Grupos Investigadores

Miembros del Grupo

Líneas de Investigación

  • Profundizar en el papel del micromedioambiente y el sistema inmune en la patogenia de estas enfermedades y sus posibles implicaciones pronosticas y terapéuticas.
  • Desarrollo de nuevos métodos ultra-sensibles para monitorización de enfermedad mínima residual.
  • Caracterización de la célula tumoral basada en modelos pre-clínicos y ensayos clínicos e identificación de biomarcadores de resistencia y potenciales dianas terapéuticas.
  • Caracterización de la amiloidosis sistémica primaria, manifestaciones clínicas y pronóstico de la enfermedad.

Palabras Clave

  • Mieloma
  • Micromedioambiente
  • Enfermedad mínima residual
  • Amiloidosis

Publicaciones Científicas desde 2018

  • Autores: Raje, N. S. (Autor de correspondencia); Anaissie, E.; Kumar, S. K.; et al.
    Revista: THE LANCET. HAEMATOLOGY
    ISSN 2352-3026 Vol.9 N° 2 2022 págs. E143 - E161
    Resumen
    Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.
  • Autores: Facón, T.; San Miguel Izquierdo, Jesús; Dimopoulos, M. A.; et al.
    Revista: ADVANCES IN THERAPY
    ISSN 0741-238X Vol.39 N° 5 2022 págs. 1976 - 1992
    Resumen
    Introduction Many treatment regimens have been evaluated in transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). The objective of this study was to compare the efficacy of relevant therapies for the treatment of TIE patients with NDMM. Methods Progression-free survival (PFS) and overall survival (OS) from large randomised controlled trials (RCTs) evaluating different treatment options for TIE patients with NDMM were compared in a network meta-analysis (NMA). The NMA includes recent primary and long-term OS readouts from SWOG S0777, ENDURANCE, MAIA, and ALCYONE. Relevant trials were identified through a systematic literature review. Relative efficacy measures (i.e., hazard ratios [HRs] for PFS and OS) were extracted and synthesised in random-effects NMAs. Results A total of 122 publications describing 45 unique RCTs was identified. Continuous lenalidomide/dexamethasone (Rd) was selected as the referent comparator. Daratumumab-containing treatments (daratumumab/lenalidomide/dexamethasone [D-Rd], daratumumab/bortezomib/melphalan/prednisone [D-VMP]) and bortezomib/lenalidomide/dexamethasone (VRd) had the highest probabilities of being more effective than Rd continuous for PFS (HR: D-Rd, 0.53; D-VMP, 0.57, VRd, 0.77) and OS (HR: D-Rd, 0.68; VRd, 0.77, D-VMP, 0.78). D-Rd had the highest chance of being ranked as the most effective treatment with respect to PFS and OS. Results using a smaller network focusing on only those regimens that are relevant in Europe were consistent with the primary analysis. Conclusions These comparative effectiveness data may help inform treatment selection in TIE patients with NDMM.
  • Autores: Ocio, E. M. (Autor de correspondencia); Perrot, A.; Bories, P.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.22 N° 6 2022 págs. 425
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Moreau, P.; Terpos, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.33 N° 1 2022 págs. 117
  • Autores: Bronte Viedma, Angela (Autor de correspondencia); Rosales Castillo, Juan Jose; Bastidas Tamayo, Juan Fernando; et al.
    Revista: REVISTA ESPAÑOLA DE MEDICINA NUCLEAR E IMAGEN MOLECULAR
    ISSN 2253-8089 Vol.41 N° Supl. 1 2022 págs. S48 - S50
  • Autores: Botta, C. (Autor de correspondencia); Da Silva Maia, Catarina Alexandra; Garcés Latre, Juan José; et al.
    Revista: BLOOD ADVANCES
    ISSN 2473-9529 Vol.6 N° 2 2022 págs. 690 - 703
    Resumen
    Large-scale immune monitoring is becoming routinely used in clinical trials to identify determinants of treatment responsiveness, particularly to immunotherapies. Flow cytometry remains one of the most versatile and high throughput approaches for single cell analysis; however, manual interpretation of multidimensional data poses a challenge when attempting to capture full cellular diversity and provide reproducible results. We present FlowCT, a semi-automated workspace empowered to analyze large data sets. It includes pre-processing, normalization, multiple dimensionality reduction techniques, automated clustering, and predictive modeling tools. As a proof of concept, we used FlowCT to compare the T-cell compartment in bone marrow (BM) with peripheral blood (PB) from patients with smoldering multiple myeloma (SMM), identify minimally invasive immune biomarkers of progression from smoldering to active MM, define prognostic T-cell subsets in the BM of patients with active MM after treatment intensification, and assess the longitudinal effect of maintenance therapy in BM T cells. A total of 354 samples were analyzed and immune signatures predictive of malignant transformation were identified in 150 patients with SMM (hazard ratio [HR], 1.7; P < .001). We also determined progression-free survival (HR, 4.09; P < .0001) and overall survival (HR, 3.12; P 5 .047) in 100 patients with active MM. New data also emerged about stem cell memory T cells, the concordance between immune profiles in BM and PB, and the immunomodulatory effect of maintenance therapy. FlowCT is a new open-source computational approach that can be readily implemented by research laboratories to perform quality control, analyze high-dimensional data, unveil cellular diversity, and objectively identify biomarkers in large immune monitoring studies. These trials were registered at www. clinicaltrials.gov as #NCT01916252 and #NCT02406144.
  • Autores: Delforge, M. (Autor de correspondencia); Shah, N. (Autor de correspondencia); San Miguel Izquierdo, Jesús; et al.
    Revista: BLOOD ADVANCES
    ISSN 2473-9529 Vol.6 N° 4 2022 págs. 1309 - 1318
    Resumen
    Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, showed deep, durable responses in patients with triple-class exposed, relapsed and refractory multiple myeloma (RRMM) in the phase 2 KarMMa (Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma) trial. We assessed health-related quality of life (HRQoL) among KarMMa patients. The European Organization for Research and Treatment of Cancer Quality of Life C30 Questionnaire and its supplementary 20-item multiple myeloma module, as well as the EuroQol 5-dimension 5-level instrument, were administered at screening, baseline (<= 72 hours before or same day as lymphodepletion), day of ide-cel treatment, and after ide-cel treatment. Mean changes from baseline that exceeded the predetermined threshold of minimally important difference were deemed clinically meaningful. The proportions of patients experiencing clinically meaningful changes in HRQoL were assessed using within-patient change thresholds. Time to stable improvement (<= consecutive visits with clinically meaningful HRQoL improvements) was analyzed by using the Kaplan-Meier method. A total of 126 (98%) of 128 patients treated with ide-cel were included in the HRQoL analysis. Pretreatment baseline RRMM burden was high and meaningfully worse than that in the age- and sex-weighted general population. Statistically significant and clinically meaningful improvements from baseline were observed by month 1 for pain (-8.9) and disease symptoms (-10.2), and by month 2 for fatigue (-7.2), physical functioning (6.1), cognitive functioning (6.7), and global health status/QoL (8.0). Clinically meaningful improvements in fatigue, pain, and physical functioning were most prominent at months 9, 12, and 18, respectively, and were sustained through 15 to 18 months after ide-cel treatment. For triple-class exposed patients with RRMM with a poor prognosis and few treatment options, a single ide-cel infusion provides early, sustained, statistically significant, and clinically meaningful improvements in HRQoL.
  • Autores: Larocca, A.; Leleu, X.; Touzeau, C.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.196 N° 3 2022 págs. 639 - 648
    Resumen
    Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.
  • Autores: Rodríguez Díaz, Saray; Celay Leoz, Ion; Goicoechea Oroz, Ibai; et al.
    Revista: SCIENCE ADVANCES
    ISSN 2375-2548 Vol.8 N° 3 2022 págs. eabl4644
    Resumen
    Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
  • Autores: Rojas, E. A.; Corchete, L. A.; De Ramon, C.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN 0361-8609 Vol.97 N° 6 2022 págs. 700 - 710
    Resumen
    Loss and/or mutation of the TP53 gene are associated with short survival in multiple myeloma, but the p53 landscape goes far beyond. At least 12 p53 protein isoforms have been identified as a result of a combination of alternative splicing, alternative promoters and/or alternative transcription site starts, which are grouped as alpha, beta, gamma, from transactivation domain (TA), long, and short isoforms. Nowadays, there are no studies evaluating the expression of p53 isoforms and its clinical relevance in multiple myeloma (MM). We used capillary nanoimmunoassay to quantify the expression of p53 protein isoforms in CD138-purified samples from 156 patients with newly diagnosed MM who were treated as part of the PETHEMA/GEM2012 clinical trial and investigated their prognostic impact. Quantitative real-time polymerase chain reaction was used to corroborate the results at RNA levels. Low and high levels of expression of short and TAp53 beta/gamma isoforms, respectively, were associated with adverse prognosis in MM patients. Multivariate Cox models identified high levels of TAp53 beta/gamma (hazard ratio [HR], 4.49; p < .001) and high-risk cytogenetics (HR, 2.69; p < .001) as independent prognostic factors associated with shorter time to progression. The current cytogenetic-risk classification was notably improved when expression levels of p53 protein isoforms were incorporated, whereby high-risk MM expressing high levels of short isoforms had significantly longer survival than high-risk patients with low levels of these isoforms. This is the first study that demonstrates the prognostic value of p53 isoforms in MM patients, providing new insights on the role of p53 protein dysregulation in MM biology.
  • Autores: Encinas, C.; Hernández-Rivas, J. A.; Oriol, A.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.12 N° 4 2022 págs. 68
    Resumen
    Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could help to identify the patients that would benefit from preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin <= 30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0-2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies.
  • Autores: Bras, A. E.; Matarraz, S.; Nierkens, S.; et al.
