple myeloma
    (2022) Blanchard, M.J. (María Jesús); González, M.E. (María Esther); Cedena, M.T. (María Teresa); Casado, L.F. (Luis Felipe); Krsnik, I. (Isabel); Ríos, R. (Rafael) de los; Gironella, M. (Mercedes); Bladé, J. (Joan); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Troconiz, I.F. (Iñaki F.); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Lopez-Anglada, L. (Lucia); Arguiñano, J.M. (José María); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Rodriguez-Otero, P. (Paula); Paiva, B. (Bruno); Jarque, I. (Isidro); Oriol, A. (Albert); Marti, J.M. (J.M.); Sureda-Balari, A. M. (Anna Maria); González-Rodriguez, A.P. (Ana Pilar); Bargay, J. (Joan); Gonzalez-Montes, Y. (Yolanda); Jiménez-Ubieto, A. (Ana); San-Miguel, J.F. (Jesús F.); Tamariz-Amador, L.E. (Luis Esteban); Cabañas, V. (Valentín)
    Introduction Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a “resistance” parameter that reflects the stagnation in the response after an initial descent. Results Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P = .02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P = .02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P < .002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies.
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    Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature
    (2019) Cedena, M.T. (María Teresa); Martínez-López, J. (Joaquín); Gironella, M. (Mercedes); Martin, J. (Jesus); Bladé, J. (Joan); Ocio, E.M. (Enrique M.); Gonzalez, Y. (Yolanda); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Encinas, C. (Cristina); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Cabrera, C. (Carmen); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Rodriguez-Otero, P. (Paula); Teruel, A.I. (Ana Isabel); Paiva, B. (Bruno); Oriol, A. (Albert); Bengoechea, E. (Enrique); Bargay, J. (Joan); Pérez-de-Oteyza, J. (Jaime); Martínez, R. (Rafael); Nuñez-Cordoba, J.M. (Jorge M.); San-Miguel, J.F. (Jesús F.)
    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.
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    Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression
    (Fondazione Ferrata Storti, 2008) Alegre, A. (A.); Mateo, G. (Gemma); Bladé, J. (Joan); García-Sanz, R. (Ramón); Hernandez, J.M. (J. M.); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Esseltine, D.L. (D. L.); Hernandez, M.T. (Miguel Teodoro); Carrera, D. (D,); Garcia-Sanchez, P. (P.); Palomera, L. (Luis); Terol, M.J. (María José); Velde, H. (Helgi) van de; Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Fuertes, M. (M.); Ribas, P. (Paz); Garcia-Laraña, J. (J.); Oriol, A. (Albert); Rubia, J. (Javier) de la; Prosper-Cardoso, F. (Felipe); Sureda-Balari, A. M. (Anna Maria); Bargay, J. (Joan); San-Miguel, J.F. (Jesús F.)
    New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome.
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    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.
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    Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis
    (American Society of Hematology, 2016) Perez-Simon, J.A. (José Antonio); Hernández-Martín, J. (J.); Bladé, J. (Joan); Vidriales, M.B. (María Belén); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Sanchez-Abarca, L.I. (Luis Ignacio); Esteves, G. (Graça); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Lahuerta, J.J. (Juan José); Giraldo, P. (P.); Teruel, A.I. (Ana Isabel); Paiva, B. (Bruno); Oriol, A. (Albert); Rubia, J. (Javier) de la; Corchete, L.A. (Luis A.); Prosper-Cardoso, F. (Felipe); Bargay, J. (Joan); Lopez-Corral, L. (Lucia); San-Miguel, J.F. (Jesús F.)
    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.
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    Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study
    (American Society of Hematology, 2006) Alegre, A. (A.); Mateo, G. (Gemma); Bladé, J. (Joan); García-Sanz, R. (Ramón); Hernandez, J.M. (J. M.); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Esseltine, D.L. (D. L.); Hernandez, M.T. (Miguel Teodoro); Carrera, D. (D,); Palomera, L. (Luis); Terol, M.J. (María José); Velde, H. (Helgi) van de; Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Fuertes, M. (M.); Ribas, P. (Paz); Garcia-Laraña, J. (J.); Oriol, A. (Albert); Rubia, J. (Javier) de la; Diaz-Mediavilla, J. (J.); Prosper-Cardoso, F. (Felipe); Sureda-Balari, A. M. (Anna Maria); Bargay, J. (Joan); San-Miguel, J.F. (Jesús F.)
    Standard first-line treatment for elderly multiple myeloma (MM) patients ineligible for stem cell transplantation is melphalan plus prednisone (MP). However, complete responses (CRs) are rare. Bortezomib is active in patients with relapsed MM, including elderly patients. This phase 1/2 trial in 60 untreated MM patients aged at least 65 years (half older than 75 years) was designed to determine dosing, safety, and efficacy of bortezomib plus MP(VMP). VMP response rate was 89%, including 32% immunofixation-negative CRs, of whom half of the IF– CR patients analyzed achieved immunophenotypic remission (no detectable plasma cells at 10 4 to 10 5 sensitivity). VMP appeared to overcome the poor prognosis conferred by retinoblastoma gene deletion and IgH translocations. Results compare favorably with our historical control data for MP—notably, response rate (89% versus 42%), event-free survival at 16 months (83% versus 51%), and survival at 16 months (90% versus 62%). Side effects were predictable and manageable; principal toxicities were hematologic, gastrointestinal, and peripheral neuropathy and were more evident during early cycles and in patients aged 75 years or more. In conclusion, in elderly patients ineligible for transplantation, the combination of bortezomib plus MP appears significantly superior to MP, producing very high CR rates, including immunophenotypic CRs, even in patients with poor prognostic features.
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    Prognostic value of serum paraprotein response kinetics in patients with newly diagnosed multiple myeloma
    (2022) Blanchard, M.J. (María Jesús); González, M.E. (María Esther); Cedena, M.T. (María Teresa); Casado, L.F. (Luis Felipe); Krsnik, I. (Isabel); Ríos, R. (Rafael) de los; Gironella, M. (Mercedes); Bladé, J. (Joan); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Troconiz, I.F. (Iñaki F.); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Lopez-Anglada, L. (Lucia); Arguiñano, J.M. (José María); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Rodriguez-Otero, P. (Paula); Paiva, B. (Bruno); Jarque, I. (Isidro); Oriol, A. (Albert); Marti, J.M. (J.M.); Sureda-Balari, A. M. (Anna Maria); González-Rodriguez, A.P. (Ana Pilar); Bargay, J. (Joan); Gonzalez-Montes, Y. (Yolanda); Jiménez-Ubieto, A. (Ana); San-Miguel, J.F. (Jesús F.); Tamariz-Amador, L.E. (Luis Esteban); Cabañas, V. (Valentín)
    Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a ¿resistance¿ parameter that reflects the stagnation in the response after an initial descent. Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P =.02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P =.02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P <.002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies.
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    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.
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    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.
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    Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials
    (2017) Cedena, M.T. (María Teresa); Martínez-López, J. (Joaquín); Alegre, A. (A.); Bladé, J. (Joan); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Martin-Ramos, M.L. (Maria Luisa); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Martin, A. (Alejandro); Cordón, L. (Lourdes); Palomera, L. (Luis); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Teruel, A.I. (Ana Isabel); Paiva, B. (Bruno); Oriol, A. (Albert); Rubia, J. (Javier) de la; Martínez, R. (Rafael); San-Miguel, J.F. (Jesús F.); Echeveste, M.A. (Maria Asuncion); Raquel
    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 Español 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 withMMand 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.