Ríos-Tamayo, R. (Rafael)
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- Monoclonal gammopathies of clinical significance: a critical appraisal(2022) Martínez-López, J. (Joaquín); Duarte, R.F. (Rafael F.); Lahuerta, J.J. (Juan José); Ríos-Tamayo, R. (Rafael); Paiva, B. (Bruno)Simple Summary Monoclonal gammopathy of clinical significance (MGCS) refers to a recently coined term describing a complex and heterogeneous group of nonmalignant monoclonal gammopathies. These patients are characterized by the presence of a commonly small clone and the occurrence of symptoms that may be associated with the clone or with the monoclonal protein through diverse mechanisms. This is an evolving, challenging, and rapidly changing field. Patients are classified according to the key organ or system involved, with kidneys, skin, nerves, and eyes being the most frequently affected. However, multiorgan involvement may be the most relevant clinical feature at the presentation or during the course. This review delves into the definition, history, differential diagnosis, classification, prognosis, and treatment of this group of entities by analyzing the evidence accumulated to date from a critical perspective. Monoclonal gammopathies of clinical significance (MGCSs) represent a group of diseases featuring the association of a nonmalignant B cells or plasma cells clone, the production of an M-protein, and singularly, the existence of organ damage. They present a current framework that is difficult to approach from a practical clinical perspective. Several points should be addressed in order to move further toward a better understanding. Overall, these entities are only partially included in the international classifications of diseases. Its definition and classification remain ambiguous. Remarkably, its real incidence is unknown, provided that a diagnostic biopsy is mandatory in most cases. In fact, amyloidosis AL is the final diagnosis in a large percentage of patients with renal significance. On the other hand, many of these young entities are syndromes that are based on a dynamic set of diagnostic criteria, challenging a timely diagnosis. Moreover, a specific risk score for progression is lacking. Despite the key role of the clinical laboratory in the diagnosis and prognosis of these patients, information about laboratory biomarkers is limited. Besides, the evidence accumulated for many of these entities is scarce. Hence, national and international registries are stimulated. In particular, IgM MGCS deserves special attention. Until now, therapy is far from being standardized, and it should be planned on a risk and patient-adapted basis. Finally, a comprehensive and coordinated multidisciplinary approach is needed, and specific clinical trials are encouraged.
- Results of an early access treatment protocol of daratumumab monotherapy in spanish patients with relapsed or refractory multiple myeloma(Wolters Kluwer Health, 2020) Blanchard, M.J. (María Jesús); Alegre, A. (A.); Bargay-Lleonart, J. (Joan); Casado-Montero, L.F. (Luis Felipe); Peñarrubia, M.J. (María Jesús); Gaudig, M. (Maren); Potamianou, A. (Anna); Hevia, H. (Henar); Mateos, M.V. (María Victoria); Milionis, I. (Iordanis); Couturier, C. (Catherine); Palomera, L. (Luis); Rodriguez-Otero, P. (Paula); Insunza, A. (Andrés); Ríos-Tamayo, R. (Rafael); González, M.S. (Marta Sonia); Suárez, A. (Alexia); Encinas-Rodríguez, C. (Cristina); Rubia, J. (Javier) de la; Sureda-Balari, A. (Anna); Pei, H. (Huiling)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 (16mg/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 treatmentemergent 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.
- Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC)(2018) Durie, B. (B.); Montero, J. (Juan); Gonzalez, M. (Marcos); Pontes, R. (R.); Hernández-Martín, J. (J.); Diez-Campelo, M. (M.); García-Mateo, A. (A.); Corral-Mateos, A. (A.); García-Sanz, R. (Ramón); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Mateos, M.V. (María Victoria); Romero, A. (A.); Puig, N. (Noemí); Millacoy, P. (P.); Blanco, J.F. (J. F.); Garcés-Latre, J.J. (Juan José); Burgos, L. (Leire); García-Sanchez, O. (O.); Palomera, L. (Luis); Rodriguez-Otero, P. (Paula); Ríos-Tamayo, R. (Rafael); Dongen, J.J.M. (Jacques J. M.) van; Blanco, E. (E.); Paiva, B. (Bruno); EuroFlow-Consortium; Sanoja-Flores, L. (L.); Prosper-Cardoso, F. (Felipe); Merino, J. (Juana); San-Miguel, J.F. (Jesús F.); Pérez-Andrés, M. (M.)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.
- Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial(Springer Nature, 2021) Puig, N. (Noemí); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); González, M.E. (María Esther); Arriba, F. (Felipe) de; Oriol, A. (Albert); Gonzalez-Calle, V. (Veronica); Escalante, F. (Fernando); Rubia, J. (Javier) de la; Gironella, M. (Mercedes); Ríos-Tamayo, R. (Rafael); García-Sánchez, R. (Ricarda); Arguiñano, J.M. (José María); Alegre, A. (A.); Martin, J. (Jesus); Gutierrez, N.C. (Norma C.); Calasanz-Abinzano, M.J. (Maria Jose); Martin-Ramos, M.L. (Maria Luisa); Couto, M.C. (María del Carmen); Casanova, M. (María); Arnao, M. (Mario); Pérez-Persona, E. (Ernesto); Garzón, S. (Sebastián); González, M.S. (Marta Sonia); Martín-Sánchez, G. (Guillermo); Ocio, E.M. (Enrique M.); Coleman, M. (Morton); Encinas, C. (Cristina); Vale, A.M. (Ana M.); Teruel, A.I. (Ana Isabel); Cortés-Rodríguez, M. (María); Paiva, B. (Bruno); Cedena, M.T. (María Teresa); San-Miguel, J.F. (Jesús F.); Lahuerta, J.J. (Juan José); Bladé, J. (Joan); Niesvizky, R. (Ruben); Mateos, M.V. (María Victoria)Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the CRd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the CRd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEMCLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.
- A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma(AACR Journals, 2022) Guerrero, C. (Camila); Puig, N. (Noemí); Cedena, M.T. (María Teresa); Goicoechea, I. (Ibai); Perez, C. (Cristina); Garcés-Latre, J.J. (Juan José); Botta, C. (Cirino); Calasanz-Abinzano, M.J. (Maria Jose); Gutierrez, N.C. (Norma C.); Martin-Ramos, M.L. (Maria Luisa); Oriol, A. (Albert); Ríos-Tamayo, R. (Rafael); Hernandez, M.T. (Miguel Teodoro); Martínez-Martínez, R. (Rafael); Bargay, J. (Joan); Arriba, F. (Felipe) de; Palomera, L. (Luis); González-Rodriguez, A.P. (Ana Pilar); Mosquera-Orgueira, A. (Adrián); Pérez-González, M. (Marta); Martínez-López, J. (Joaquín); Lahuerta, J.J. (Juan José); Rosiñol, L. (Laura); Bladé, J. (Joan); Mateos, M.V. (María Victoria); San-Miguel, J.F. (Jesús F.)Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma. Experimental Design: This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial. Results: The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years. Conclusions: It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma.
- The current role of the heavy/light chain assay in the diagnosis, prognosis and monitoring of multiple myeloma: an evidence-based approach(MDPI, 2021) Ríos-Tamayo, R. (Rafael); Puig, N. (Noemí); Algarín, M. (Macarena); García-de-Veas-Silva, J.L. (José Luís); Barbosa, N. (Nuno); Encinas, C. (Cristina); Hernández-Rivas, J.Á. (José Ángel); Alonso, R. (Rafael); Campos, M.L. (María Luisa); Rodríguez, T. (Teresa); Leivas, A. (Alberto); Olivares, M.J. (María José); Sánchez, M.J. (María-José); Paiva, B. (Bruno); Lahuerta, J.J. (Juan José); Martínez-López, J. (Joaquín)Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.
- Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma(ASH Publications, 2024) Guerrero, C. (Camila); Puig, N. (Noemí); Cedena, M.T. (María Teresa); Calasanz-Abinzano, M.J. (Maria Jose); Gutierrez, N.C. (Norma C.); Fernández, M. (Manuela); Oriol, A. (Albert); Ríos-Tamayo, R. (Rafael); Hernandez, M.T. (Miguel Teodoro); Martinez-Monge, R. (Rafael); Bargay, J. (Joan); Arriba, F. (Felipe) de; Palomera, L. (Luis); González-Rodriguez, A.P. (Ana Pilar); González, M.S. (Marta Sonia); Orfao, A. (Alberto); Mateos, M.V. (María Victoria); Martínez-López, J. (Joaquín); Rosiñol, L. (Laura); Bladé, J. (Joan); Lahuerta-Vargas, J.J. (Juan José); San-Miguel, J.F. (Jesús F.); Pavia, B. (Bruno)The role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144.
- Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma(Elsevier, 2024) Guerrero, C. (Camila); Puig, N. (Noemí); Cedena, M.T. (María Teresa); Calasanz-Abinzano, M.J. (Maria Jose); Gutierrez, N.C. (Norma C.); Fernández, M. (Manuela); Oriol, A. (Albert); Ríos-Tamayo, R. (Rafael); Hernandez, M.T. (Miguel Teodoro); Martínez-Martínez, R. (Rafael); Bargay, J. (Joan); Arriba, F. (Felipe) de; Palomera, L. (Luis); González-Rodriguez, A.P. (Ana Pilar); Gonzalez-Perez, M.S. (Marta-Sonia); Orfao, A. (Alberto); Mateos, M.V. (María Victoria); Martínez-López, J. (Joaquín); Rosiñol, L. (Laura); Bladé, J. (Joan); Lahuerta, J.J. (Juan José); San-Miguel, J.F. (Jesús F.); Paiva, B. (Bruno)The role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/ or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www. clinicaltrials.gov as NCT01916252 and NCT02406144.