    Revista: CANCERS
    ISSN 2072-6694 Vol.14 N° 8 2022 págs. 2011
    Resumen
    Simple Summary Flow cytometry allows detailed characterization of large numbers of cells and plays an important role in the diagnosis of acute myeloid leukemia. To facilitate analysis of flowcytometric data, reference databases of normal bone marrow samples and samples from acute myeloid leukemia patients, together with new software tools, are required. We here report on the building of a large database of acute myeloid leukemia patients (n = 1142) and 22 normal samples. We report on the quality assessment procedure used and its validation, discuss potential pitfalls, and provide possible solutions for avoiding such flaws in the construction of other databases. Our data show that obtaining and collecting reproducible flow cytometric data over time and across centers is feasible, but also that strict quality assessment remains crucial, even when standardized protocols for staining and instrument settings are being used in a multicenter setting. Flowcytometric analysis allows for detailed identification and characterization of large numbers of cells in blood, bone marrow, and other body fluids and tissue samples and therefore contributes to the diagnostics of hematological malignancies. Novel data analysis tools allow for multidimensional analysis and comparison of patient samples with reference databases of normal, reactive, and/or leukemia/lymphoma patient samples. Building such reference databases requires strict quality assessment (QA) procedures. Here, we compiled a datase
  • Autores: Mosquera Orgueira, A.; González Pérez, M. S.; Díaz Arias, J.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.12 N° 4 2022 págs. 76
    Resumen
    The International Staging System (ISS) and the Revised International Staging System (R-ISS) are commonly used prognostic scores in multiple myeloma (MM). These methods have significant gaps, particularly among intermediate-risk groups. The aim of this study was to improve risk stratification in newly diagnosed MM patients using data from three different trials developed by the Spanish Myeloma Group. For this, we applied an unsupervised machine learning clusterization technique on a set of clinical, biochemical and cytogenetic variables, and we identified two novel clusters of patients with significantly different survival. The prognostic precision of this clusterization was superior to those of ISS and R-ISS scores, and appeared to be particularly useful to improve risk stratification among R-ISS 2 patients. Additionally, patients assigned to the low-risk cluster in the GEM05 over 65 years trial had a significant survival benefit when treated with VMP as compared with VTD. In conclusion, we describe a simple prognostic model for newly diagnosed MM whose predictions are independent of the ISS and R-ISS scores. Notably, the model is particularly useful in order to re-classify R-ISS score 2 patients in 2 different prognostic subgroups. The combination of ISS, R-ISS and unsupervised machine learning clusterization brings a promising approximation to improve MM risk stratification.
  • Autores: Böttcher, S. (Autor de correspondencia); Engelmann, R.; Grigore, G.; et al.
    Revista: BLOOD ADVANCES
    ISSN 2473-9529 Vol.6 N° 3 2022 págs. 976 - 992
    Resumen
    Reproducible expert-independent flow-cytometric criteria for the differential diagnoses between mature B-cell neoplasms are lacking. We developed an algorithm-driven classification for these lymphomas by flow cytometry and compared it to the WHO gold standard diagnosis. Overall, 662 samples from 662 patients representing 9 disease categories were analyzed at 9 laboratories using the previously published EuroFlow 5-tube-8-color B-cell chronic lymphoproliferative disease antibody panel. Expression levels of all 26 markers from the panel were plotted by B-cell entity to construct a univariate, fully standardized diagnostic reference library. For multivariate data analysis, we subsequently used canonical correlation analysis of 176 training cases to project the multidimensional space of all 26 immunophenotypic parameters into 36 2-dimensional plots for each possible pairwise differential diagnosis. Diagnostic boundaries were fitted according to the distribution of the immunophenotypes of a given differential diagnosis. A diagnostic algorithm based on these projections was developed and subsequently validated using 486 independent cases. Negative predictive values exceeding 92.1% were observed for all disease categories except for follicular lymphoma. Particularly high positive predictive values were returned in chronic lymphocytic leukemia (99.1%), hairy cell leukemia (97.2%), follicular lymphoma (97.2%), and mantle cell lymphoma (95.4%). Burkitt and CD101 diffuse large B-cell lymphomas were difficult to distinguish by the algorithm. A similar ambiguity was observed between marginal zone, lymphoplasmacytic, and CD102 diffuse large B-cell lymphomas. The specificity of the approach exceeded 98% for all entities. The univariate immunophenotypic library and the multivariate expert-independent diagnostic algorithm might contribute to increased reproducibility of future diagnostics in mature B-cell neoplasms.
  • Autores: Guerrero De Blois, Camila; Puig, N.; Cedena, M. T.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN 1078-0432 Vol.28 N° 12 2022 págs. 2598 - 2609
    Resumen
    Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treat-ment individualization based on the probability of a patient achiev-ing 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 trans-plant-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 Espanol 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 predic -ti ons 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 main-tenance (GEM2014MAIN). High-confidence prediction of unde-tectable 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.
  • Autores: Garcés Latre, Juan José (Autor de correspondencia); San Miguel Izquierdo, Jesús; Paiva, Bruno (Autor de correspondencia)
    Revista: CANCERS
    ISSN 2072-6694 Vol.14 N° 6 2022 págs. 1430
    Resumen
    Simple Summary Bone marrow (BM) aspirates are mandatory for diagnosis and follow-up of patients with multiple myeloma (MM). However, they present two important caveats: Their invasiveness and limited scope to capture the broad tumor heterogeneity. Conversely, circulating tumor cells (CTCs) are detectable in the peripheral blood of patients with precursor and malignant disease states and have strong prognostic value. Moreover, the high genetic and transcriptomic overlap between both plasma cell compartments suggests that CTCs might reflect with notable precision the medullar clone. Furthermore, the study of CTCs could be used as a model to identify mechanisms favoring BM egression and disease spreading. Here, we summarize the state of the art on MM CTCs and provide insights on what they may offer in research and clinical scenarios. Bone marrow (BM) aspirates are the gold standard for patient prognostication and genetic characterization in multiple myeloma (MM). However, they represent an important limitation for periodic disease monitoring because they entail an aggressive procedure. Moreover, recent findings show that a single BM aspirate is unable to reflect the complex MM heterogeneity. Recent advances in flow cytometry, microfluidics, and "omics" technologies have opened Pandora's box of MM: The detection and isolation of circulating tumor cells (CTCs) offer a promising and minimally invasive alternative for tumor assessment and metastasis study. CTCs are detectable in premalignant and active MM states, and their enumeration has strong prognostic value, to the extent that it is challenging current stratification systems. In addition, CTCs reflect with high precision both intra- and extra-medullary disease at the phenotypic, genomic, and transcriptomic levels. Despite this high resemblance between tumor clones in distinct locations, some subtle (not random) differences might shed some light on the metastatic process. Thus, it has been suggested that a hypoxic and pro-inflammatory microenvironment could induce an arrest in proliferation forcing tumor cells to recirculate. Herein, we summarize data on the characterization of MM CTCs as well as their clinical and research potential.
  • Autores: Richardson, P. G. (Autor de correspondencia); Schjesvold, F.; Weisel, K.; et al.
    Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
    ISSN 0902-4441 Vol.108 N° 1 2022 págs. 73 - 83
    Resumen
    Objective We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse. Methods OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS). Results Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged <= 65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports. Conclusions These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.
  • Autores: Mateos, M. V. (Autor de correspondencia); Weisel, K.; De Stefano, V.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.36 N° 5 2022 págs. 1371 - 1376
    Resumen
    Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, >= 3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.
  • Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Avet-Loiseau, H.; Paiva, Bruno; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.139 N° 4 2022 págs. 492 - 501
    Resumen
    In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/ lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/ melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10(-5)) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting >= 6 and >= 12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting >= 6 and >= 12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting >= 6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and >= 12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes.
  • Autores: Cavo, M. (Autor de correspondencia); San Miguel Izquierdo, Jesús; Usmani, S. Z.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.139 N° 6 2022 págs. 835 - 844
    Resumen
    We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (>= CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10(-5) sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received <= 2 prior lines of therapy (<= 2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved >= CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM <= 2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that >= CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching >= CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support >= CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM.
  • Autores: Nevone, A.; Girelli, M.; Mangiacavalli, S.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.36 N° 8 2022 págs. 2076 - 2085
    Resumen
    Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal kappa LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic kappa LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies.
  • Autores: Popat, R.; Usmani, S. Z.; Garfall, A.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.197 N° Supl. 1 2022 págs. 35 - 36
  • Autores: Terpos, E. (Autor de correspondencia); Zamagni, E.; Lentzsch, S.; et al.
    Revista: LANCET ONCOLOGY
    ISSN 1470-2045 Vol.22 N° 3 2021 págs. e119 - e130
    Resumen
    In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.
  • Autores: Ludwig, H. (Autor de correspondencia); Sonneveld, P.; Facon, T.; et al.
    Revista: THE LANCET. HAEMATOLOGY
    ISSN 2352-3026 Vol.8 N° 12 2021 págs. e934 - e946
    Resumen
    Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19 vaccination in patients with multiple myeloma was condensed into this Review.
  • Autores: Ludwig, H. (Autor de correspondencia); Boccadoro, M.; Moreau, P.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.35 N° 1 2021 págs. 31 - 44
    Resumen
    Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice.
  • Autores: Rodríguez Otero, Paula; Paiva, Bruno; San Miguel Izquierdo, Jesús (Autor de correspondencia)
    Revista: CANCER TREATMENT REVIEWS
    ISSN 0305-7372 Vol.100 2021 págs. 102284
    Resumen
    Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains elusive. We propose in this review a roadmap to achieve the dream of cure for multiple myeloma based on five complementary strategies. First, to increase knowledge about disease pathogenesis with a focus on the biology of circulating tumor cells, responsible for dissemination and extramedullary disease, and minimal residual disease clones who represent the reservoir of clonal evolution and disease recurrence. Second, to consider undetectable measurable residual disease (MRD), defined by high-sensitive techniques, as the new endpoint of therapy. Third, to treat disease causation instead of symptomatology through early detection and intervention. Thereby, by treating high-risk smoldering myeloma patients early, we may not only contribute to delay disease progression into active disease but also to increase the cure rates. Fourth, to use the most active scheme in standard-risk patients if the cure is in the horizon. Fifth, to investigate experimental therapies in newly diagnosed patients with high-risk MM, implementing early rescue intervention strategies with the goal of eradicating all tumor clones, and achieving minimal residual disease negativity.
  • Autores: Musto, P. (Autor de correspondencia); Engelhardt, M.; Caers, J.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 11 2021 págs. 2799 - 2812
    Resumen
    According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of monoclonal gammopathy of undetermined significance-like, in which patients never progress during their lifetimes, to early multiple myeloma, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a split personality makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide +/- dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.
  • Autores: Ríos-Tamayo, R. (Autor de correspondencia); Puig, N.; Algarín, M.; et al.
    Revista: DIAGNOSTICS
    ISSN 2075-4418 Vol.11 N° 11 2021 págs. 2020
    Resumen
    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.
  • Autores: Ruiz-Pablos, M. (Autor de correspondencia); Paiva, Bruno; Montero-Mateo, R.; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN 1664-3224 Vol.12 2021 págs. 656797
    Resumen
    Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.
  • Autores: Moreau, P. (Autor de correspondencia); Kumar, S. K.; San Miguel Izquierdo, Jesús; et al.
    Revista: LANCET ONCOLOGY
    ISSN 1470-2045 Vol.22 N° 3 2021 págs. e105 - e118
    Resumen
    This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.
  • Autores: Munshi, N. C. (Autor de correspondencia); Hege, K.; San Miguel Izquierdo, Jesús
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN 0028-4793 Vol.384 N° 24 2021 págs. 2357 - 2358
  • Autores: Moreau, P. (Autor de correspondencia); Ghori, R.; Farooqui, M.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.194 N° 1 2021 págs. E48 - E51
  • Autores: Lahuerta Alsina, Juan José; Paiva, Bruno; de-Ubieto, A. J.; et al.
    Revista: BLOOD ADVANCES
    ISSN 2473-9529 Vol.5 N° 5 2021 págs. 1340 - 1343
  • Autores: Jiménez-Ubieto, A.; Paiva, Bruno; Puig, N.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.138 N° 19 2021 págs. 1901 - 1905
  • Autores: Ludwig, H. (Autor de correspondencia); San Miguel Izquierdo, Jesús; Munshi, N.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN 0361-8609 Vol.96 N° 8 2021 págs. 896 - 900
  • Autores: Ocio, E. M. (Autor de correspondencia); Motllo, C.; Rodríguez Otero, Paula; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.192 2021 págs. 522 - 530
    Resumen
    This phase I/II trial evaluated the combination of the kinesin spindle protein inhibitor filanesib with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM) patients. Forty-seven RRMM patients with a median of three prior lines (2-8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. The recommended dose was 1 center dot 25 mg/m(2) of filanesib on days 1, 2, 15, 16, with pomalidomide 4 mg on days 1-21 and dexamethasone 40 mg weekly. The defined threshold for success was achieved, with 18 out of 31 patients obtaining at least minor response (MR) in the phase II. In the global population, 51% of patients achieved at least partial response (PR) and 60% >= MR, resulting in a median progression-free survival (mPFS) of seven months and overall survival (OS) of 19 months. The main toxicity was haematological. Importantly, patients with low serum levels of alpha 1-acid glycoprotein (AAG) at baseline (<800 mg/l) had a superior response (overall response rate of 62% vs. 17%; P = 0 center dot 04), which also translated into a longer mPFS (9 vs. 2 months; P = 0 center dot 014). In summary, filanesib with pomalidomide and dexamethasone is active in RRMM although with significant haematological toxicity. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy.
  • Autores: Dimopoulos, M. A.; Moreau, P.; Terpos, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.32 N° 3 2021 págs. 309 - 322
  • Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Usmani, S. Z.; Mateos, M. V.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 6 2021 págs. 1725 - 1732
    Resumen
    Intravenous daratumumab is approved for the treatment of multiple myeloma. In part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and an efficacy similar to that of intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumumab and rHuPH20 (DARA SC). Patients who had received two or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, were given daratumumab (1,800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3 to 5 minutes as per the approved intravenous monotherapy dosing schedule. Primary endpoints were daratumumab trough concentration at the end of weekly dosing (just prior to the day 1 dose of cycle 3) and safety. Twenty-five patients were enrolled in PAVO part 2. DARA SC achieved daratumumab trough concentrations similar to or greater than those achieved with intravenous daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with that of intravenous daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, the median duration of response was 15.7 months, and the median progression-free survival was 12.0 months. DARA SC 1,800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with those following intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in the treatment of multiple myeloma and other conditions.
  • Autores: Dimopoulos, M. (Autor de correspondencia); Weisel, K.; Moreau, P.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.35 N° 6 2021 págs. 1722 - 1731
    Resumen
    In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months;P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months;P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months;P = 0.0068), and patients with (22.0 vs 13.8 months;P = 0.0241) or without (16.5 vs 9.5 months;P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%;P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%;P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); Ayers, D.; Cope, S.; et al.
    Revista: LEUKEMIA AND LYMPHOMA
    ISSN 1042-8194 Vol.62 N° 10 2021 págs. 2482 - 2491
    Resumen
    Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM.
  • Autores: Murray, D. L.; Puig, N.; Kristinsson, S.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.11 N° 2 2021 págs. 24
    Resumen
    Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs.
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Moreau, P.; Terpos, E.; et al.
    Revista: HEMASPHERE
    ISSN 2572-9241 Vol.5 N° 24 2021 págs. e528
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); Sirvent, M.; González-Rodríguez, A. P.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° 6 2021 págs. 413 - 420
    Resumen
    Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging. We analyzed the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex) in a real-world RRMM population. Median progression-free and overall survival were 7.6 and 12.6 months, respectively, which compares favorably with other triplets in the same setting. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM. Introduction: Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations. Patients and Methods: A real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy. Results: Overall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease. Conclusion: Our results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients. (C) 2021 Published by Elsevier Inc.
  • Autores: Nooka, A. K. ; Weisel, K.; van de Donk, N. W. C. J. ; et al.
    Revista: FUTURE ONCOLOGY
    ISSN 1479-6694 Vol.17 N° 16 2021 págs. 1987 - 2003
    Resumen
    Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ¿4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).
  • Autores: Paiva, B.; Vidriales, M. B. ; Sempere, A.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.35 N° 8 2021 págs. 2358 - 2370
    Resumen
    The role of decentralized assessment of measurable residual disease (MRD) for risk stratification in acute myeloid leukemia (AML) remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using multiparameter flow cytometry (MFC). We analyzed 1076 AML patients in first remission after induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories of 60 Hospitals participating in the PETHEMA registry. We also conducted a survey on technical aspects of MRD testing to determine the impact of methodological heterogeneity in the prognostic value of MFC. Our results confirmed the recommended cutoff of 0.1% to discriminate patients with significantly different cumulative-incidence of relapse (-CIR- HR:0.71, P < 0.001) and overall survival (HR: 0.73, P = 0.001), but uncovered the limited prognostic value of MFC based MRD in multivariate and recursive partitioning models including other clinical, genetic and treatment related factors. Virtually all aspects related with methodological, interpretation, and reporting of MFC based MRD testing impacted in its ability to discriminate patients with different CIR. Thus, this study demonstrated that "real-world" assessment of MRD using MFC is prognostic in patients at first remission, and urges greater standardization for improved risk-stratification toward clinical decisions in AML.
  • Autores: Prieto Azcárate, Elena; García Velloso, María José (Autor de correspondencia); Dámaso-Aquerreta, J.; et al.
    Revista: PHYSICA MEDICA
    ISSN 1120-1797 Vol.84 2021 págs. 1 - 9
    Resumen
    Purpose: To investigate within phantoms the minimum CT dose allowed for accurate attenuation correction of PET data and to quantify the effective dose reduction when a CT for this purpose is incorporated in the clinical setting. Methods: The NEMA image quality phantom was scanned within a large parallelepiped container. Twenty-one different CT images were acquired to correct attenuation of PET raw data. Radiation dose and image quality were evaluated. Thirty-one patients with proven multiple myeloma who underwent a dual tracer PET/CT scan were retrospectively reviewed. 18F-fluorodeoxyglucose PET/CT included a diagnostic whole-body low dose CT (WBLDCT: 120 kV-80mAs) and 11C-Methionine PET/CT included a whole-body ultra-low dose CT (WBULDCT) for attenuation correction (100 kV-40mAs). Effective dose and image quality were analysed. Results: Only the two lowest radiation dose conditions (80 kV-20mAs and 80 kV-10mAs) produced artifacts in CT images that degraded corrected PET images. For all the other conditions (CTDIvol ¿ 0.43 mGy), PET contrast recovery coefficients varied less than ± 1.2%. Patients received a median dose of 6.4 mSv from diagnostic CT and 2.1 mSv from the attenuation correction CT. Despite the worse image quality of this CT, 94.8% of bone lesions were identifiable. Conclusion: Phantom experiments showed that an ultra-low dose CT can be implemented in PET/CT procedures without any noticeable degradation in the attenuation corrected PET scan. The replacement of the standard CT for this ultra-low dose CT in clinical PET/CT scans involves a significant radiation dose reduction.
  • Autores: Avet-Loiseau, H. (Autor de correspondencia); San Miguel Izquierdo, Jesús; Casneuf, T.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 10 2021 págs. 1139 - 1149
    Resumen
    PURPOSE In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies. METHODS MRD was assessed via next-generation sequencing (10(-5)) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (>= 6 or >= 12 months) was evaluated in the intention-to-treat (ITT) and >= CR populations. RESULTS The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in >= CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity >= 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and >= 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity
  • Autores: Luo, M. M. (Autor de correspondencia); Usmani, S. Z. ; Mateos, M. V. ; et al.
    Revista: JOURNAL OF CLINICAL PHARMACOLOGY
    ISSN 0091-2700 Vol.61 N° 5 2021 págs. 614 - 627
    Resumen
    We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (C-trough) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the <= 65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients <= 50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.
  • Autores: Mendonca-de-Pontes, R.; Flores-Montero, J.; Sanoja-Flores, L.; et al.
    Revista: CANCERS
    ISSN 2072-6694 Vol.13 N° 7 2021 págs. 1704
    Resumen
    Simple Summary B-cell regeneration during therapy has been associated with the outcome of multiple myeloma (MM) patients. However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated. Here, we show that hemodilution is present in a significant fraction of MM BM samples, leading to lower total B-cell, B-cell precursor (BCP), and normal plasma cell (nPC) counts. Among MM BM samples, decreased percentages (vs. healthy donors) of BCP, transitional/naive B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP, but not TBC/NBC, increased after induction therapy. At day+100 post-autolo-gous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19(-) nPC counts vs. non-CR specimens with no clear association between BM B-cell regeneration profiles and patient outcomes. B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (>= 50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naive B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19(-) nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome.
  • Autores: Alameda Serrano, Daniel; Goicoechea Oroz, Ibai; Vicari, M.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.138 N° 17 2021 págs. 1583 - 1589
    Resumen
    Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, but there are no studies investigating the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development (n=11) in secondary lymphoid organs (SLO), peripheral blood (PB) and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL (n=37), MM (n=46) and MGUS (n=6). Based on bulk and single-cell RNAseq, we observed thirteen TPs during transition of normal PCs throughout SLO, PB and BM; that CD39 outperforms CD19 to discriminate new-born from long-lived BM-PCs; that tumor PCs expressed the most advantageous TPs of normal PC differentiation; that AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and new-born BM-PCs; that AL and MM patients enriched in immature TPs had inferior survival; and that TPs related with protein N-linked glycosylation are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies.
  • Autores: Plesner, T. (Autor de correspondencia); Dimopoulos, M. A.; Oriol, A.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.194 N° 1 2021 págs. 132 - 139
    Resumen
    In the phase 3 POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma (RRMM) compared with lenalidomide and dexamethasone (Rd) alone. Here, we present patient-reported outcomes (PROs) from POLLUX, assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaires. Changes from baseline are presented as least-squares mean changes with 95% confidence intervals (CIs) derived from a mixed-effects model. PRO assessment compliance rates were high and similar in both D-Rd and Rd groups through cycle 40 (week 156). In this on-treatment analysis, mean changes from baseline were significantly greater in EORTC QLQ-C30 global health status, physical functioning, and pain scores in the D-Rd group versus the Rd group at multiple time points; however, magnitude of changes was low, suggesting no meaningful impact on health-related quality of life (HRQoL). Subgroup results were similar to those in the overall population. In the POLLUX study, baseline HRQoL was maintained with prolonged D-Rd treatment. These findings complement the sustained and significant improvement in progression-free survival observed with D-Rd and supports its use in patients with RRMM. Clinical trial registration: NCT02076009.
  • Autores: Knop, S. (Autor de correspondencia); Mateos, M. V.; Dimopoulos, M. A.; et al.
    Revista: BMC CANCER
    ISSN 1471-2407 Vol.21 N° 1 2021 págs. 659
    Resumen
    BackgroundIn the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE.MethodsThe European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3months (year 1) and every 6months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model.ResultsCompliance with PRO assessments was comparable at baseline (>90%) and throughout study (>76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p =0.0240) and VAS (p =0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful.ConclusionsPatients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP.Trial registrationClinicalTrials.gov identifier NCT02195479, registered September 21, 2014
  • Autores: Goicoechea Oroz, Ibai; Puig, N.; Cedena, M. T.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.137 N° 1 2021 págs. 49 - 60
    Resumen
    Patients with multiple myeloma (MM) carrying high-risk cytogenetic abnormalities (CA) have inferior outcome despite achieving similar complete response (CR) rates when compared to cases with standard-risk CA. This questions the legitimacy of CR as treatment endpoint for high-risk MM, and represents a biological conundrum regarding the nature of tumor reservoirs persisting after therapy in patients with standard- and high-risk CA. Here, we used next-generation flow (NGF) to evaluate measurable residual disease (MRD) in MM patients with standard- (N=300) vs high-risk CA (N=90) enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and to identify mechanisms determining MRD resistance in both patient subgroups (N=40). The 36-month progression-free and overall survival rates were higher than 90% in patients with undetectable MRD, with no significant differences (P¿0.202) between cases having standard- vs high-risk CA. Persistent MRD resulted in median progression-free survival of approximately three and two years in patients with standard- and high-risk CA, respectively (P<0.001). Further use of NGF to isolate MRD followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CA, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying lost or acquired genetic abnormalities driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and ROS-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as treatment endpoint for MM patients with high-risk CA and proposes characterizing MRD clones to understand and overcome MRD resistance.
  • Autores: Munshi, N. C. (Autor de correspondencia); Anderson, L. D. ; Shah, N.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN 0028-4793 Vol.384 N° 8 2021 págs. 705 - 716
    Resumen
    BACKGROUND Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigendirected chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulating agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 x 10(6) to 450 x 10(6) CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10(-5) nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion. CONCLUSIONS Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome.
  • Autores: Lhermitte, L.; Barreau, S.; Morf, D.; et al.
    Revista: MODERN PATHOLOGY
    ISSN 0893-3952 Vol.34 N° 1 2021 págs. 59 - 69
    Resumen
    Precise classification of acute leukemia (AL) is crucial for adequate treatment. EuroFlow has previously designed an AL orientation tube (ALOT) to guide toward the relevant classification panel and final diagnosis. In this study, we designed and validated an algorithm for automated (database-supported) gating and identification (AGI tool) of cell subsets within samples stained with ALOT. A reference database of normal peripheral blood (PB,n = 41) and bone marrow (BM;n = 45) samples analyzed with the ALOT was constructed, and served as a reference for the AGI tool to automatically identify normal cells. Populations not unequivocally identified as normal cells were labeled as checks and were classified by an expert. Additional normal BM (n = 25) and PB (n = 43) and leukemic samples (n = 109), analyzed in parallel by experts and the AGI tool, were used to evaluate the AGI tool. Analysis of normal PB and BM samples showed low percentages of checks (<3% in PB, <10% in BM), with variations between different laboratories. Manual analysis and AGI analysis of normal and leukemic samples showed high levels of correlation between cell numbers (r(2) > 0.95 for all cell types in PB andr(2) > 0.75 in BM) and resulted in highly concordant classification of leukemic cells by our previously published automated database-guided expert-supervised orientation tool for immunophenotypic diagnosis and classification of acute leukemia (Compass tool).
  • Autores: Usmani, S. Z. (Autor de correspondencia); Garfall, A. L.; van-de-Donk, N. W. C. J.; et al.
    Revista: LANCET
    ISSN 0140-6736 Vol.398 N° 10301 2021 págs. 665 - 674
    Resumen
    Background There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma. Methods This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0.3-19.2 mu g/kg [once every 2 weeks] or 19.2-720 mu g/kg [once per week]) or subcutaneously (range 80-3000 mu g/kg [once per week]) in different cohorts, with step-up dosing for 38.4 mu g/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181. Findings Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 mu g/kg, after 60 mu g/kg and 300 mu g/kg step-up doses (median follow-up 6.1 months, IQR 3.6-8.2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 [40%]). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48-79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7.1 months' median follow-up (IQR 5.1-9.1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported. Interpretation Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development.
  • Autores: Dimopoulos, M. (Autor de correspondencia); Bringhen, S.; Anttila, P.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.137 N° 9 2021 págs. 1154 - 1165
    Resumen
    This phase 2 study evaluated isatuximab as monotherapy or combined with dexamethasone in relapsed/refractory multiple myeloma (RRMM). Patients had RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received ¿3 prior lines of therapy incorporating an IMiD and PI. Patients received isatuximab either as monotherapy (20 mg/kg on days 1, 8, 15, and 22 [once weekly] of cycle 1 followed by 20 mg/kg on days 1 and 15 of subsequent cycles; Isa group) or in combination with dexamethasone (40 mg/d [20 mg/d in patients aged ¿75 years] once weekly; Isa-dex group). Treated patients (N = 164) had received a median of 4 (range, 2-10) prior treatment lines. Patients received a median of 5 (1-24) and 7 (1-22) treatment cycles; at data cutoff, 13 (11.9%) of 109 and 15 (27.3%) of 55 patients remained on treatment in the Isa and Isa-dex arms, respectively. Overall response rate (primary efficacy end point) was 23.9% in the Isa arm and 43.6% in the Isa-dex arm (odds ratio, 0.405; 95% confidence interval, 0.192-0.859; P = .008). Median progression-free survival and overall survival were 4.9 and 18.9 months for Isa, and 10.2 and 17.3 months for Isa-dex. Infusion reactions (mostly grade 1/2) and hematologic abnormalities were the most common adverse events. There was a similar incidence of grade 3 or higher infections in both groups (22.0% and 21.8%). In conclusion, addition of dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety. This trial was registered at www.clinicaltrials.gov as #NCT01084252.
  • Autores: Martín-Sánchez, E. ; Garcés, J. J.; Maia, C.; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN 1664-3224 Vol.12 2021 págs. 659018
    Resumen
    Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.
  • Autores: Mateos, M. V. (Autor de correspondencia); Dimopoulos, M. A.; Cavo, M.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° 11 2021 págs. 785 - 798
    Resumen
    In the global phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved outcomes versus VMP in transplant-ineligible patients with newly diagnosed multiple myeloma. In this subgroup analysis of ALCYONE, frailty was assessed retrospectively among all randomized patients (D-VMP, n = 350; VMP, n = 356). Improved efficacy with D-VMP versus VMP was observed across frailty subgroups, with no new safety concerns. Background: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status. Patients and Methods: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (>= 2); a nonfrail category combined fit and intermediate patients. Results: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median followup, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P <.0001), frail (32.9 vs. 19.5 months; HR, 0.51; P <.0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10(-5))-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%). Conclusion: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
  • Autores: Palladini, G. (Autor de correspondencia); Paiva, Bruno; Wechalekar, A.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.11 N° 2 2021 págs. 34
    Resumen
    Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.
  • Autores: Richardson, P. G. (Autor de correspondencia); Oriol, A.; Larocca, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 7 2021 págs. 757 - 767
    Resumen
    Purpose: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. Patients and methods: Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. Results: Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ¿ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. Conclusion: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease. Trial registration: ClinicalTrials.gov NCT02963493.
  • Autores: Fernández de Larrea, C. (Autor de correspondencia); Kyle, R.; Rosinol, L.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.11 N° 12 2021 págs. 192
    Resumen
    Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of >= 5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma.
  • Autores: Costa, L. J. (Autor de correspondencia); Derman, B. A.; Bal, S.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.35 N° 1 2021 págs. 18 - 30
    Resumen
    Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.
  • Autores: Simoes Pinto, Cátia Patricia; Paiva, Bruno; Martínez Cuadrón, D.; et al.
    Revista: BLOOD ADVANCES
    ISSN 2473-9529 Vol.5 N° 3 2021 págs. 760 - 770
    Resumen
    The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase 3 FLUGAZA clinical trial, which randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine (FLUGA) vs 5-azacitidine. After consolidation, patients continued treatment if MRD was ¿0.01% or stopped if MRD was <0.01%, as assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N = 72) was the only independent prognostic factor for relapse-free survival (RFS) (HR, 3.45;P= .002). Achieving undetectable MRD significantly improved RFS of patients with adverse genetics (HR, 0.32;P= .013). Longer overall survival was observed in patients with undetectable MRD after induction though not after consolidation. Although leukemic cells from most patients displayed phenotypic aberrancies vs their normal counterpart (N = 259 of 265), CD34 progenitors from cases with undetectable MRD by MFC carried extensive genetic abnormalities identified by whole-exome sequencing. Interestingly, the number of genetic alterations significantly increased from diagnosis to MRD stages in patients treated with FLUGA vs 5-azacitidine (2.2-fold vs 1.1-fold;P
  • Autores: Cohen, Y. C. (Autor de correspondencia); Oriol, A.; Wu, K. L.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° 1 2021 págs. 46-54.e4
    Resumen
    Background: Daratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 inhibitor, in RRMM. Patients and methods: This open-label, multiphase study enrolled adults with RRMM with ¿ 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses. Results: Nine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee's global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had ¿ 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had ¿ 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%. Conclusions: No new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination.
  • Autores: Vives, S.; Martinez Cuadron, D.; Bergua Burgues, J.; et al.
    Revista: CANCER
    ISSN 0008-543X Vol.127 N° 12 2021 págs. 2003 - 2014
    Resumen
    BACKGROUND Options to treat elderly patients (>= 65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA). METHODS Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was >= 0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. RESULTS The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). CONCLUSIONS FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.
  • Autores: Puig, N. (Autor de correspondencia); Flores-Montero, J.; Burgos Rodríguez, Leire; et al.
    Revista: CANCERS
    ISSN 2072-6694 Vol.13 N° 19 2021 págs. 4924
    Resumen
    Although the majority of patients with myeloma who achieve undetectable minimal residual disease show prolonged survival, some of them relapse shortly afterwards. False-negative results due to hemodiluted bone marrow samples could explain this inconsistency, but there is no guidance on how to evaluate them. We analyzed three cell populations normally absent in peripheral blood in 1404 aspirates obtained in numerous disease settings and in 85 healthy adults. Pairwise comparisons according to age and treatment showed significant variability, thus suggesting that hemodilution should be preferably evaluated with references obtained after receiving identical regimens. Leveraging the minimal residual disease results from 118 patients, we showed that a comparison with age-matched healthy adults could also inform on potential hemodilution. Our study supports the routine assessment of bone marrow cellularity to evaluate hemodilution, using as reference values either treatment-specific or from healthy adults if the former are unavailable.
  • Autores: Damasceno, D.; Almeida, J.; Teodosio, C.; et al.
    Revista: CANCERS
    ISSN 2072-6694 Vol.13 N° 6 2021 págs. 1454
    Resumen
    Simple Summary We investigated the distribution of different subsets of monocytes (Mo) in blood and bone marrow (BM) of newly-diagnosed untreated monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), and its relationship with immune/bone serum-marker profiles. Our results showed decreased production of BM Mo with decreased counts of classical Mo (cMo) in BM and blood of SMM and MM, but not MGUS. Conversely, intermediate and non-classical Mo were significantly increased in MGUS, SMM and MM BM. In parallel, increased levels of interleukin (IL)1 beta were observed in a fraction of MGUS and SMM, while increased serum IL8 was characteristic of SMM and MM, and higher serum IL6, RANKL and bone alkaline phosphatase concentrations, together with decreased counts of Fc epsilon RI(+)cMo, were restricted to MM presenting with bone lesions. These results provide new insights in the pathogenesis of plasma cell neoplasms and the potential role of Fc epsilon RI(+)cMo in normal bone homeostasis. Background. Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment. Methods: We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly-diagnosed untreated MGUS (n = 23), SMM (n = 14) and MM (n = 99) patients vs. healthy donors (HD; n = 107), in parallel to a large panel of cytokines and bone-associated serum biomarkers. Results: Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (p <= 0.02), in association with lower blood counts of recently-produced CD62L(+) cMo in SMM (p = 0.004) and of all subsets of (CD62L(+), CD62L(-) and Fc epsilon RI+) cMo in MM (p <= 0.02). In contrast, intermediate and end-stage non-classical Mo were increased in BM of MGUS (p <= 0.03), SMM (p <= 0.03) and MM (p <= 0.002), while normal (MGUS and SMM) or decreased (MM; p = 0.01) in blood. In parallel, increased serum levels of interleukin (IL)1 beta were observed in MGUS (p = 0.007) and SMM (p = 0.01), higher concentrations of serum IL8 were found in SMM (p = 0.01) and MM (p = 0.002), and higher serum IL6 (p = 0.002), RANKL (p = 0.01) and bone alkaline phosphatase (BALP) levels (p = 0.01) with decreased counts of Fc epsilon RI+ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three distinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent-like (increased IL1 beta and/or IL8, found in a minority of MGUS, most SMM and few MM cases with no bone lesions); and (3) pro-inflammatory-high serum IL6, RANKL and BALP with significantly (p = 0.01) decreased blood counts of immunomodulatory Fc epsilon RI+ cMo-, typical of MM presenting with bone lesions. Conclusions: These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of Fc epsilon RI+ cMo in normal bone homeostasis.
  • Autores: Laubach, J. P. (Autor de correspondencia); Schjesvold, F.; Mariz, M.; et al.
    Revista: LANCET ONCOLOGY
    ISSN 1470-2045 Vol.22 N° 1 2021 págs. 142 - 154
    Resumen
    Background: Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. Methods: PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov, NCT02654990. Findings: Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8-24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8-72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8-75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4-61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3-4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (¿20% patients in any group) grade 3-4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (¿10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. Interpretation: The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. Funding: Novartis Pharmaceuticals and Secura Bio.
  • Autores: Dhanasiri, S. (Autor de correspondencia); Hollier-Hann, G.; Stothard, C.; et al.
    Revista: CLINICAL THERAPEUTICS
    ISSN 0149-2918 Vol.43 N° 11 2021 págs. 1983 - +
    Resumen
    Purpose: Patients with relapsed and refractory multiple myeloma (RRMM) have a poor prognosis and limited treatment options after exposure to an immunomodulatory drug, proteasome inhibitor (PI), and anti-CD38 antibody (triple-class exposure [TCE]). However, current understanding about the management of these patients and associated health care resource use (HCRU) is limited outside the United States. The objective of the International Treatment pattern and resource use Evaluation for Multiple myeloma In a Study of triple-class Exposed patients (ITEMISE) study was to use a physician-developed survey fielded to hematologists across Europe and Canada to assess the treatment, management, HCRU, and end of-life care for patients with RRMM after TCE. Methods: The ITEMISE study used a 3-phase Delphi-like approach that consisted of in-depth interviews with 7 hematology experts; the development of a cross-sectional survey fielded to hematologists across Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom from August to October 2020; and a final workshop of hematology experts to validate the pooled findings. Hematologists were asked to consider the management of patients in the first 3 treatment lines after TCE, including treatment options, treatment duration and outcomes, and frequency of outpatient visits and hospitalizations. Findings: The survey was completed by 202 hematologists (60% from academic hospitals, 38% from other public hospitals, and 2% from private hospitals). Hematologists estimated that 55% of patients would receive active treatment after TCE, the equivalent of fourth-line treatment onward since diagnosis of multiple myeloma. Immunomodulatory drug, anti-CD38 antibody plus immunomodulatory drug, and PI-based regimens (received by 22.5%, 17.8%, and 15.1% of patients, respectively) were reported for first treatment strategy after TCE. Pomalidomide, daratumumab, lenalidomide, bortezomib, and carfilzomib were the most frequently selected antimyeloma agents. Associated outcomes of median overall survival, progression-free survival, and objective response rate for first treatment after TCE were estimated as 12 months, 4 months, and 40%, respectively. HCRU included outpatient visits and unplanned hospitalizations that were commonly reported during treatment after TCE. Implications: Findings indicate an intent to actively treat patients after TCE with a range of combination regimens frequently consisting of immunomodulatory drugs, PIs, and anti-CD38 antibodies, highlighting the lack of standard of care and suggesting a large clinical unmet need. Estimated clinical outcomes are consistent with data from US studies and indicate the poor prognosis for patients after TCE. Substantial HCRU is associated with management of patients after TCE across Europe and Canada, signifying a high patient and societal impact and a need for better treatment options to reduce this burden. (Clin Ther. 2021;43:1983- 1996.) (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC ND license ( http://creativecommons.org/licenses/bync-nd/4.0/ )
  • Autores: Tamariz Amador, Luis Esteban; Battaglia, A. M.; Da Silva Maia, Catarina Alexandra; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.11 N° 12 2021 págs. 202
    Resumen
    There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.
  • Autores: Rossi, M. (Autor de correspondencia); Altomare, E.; Botta, C. ; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.35 N° 3 2021 págs. 823 - 834
    Resumen
    Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.
  • Autores: Puig, N.; Hernández, M. T.; Rosiñol, L.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.11 N° 5 2021 págs. 101
    Resumen
    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 C-Rd 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 C-Rd 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 GEM-CLARIDEX: 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.
  • Autores: Anderson, K. C.; Auclair, D.; Adam, S. J.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN 1078-0432 Vol.27 N° 19 2021 págs. 5195 - 5212
    Resumen
    The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.
  • Autores: Rodríguez Otero, Paula; Mateos, M. V.; Oriol, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: Lonial, S.; Berdeja, J. G.; Dimopoulos, M. A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S150
  • Autores: Ghobrial, I.; Rodríguez Otero, Paula; Koh, Y.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S109 - S110
  • Autores: Richardson, P. G.; Mateos, M. V.; Oriol, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 1 2021 págs. S427
  • Autores: Rodríguez Otero, Paula; Mateos, M. V.; Oriol, A.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN 0361-8609 Vol.96 N° Supl. 1 2021 págs. S8 - S9
  • Autores: Oriol, A.; San Miguel Izquierdo, Jesús; Kansagra, A.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 76 - 77
  • Autores: Goldschmidt, H.; Raje, N. S.; Siegel, D.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supl. 2 2021 págs. 18 - 19
  • Autores: Kortuem, M.; Terpos, E.; Badros, A.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supl. 2 2021 págs. 204
  • Autores: Zamagni, E.; Richardson, P. G.; Mateos, M. V.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 Supl. 3 2021 págs. 14
  • Autores: Rosa-Rosa, J. M.; Cuenca, I.; Medina, A.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 65 - 65
  • Autores: Terpos, E. ; Badros, A.; Popat, R.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 1 2021 págs. S421
  • Autores: Rodríguez Otero, Paula; Mateos, M. V.; Oriol, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 1 2021 págs. S426 - S427
  • Autores: Puig, N.; Paiva, Bruno; Contreras, T.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: Terpos, E.; Badros, A.; Popat, R.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: Ayers, D.; Cope, S.; Dhanda, D. S.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S139 - S140
  • Autores: Lonial, S.; Richardson, P. G.; Popat, R.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S9
  • Autores: Dimopoulos, M. A.; Dytfeld, D.; Grosicki, S.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S143 - S144
  • Autores: Rodríguez Otero, Paula; Mateos, M. V.; Oriol, A.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 144 - 144
  • Autores: Weisel, K.; Richardson, P. G.; Trudel, S.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supplement 2 (ep224) 2021 págs. 204 - 205
  • Autores: Einsele, H.; Berdeja, J.; Raje, N. S.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supplement 2 (ep322) 2021 págs. 198 - 199
  • Autores: Terpos, E.; Badros, A. Z.; Popat, R.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S160
  • Autores: Richardson, P. G.; Trudel, S.; Callander, N. S.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 2021 págs. S156 - S156
  • Autores: Van De Donk, N. W. C. J.; Krishnan, A.; Oriol, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S16 - S17
  • Autores: Rodríguez Otero, Paula; Michel, D.; Nina, S.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 287 - 288
  • Autores: Cardona-Benavides, I. J.; Irena, M. K.; Corchete Sánchez, L.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 65 - 66
  • Autores: Rodríguez Otero, Paula; Berdeja, J.; Raje, N.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 76 - 76
  • Autores: Weisel, K.; Manier, S.; Kansagra, A.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supplement 2 (ep520) 2021 págs. 179 - 180
  • Autores: Richardson, P. G.; Perrot, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: Cavo, M.; Oriol, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 Supl. 3 2021 págs. 5
  • Autores: Manier, S.; Kansagra, A. J.; Anderson, L. D.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: Larocca, A.; Rodríguez Otero, Paula; Mateos, M.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 Supl. 3 2021 págs. 72 - 73
  • Autores: Krishnan, A. Y.; Garfall, A. L.; Mateos, M. V.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: Richardson, P. G.; Perrot, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 1 2021 págs. S423 - S424
  • Autores: Rodríguez Otero, Paula; Dhanasiri, S.; Hollier-Hann, G.; et al.
    Revista: VALUE IN HEALTH
    ISSN 1098-3015 Vol.24 N° Supl. 1 2021 págs. S30
  • Autores: Puig, N.; Contreras, T.; Paiva, Bruno; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 72 - 73
  • Autores: Weisel, K.; Knop, S.; Lonial, S.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supl. 2 2021 págs. 86 - 87
  • Autores: Goldschmidt, H.; Chari, A.; Haenel, M.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supl. 2 2021 págs. 200 - 201
  • Autores: Anderson, L. D.; Munshi, N. C.; Shah, N.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: van-de-Donk, N. W. C. J.; Popat, R.; Larsen, J.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.193 N° Supl. 1 2021 págs. 17 - 18
  • Autores: Berdeja, J. G.; Krishnan, A. Y.; Oriol, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.39 N° 15 2021
  • Autores: Guerrero De Blois, Camila; Puig, N.; Cedena, M. T.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° S2 2021 págs. S35 - S35
    Resumen
    There is expectation of using biomarkers to personalize treatment. Yet, a successful treatment selection cannot be confirmed before 5 or 10 years of progression-free survival (PFS). Treatment individualization based on the probability of an individual patient to achieve undetectable MRD with a singular regimen, could represent a new model towards personalized treatment with fast assessment of its success. This idea has not been investigated previously.
  • Autores: Weisel, K.; Dimopoulos, M. A.; Oriol, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S163
  • Autores: Moreno, D.; Oriol, A.; de la Rubia, J.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° S2 2021 págs. S134 - S135
  • Autores: Termini, R.; Pèrez, A.; Bargay, J.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 64 - 64
  • Autores: Einsele, H.; Oriol, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supl.2 2021 págs. 120 - 121
  • Autores: Ocio, E.; Perrot, A.; Bories, P.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.21 N° Supl. 2 2021 págs. S3 - S4
  • Autores: Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; Calviño Sampedro, Cristina; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 2021 págs. 260 - 260
  • Autores: Richardson, P.; Mateos, M. V.; Oriol, A.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN 0361-8609 Vol.96 N° Supl. 1 2021 págs. S10
  • Autores: Garcés Latre, Juan José; Cedena, M. T.; Puig, N.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 1 - 1
  • Autores: San Miguel Izquierdo, Jesús; Raje, N. S.; Siegel, D.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 77 - 77
  • Autores: Einsele, H.; Shah, N.; Delforge, M.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.44 N° Supl. 2 2021 págs. 206 - 208
  • Autores: Terpos, E. (Autor de correspondencia); Engelhardt, M. (Autor de correspondencia); Cook, G.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.34 N° 8 2020 págs. 2000 - 2011
    Resumen
    Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed
  • Autores: Burgos Rodríguez, Leire; Puig, N.; Cedeña, M. T. ; et al.
    Revista: JOURNAL OF HEMATOLOGY AND ONCOLOGY
    ISSN 1756-8722 Vol.13 N° 1 2020 págs. 82
    Resumen
    The landscape of multiple myeloma (MM) has changed considerably in the past two decades regarding new treatments, insight into disease biology and innovation in the techniques available to assess measurable residual disease (MRD) as the most accurate method to evaluate treatment efficacy. The sensitivity and standardization achieved by these techniques together with unprecedented rates of complete remission (CR) induced by new regimens, raised enormous interest in MRD as a surrogate biomarker of patients' outcome and endpoint in clinical trials. By contrast, there is reluctance and general lack of consensus on how to use MRD outside clinical trials. Here, we discuss critical aspects related with the implementation of MRD in clinical practice.
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); Prosper Cardoso, Felipe; Alfonso Piérola, Ana; et al.
    Revista: JOURNAL OF CLINICAL MEDICINE
    ISSN 2077-0383 Vol.9 N° 11 2020 págs. 3577
    Resumen
    The survival of patients with multiple myeloma (MM) has been dramatically improved in the last decade thanks to the incorporation of second-generation proteasome inhibitors (PI), immunomodulatory drugs (IMID), and, more recently, anti-CD38 monoclonal antibodies (MoAb). Nevertheless, still, a major proportion of MM patients will relapse, underscoring the need for new therapies in this disease. Moreover, survival in patients failing the current standard of care regimens (including PI, IMIDs, and anti-CD38 MoAb), which is now defined as triple-class refractory, remains dismal, and new drugs with different mechanism of action are needed. B-cell maturation antigen (BCMA)-targeted therapies and in particular chimeric antigen receptor T cell (CAR T-cell) treatment have emerged as promising platforms to overcome refractoriness to conventional drugs. In this manuscript, we review the current available data regarding CAR T-cell therapy for MM, with a special focus on target selection, clinical results, limitations, and future strategies.
  • Autores: Alameda Serrano, Daniel; Sáez Ochoa, Borja; Lara-Astiaso, D. ; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.105 N° 9 2020 págs. E470 - E473
  • Autores: Herr, M. M.; Torka, P. ; Zhang, Y.; et al.
    Revista: BONE MARROW TRANSPLANTATION
    ISSN 0268-3369 Vol.55 N° 1 2020 págs. 272
  • Autores: Oriol, A.; Larocca, A. ; Leleu, X.; et al.
    Revista: EXPERT OPINION ON INVESTIGATIONAL DRUGS
    ISSN 1354-3784 Vol.29 N° 10 2020 págs. 1069 - 1078
    Resumen
    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: Medina, A.; Jimenez, C.; Sarasquete, M. E. (Autor de correspondencia); et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.10 N° 2 2020 págs. 14
    Resumen
    Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (>= 7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361-0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation >= 7% (HR: 0.291, 95% CI: 0.137-0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.
  • Autores: Bahlis, N. J. (Autor de correspondencia); Dimopoulos, M. A. ; White, D. J.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.34 N° 7 2020 págs. 1875 - 1884
    Resumen
    In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with >= 1 prior line received Rd (lenalidomide, 25 mg, on Days 1-21 of each 28-day cycle; dexamethasone, 40 mg, weekly) +/- daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35-0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10(-5); 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31-0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42-0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Lonial, S.; White, D.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.10 N° 9 2020 págs. 91
    Resumen
    Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1-3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1-3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68-1.00];P = 0.0408 [less than allotted alpha of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1-3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2-3 prior LoTs.
  • Autores: Vij, R. (Autor de correspondencia); Nath, R.; Afar, D. E. H.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN 1078-0432 Vol.26 N° 10 2020 págs. 2308 - 2317
    Resumen
    Purpose: ABBV-838 is an antibody-drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-inhuman, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM). Patients and Methods: Eligible patients (>= 18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel. Results: As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838-related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively. Conclusions: These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy.
  • Autores: Pérez Ruiz, Cristina; Botta, C.; Zabaleta, A.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.136 N° 2 2020 págs. 199 - 209
    Resumen
    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: Mikhael, J. (Autor de correspondencia); Richter, J. ; Vij, R.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.34 N° 12 2020 págs. 3298 - 3309
    Resumen
    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 non-hematologic 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.
  • Autores: Misiewicz-Krzeminska, I. ; de Ramon, C. ; Corchete, L. A. ; et al.
    Revista: BLOOD ADVANCES
    ISSN 2473-9529 Vol.4 N° 23 2020 págs. 6023 - 6033
    Resumen
    The search for biomarkers based on the mechanism of drug action has not been thoroughly addressed in the therapeutic approaches to multiple myeloma (MM), mainly because of the difficulty in analyzing proteins obtained from purified plasma cells. Here, weinvestigated the prognostic impact of the expression of 12 proteins involved in the mechanism of action of bortezomib, lenalidomide, and dexamethasone (VRD), quantified by capillary nanoimmunoassay, in CD138-purified samples from 174 patients with newly diagnosed MM treated according to the PETHEMA/GEM2012 study. A high level of expression of 3 out of 5 proteasome components tested (PSMD1, PSMD4, and PSMD10) negatively influenced survival. The 5 analyzed proteins involved in lenalidomide's mode of action were associated with time to progression (TTP); low levels of cereblon and IRF4 protein and high levels of Ikaros, AGO2, and Aiolos were significantly associated with shorter TTP. Although the glucocorticoid receptor (GCR) level by itself had no significant impact on MM prognosis, a high XPO1 (exportin 1)/GCR ratio was associated with shorter TTP and progression-free survival (PFS). The multivariate Cox model identified high levels of PSMD10 (hazard ratio [HR] TTP, 3.49; P = .036; HR PFS, 5.33; P = .004) and Ikaros (HR TTP, 3.01, P = .014; HR PFS, 2.57; P = .028), and low levels of IRF4 protein expression (HR TTP, 0.33; P = .004; HR PFS, 0.35; P = .004) along with high-risk cytogenetics (HR TTP, 3.13; P = .001; HR PFS, 2.69; P = .002), as independently associated with shorter TTP and PFS. These results highlight the value of assessing proteins related to the mechanism of action of drugs used in MM for predicting treatment outcome.
  • Autores: Chari, A.; Samur, M. K.; Martínez-López, J.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.136 N° 26 2020 págs. 3033 - 3040
    Resumen
    The primary cause of morbidity and mortality in patients with multiple myeloma (MM) is an infection. Therefore, there is great concern about susceptibility to the outcome of COVID-19-infected patients with MM. This retrospective study describes the baseline characteristics and outcome data of COVID-19 infection in 650 patients with plasma cell disorders, collected by the International Myeloma Society to understand the initial challenges faced by myeloma patients during the COVID-19 pandemic. Analyses were performed for hospitalized MM patients. Among hospitalized patients, the median age was 69 years, and nearly all patients (96%) had MM. Approximately 36% were recently diagnosed (2019-2020), and 54% of patients were receiving first-line therapy. Thirty-three percent of patients have died, with significant geographic variability, ranging from 27% to 57% of hospitalized patients. Univariate analysis identified age, International Staging System stage 3 (ISS3), high-risk disease, renal disease, suboptimal myeloma control (active or progressive disease), and 1 or more comorbidities as risk factors for higher rates of death. Neither history of transplant, including within a year of COVID-19 diagnosis, nor other anti-MM treatments were associated with outcomes. Multivariate analysis found that only age, high-risk MM, renal disease, and suboptimal MM control remained independent predictors of adverse outcome with COVID-19 infection. The management of MM in the era of COVID-19 requires careful consideration of patient- and disease-related factors to decrease the risk of acquiring COVID-19 infection, while not compromising disease control through appropriate MM treatment. This study provides initial data to develop recommendations for the management of MM patients with COVID-19 infection.
  • Autores: Cavo, M. (Autor de correspondencia); Dimopoulos, M. A. ; San Miguel Izquierdo, Jesús; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.20 N° 7 2020 págs. 480 - 489
    Resumen
    ntroduction: Bortezomib, melphalan, and prednisone (VMP) is the standard of care for transplant-ineligible newly diagnosed multiple myeloma. The phase III VISTA trial established the bortezomib dosing schedule for VMP. To mitigate bortezomib-associated toxicity, the phase III ALCYONE study of daratumumab plus VMP (D-VMP) versus VMP used modified bortezomib dosing. D-VMP demonstrated improved progression-free survival and overall response rate. Propensity score matching enables indirect comparisons by controlling for differences in baseline covariates. Patients and methods: The efficacy and safety of both arms of ALCYONE were compared with VISTA VMP using propensity score matching. ALCYONE D-VMP and VMP patients were matched on selected baseline characteristics to VISTA VMP patients, reducing or eliminating systematic differences between treatment groups. Results: After matching, median progression-free survival and overall response rate were comparable for ALCYONE VMP and VISTA VMP, and were significantly improved with ALCYONE D-VMP versus VISTA VMP. Rates of grade 3/4 peripheral sensory neuropathy were significantly lower for both arms of ALCYONE versus VISTA VMP, with or without matching. Conclusion: This propensity score matching analysis demonstrates significant improvements in efficacy with ALCYONE D-VMP versus VISTA VMP and a significantly lower incidence of peripheral sensory neuropathy in both arms of ALCYONE versus VISTA VMP, although safety improvements may be due to different bortezomib administration routes (ALCYONE, subcutaneous; VISTA, intravenous).
  • Autores: Alegre, A.; de la Rubia, J. ; Balari, A. S.; et al.
    Revista: HEMASPHERE
    ISSN 2572-9241 Vol.4 N° 3 2020 págs. e380
    Resumen
    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: Parasrampuria, D. A.; He, J. M.; Zhang, L. P.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.189 N° 5 2020 págs. 860 - 868
    Resumen
    Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42 center dot 2 vs. 38 center dot 5 mg/m(2)) and ALCYONE patients stayed on treatment longer (mean: 7 center dot 2 vs. 5 center dot 8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with >= 39 center dot 0 versus < 39 center dot 0 mg/m(2) cumulative dose (hazard ratio, 0 center dot 119; P < 0 center dot 0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.
  • Autores: Ezponda Casajús, Ana (Autor de correspondencia); Calvo Imirizaldu, Marta; de Torres Tajes, Juan Pablo; et al.
    Revista: RADIOLOGIA
    ISSN 0033-8338 Vol.62 N° 2 2020 págs. 131 - 138
    Resumen
    Objective: To determine the incidence of immune-mediated adverse reactions with and without radiologic manifestations and to correlate them with the response to immunotherapy. Material and methods: We retrospectively included 79 patients with stage IV lung carcinomas (n=24), renal carcinomas (n=11), or melanoma (n=44) treated with immunotherapy. We evaluated the occurrence of immune-mediated adverse reactions, their radiologic manifestations, and the response pattern according to the immune-related response criteria (irRC). We correlated the presence of immune-mediated adverse reactions with the response pattern. Results: Immune-mediated adverse reactions occurred in 27.8%, being most common in patients with melanoma (40.9%). In 59.1% of patients with adverse reactions, there were radiologic manifestations such as pneumonitis, colitis, hypophysitis, thyroiditis, or myocarditis. Pneumonitis was the most common radiologic manifestation of immune-mediated adverse reactions, even in asymptomatic patients. The rate of response to immunotherapy was higher among patients who developed immune-mediated adverse reactions than in those who did not (68.2% vs. 38.6%, respectively, ¿2 5.58; p=0.018). The rate of favorable responses was higher in patients with radiologic manifestations of immune-mediated adverse reactions than in those without radiologic manifestations (84.6% vs. 44.4%, respectively; p=0.023). Conclusions: The presence of immune-mediated adverse reactions is associated with a better response to immunotherapy. The association with a favorable response is even stronger in patients with radiologic manifestations of the immune-mediated adverse reactions.
  • Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús; Goldschmidt, H. ; et al.
    Revista: LEUKEMIA AND LYMPHOMA
    ISSN 1042-8194 Vol.61 N° 3 2020 págs. 680 - 690
    Resumen
    For patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible, bortezomib-melphalan-prednisone (VMP) demonstrated superior efficacy based on the VISTA trial. In subsequent trials, twice-weekly bortezomib was limited to the first cycle or completely replaced with once-weekly bortezomib to reduce toxicity. Following a systematic literature review, the efficacy and safety of modified VMP schedules (pooled data from the once-weekly bortezomib VMP arm of the GIMEMA trial and the VMP arm of the ALCYONE trial) were compared to the VISTA schedule using naive and unanchored matching-adjusted indirect comparison (MAIC). Median progression-free survival was similar between VISTA and modified VMP (20.7 months [95% CI, 18.4-24.3] vs 19.6 months [95% CI, 18.8-21.0]). Peripheral neuropathy was significantly reduced with modified VMP versus VISTA VMP (all grades: naive, 32.1% vs 46.8% and MAIC, 32.1% vs 46.7%; both p < .0001). These findings support a modified VMP dosing schedule for patients with NDMM who are transplant ineligible.
  • Autores: Paiva, Bruno; Puig, N.; Cedena, M. T.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 8 2020 págs. 784 - 792
    Resumen
    PURPOSE: Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). PATIENTS AND METHODS: In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 * 10-6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial.
  • Autores: Da Silva Maia, Catarina Alexandra; Puig, N. ; Cedena, M. T.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.135 N° 26 2020 págs. 2375 - 2387
    Resumen
    Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.
  • Autores: Martínez-López, J.; Mateos, M. V. (Autor de correspondencia); Encinas, C.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.10 N° 10 2020 págs. 103
    Resumen
    There is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19.
  • Autores: Caballero-Velazquez, T.; Calderon-Cabrera, C.; Lopez-Corral, L.; et al.
    Revista: BONE MARROW TRANSPLANTATION
    ISSN 0268-3369 Vol.55 N° 2 2020 págs. 419 - 430
    Resumen
    This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days -9 and -2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day -5 and tacrolimus (Tk) from -3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2-4 and 3-4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD.
  • Autores: Puig, N. ; Corchete-Sanchez, L. A. ; Perez-Moran, J. J. ; et al.
    Revista: CANCERS
    ISSN 2072-6694 Vol.12 N° 12 2020 págs. 3615
    Resumen
    Simple Summary Multiple myeloma patients with persistent disease after treatment show increased expression of PDL1 in tumor plasma cells and of PD1 in T lymphocytes. This suggests a role of the PD1/PDL1 axis in treatment failure that could potentially be reverted with pembrolizumab, an anti-PD1 monoclonal antibody. The GEM-Pembresid trial enrolled 20 patients with multiple myeloma achieving a suboptimal response to the previous treatment that received intravenous pembrolizumab every 3 weeks with the objective of eradicating the residual disease. Pembrolizumab was acceptably well tolerated in the 17 patients evaluable for safety, but no improvement in the baseline responses was documented. Although no determinants of response could be identified, we detected a lower expression of PD1/PDL1 in a subgroup of patients progressing in the first 4 months after enrollment; furthermore, a reduction in the percentage of NK cells induced by pembrolizumab was observed. 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.
  • Autores: Medina, A.; Puig, N.; Flores-Montero, J.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.10 N° 10 2020 págs. 108
    Resumen
    Detecting persistent minimal residual disease (MRD) allows the identification of patients with an increased risk of relapse and death. In this study, we have evaluated MRD 3 months after transplantation in 106 myeloma patients using a commercial next-generation sequencing (NGS) strategy (LymphoTrack (R)), and compared the results with next-generation flow (NGF, EuroFlow). The use of different marrow pulls and the need of concentrating samples for NGS biased the applicability for MRD evaluation and favored NGF. Despite that, correlation between NGS and NGF was high (R-2 = 0.905). The 3-year progression-free survival (PFS) rates by NGS and NGF were longer for undetectable vs. positive patients (NGS: 88.7% vs. 56.6%; NGF: 91.4% vs. 50%; p < 0.001 for both comparisons), which resulted in a 3-year overall survival (OS) advantage (NGS: 96.2% vs. 77.3%; NGF: 96.6% vs. 74.9%, p < 0.01 for both comparisons). In the Cox regression model, NGS and NGF negativity had similar results but favoring the latter in PFS (HR: 0.20, 95% CI: 0.09-0.45, p < 0.001) and OS (HR: 0.21, 95% CI: 0.06-0.75, p = 0.02). All these results reinforce the role of MRD detection by different strategies in patient prognosis and highlight the use of MRD as an endpoint for multiple myeloma treatment.
  • Autores: Munshi, N.C.; Avet-Loiseau, H.; Anderson, K.C.; et al.
    Revista: BLOOD ADVANCES
    ISSN 2473-9529 Vol.4 N° 23 2020 págs. 5988 - 5999
    Resumen
    The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29- 0.37; P<.001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P<.001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.
  • Autores: Kaufman, J.L.; Dimopoulos, M. A.; White, D.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.10 N° 11 2020
    Resumen
    High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10(-5)) was assessed via the clonoSEQ(R) assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.
  • Autores: Avet-Loiseau, H. (Autor de correspondencia); Ludwig, H.; Landgren, O.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.20 N° 1 2020 págs. e30 - e37
    Resumen
    Background: Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM). Materials and methods: We searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for "myeloma," "minimal residual disease," and "clinical trial." Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia.42 For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive. Results: Six randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy. Conclusions: These results support the claim that MRD status can be used as a surrogate for PFS in NDMM.
  • Autores: Facon, T.; Dimopoulos, M. A.; Meuleman, N.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.34 N° 1 2020 págs. 224 - 233
    Resumen
    Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS-containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients.
  • Autores: Mateos, M. V. (Autor de correspondencia); Cavo, M.; Blade, J.; et al.
    Revista: LANCET
    ISSN 0140-6736 Vol.395 N° 10218 2020 págs. 132 - 141
    Resumen
    Background Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. Methods ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9,2015, and July 14,2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stern-cell transplantation, because of their age (>= 65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezoinib (1.3 mg/m(2) of body surface area on days 1,4,8,11,22,25,29, and 32 of cycle one and on days 1,8,22, and 29 of cycles two through nine), oral melphalan (9 mg/m(2) once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m(2) once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cydes two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intentionto-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. Findings 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40.1 months (IQR 374-434), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0.60 (95% CI 0.46-0.80; p=0.0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78.0% (95% CI 73.2-82.0) in the D-VMP group and 67.9% (62.6-72.6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0.42 [0.34-0.51]; p<0.0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [1.5%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28[10%]). Interpretation D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stern-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns.
  • Autores: Lonial, S. (Autor de correspondencia); Lee, H. C.; Badros, A.; et al.
    Revista: LANCET ONCOLOGY
    ISSN 1470-2045 Vol.21 N° 2 2020 págs. 207 - 221
    Resumen
    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 ClinicalTrials.gov, 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: Morales Lozano, María Isabel; Viering, O.; Samnick, S. ; et al.
    Revista: CANCERS
    ISSN 2072-6694 Vol.12 N° 4 2020 págs. 1042
    Resumen
    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: Herr, M. M.; Torka, P.; Zhang, Y. L.; et al.
    Revista: BONE MARROW TRANSPLANTATION
    ISSN 0268-3369 Vol.55 N° 1 2020 págs. 77 - 85
    Resumen
    This is the first longitudinal study of immune profiles and autologous hematopoietic cell transplant (AHCT) survival in B-cell non-Hodgkin lymphoma (B-NHL) patients and the effect of plerixafor mobilization on immune reconstitution in this population. A comprehensive immunophenotyping panel was performed in 104 consecutive adult B-NHL patients (58% diffuse large B cell and 42% mantle cell) who received AHCT (1/2008-11/2014), at a median of 28 days pre-AHCT (N=104) and Day +100 (N=83) post-AHCT. Median follow-up post-AHCT was 61 months (range: 8-120 months). Compared to patients mobilized with filgrastim and plerixafor, patients mobilized with filgrastim alone had a higher proportion of CD4+ naive (p=0.006) and CD8+ central memory T-cells (p=0.006) pre-AHCT. For patients transplanted in complete remission (CR), a higher proportion of CD8+ effector memory T-cells pre-AHCT was associated with worse progression-free survival (PFS; p<0.01) and overall survival (OS; p<0.01). A higher ratio of CD8:CD4+ central memory T-cells pre-AHCT was associated with worse PFS (p<0.0001) and OS (p=0.0034). This same ratio measured post-AHCT among patients in CR on Day +100 was associated with worse and OS (p=0.008) but not PFS (p=not significant). These immune subsets are complementary biomarkers which identify patients transplanted in CR who have poor survival prognoses and may warrant further clinical interventions.
  • Autores: Mateos, M. V.; Kumar, S. (Autor de correspondencia); Dimopoulos, M. A.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.10 N° 10 2020
    Resumen
    Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2-3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with >= 3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
  • Autores: Garcés Latre, Juan José; Bretones, G. ; Burgos Rodríguez, Leire; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.34 N° 11 2020 págs. 3007 - 3018
    Resumen
    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: Solé, C.; Goicoechea Oroz, Ibai; Goñi, A.; et al.
    Revista: CANCERS
    ISSN 2072-6694 Vol.12 N° 2 2020 págs. 513
    Resumen
    Prostate cancer (PCa) is the second most common cancer of men and is typically slow-growing and asymptomatic. The use of blood PSA as a screening method has greatly improved PCa diagnosis, but high levels of false positives has raised much interest in alternative biomarkers. We used next-generation sequencing (NGS) to elucidate the urinary transcriptome of whole urine collected from high-stage and low-stage PCa patients as well as from patients with the confounding diagnosis of benign hyperplasia (BPH). We identified and validated five differentially expressed protein-coding genes (FTH1 BRPF1, OSBP, PHC3, and UACA) in an independent validation cohort of small-volume (1 mL) centrifuged urine (n = 94) and non-centrifuged urine (n = 84) by droplet digital (dd)PCR. These biomarkers were able to discriminate between BPH and PCa patients and healthy controls using either centrifuged or non-centrifuged whole urine samples, suggesting that the urinary transcriptome is a valuable source of non-invasive biomarkers for PCa that warrants further investigation.
  • Autores: Ubieto, A. J.; Paiva, Bruno; Lopez, J. M. ; et al.
    Revista: BONE MARROW TRANSPLANTATION
    ISSN 0268-3369 Vol.55 N° SUPPL 1 2020 págs. 128 - 130
  • Autores: Ocio, E. M.; Rodríguez Otero, Paula; Bringhen, S.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Lee, H.C.; Cohen, A.D.; Chari, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Jagannath, S; Lin, Y.; Goldschmidt, H.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Goldschmidt, H.; Jagannath, S. ; Lin, Y. ; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.43 N° SUPPL 4 2020 págs. 93 - 93
  • Autores: Weisel, K.; Einsele, H. ; Goldschmidt, H. ; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.43 N° SUPPL 4 2020 págs. 93 - 94
  • Autores: Lindsay, J.; Dimopoulos, M. ; Weisel, K.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.189 N° Supl. 1 2020 págs. 23 - 24
  • Autores: Einsele, H. ; Weisel, K. ; Goldschmidt, H.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.43 N° SUPPL 4 2020 págs. 90 - 91
  • Autores: Wong, L. ; Nunez, M. D. J. ; Bahlis, N. J. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Richardson, P. G.; Oriol, A.; Larocca, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.20 N° Supl. 1 2020 págs. S295 - S295
  • Autores: Kortum, M.; Lee, H. C.; Cohen, A. D.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.43 N° SUPPL 4 2020 págs. 102 - 102
  • Autores: Richardson, P. ; Oriol, A.; Larocca, A.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN 0361-8609 Vol.95 N° Supl. 1 2020 págs. S27 - S28
  • Autores: Usmani, S. Z. ; Mateos, M. V. ; Nahi, H. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Munshi, N. C. ; Anderson, L. D.; Shah, N. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Niederwieser, D.; Richardson, P.; Attal, M.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.43 N° Supl. 1 2020 págs. 40 - 41
  • Autores: Cook, G.; Kaufman, J. L.; Usmani, S. Z.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.189 N° Supl. 1 2020 págs. 20
  • Autores: Puig, N. ; Contreras, T. ; Paiva, B. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Mateos, M. V.; Oriol, A.; Larocca, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Slipicevic, A. ; Munawar, U. ; Stuhmer, T. ; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.80 N° 16 2020
  • Autores: Federico, C.; Sacco, A.; Belotti, A.; et al.
    Revista: NON-CODING RNA
    ISSN 2311-553X Vol.5 N° 2 2019 págs. 37
    Resumen
    Multiple myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow infiltration of clonal plasma cells. The recent literature has clearly demonstrated clonal heterogeneity in terms of both the genomic and transcriptomic signature of the tumor. Of note, novel studies have also highlighted the importance of the functional cross-talk between the tumor clone and the surrounding bone marrow milieu, as a relevant player of MM pathogenesis. These findings have certainly enhanced our understanding of the underlying mechanisms supporting MM pathogenesis and disease progression. Within the specific field of small non-coding RNA-research, recent studies have provided evidence for considering microRNAs as a crucial regulator of MM biology and, in this context, circulating microRNAs have been shown to potentially contribute to prognostic stratification of MM patients. The present review will summarize the most recent studies within the specific topic of microRNAs and circulating microRNAs in MM.
  • Autores: Hillengass, J. (Autor de correspondencia); Usmani, S. ; Rajkumar, S. V.; et al.
    Revista: LANCET ONCOLOGY
    ISSN 1470-2045 Vol.20 N° 6 2019 págs. E302 - E312
    Resumen
    Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.
  • Autores: Mateos, M. V.; Ludwig, H. ; Bazarbachi, A. ; et al.
    Revista: HEMASPHERE
    ISSN 2572-9241 Vol.3 N° 1 2019 págs. e163
    Resumen
    The introduction of new agents and management strategies over the past decade has resulted in a major step change in treatment outcomes with deepening responses and increased survival for patients with multiple myeloma. In daily clinical practice, healthcare professionals are now faced with challenges including, optimal treatment sequencing and changing treatment goals. In light of this, a group of experts met to discuss diagnostic and treatment guidelines, examine current clinical practice, and consider how new clinical trial data may be integrated into the management of multiple myeloma in the future.
  • Autores: Mateos, M. V. (Autor de correspondencia); Orlowski, R. Z.; Ocio, E. M.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.186 N° 5 2019 págs. e117 - e121
  • Autores: Jelinek, T. (Autor de correspondencia); Mihalyova, J. ; Kascak, M.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN 0361-8609 Vol.94 N° 1 2019 págs. E35 - E37
  • Autores: Rodríguez Otero, Paula; Mateos, M. V.; Martinez-Lopez, J.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.33 N° 4 2019 págs. 1056 - 1056
    Resumen
    Following the publication of this article, the author notes that the following information was missed from the acknowledgments section.
  • Autores: González Sánchez, Jesús Fidel; Zabaleta Azpiroz, Aintzane; Sangro del Alcazar, Paloma; et al.
    Revista: TRANSPLANTATION PROCEEDINGS
    ISSN 0041-1345 Vol.51 N° 1 2019 págs. 77 - 79
  • Autores: Rodríguez Otero, Paula; Mateos, M. V. ; Martinez-Lopez, J.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN 2044-5385 Vol.9 N° 4 2019 págs. 36
    Resumen
    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: Chari, A. (Autor de correspondencia); Martinez-Lopez, J.; Mateos, M. V.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.134 N° 5 2019 págs. 421 - 431
    Resumen
    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: Usmani, S. Z. (Autor de correspondencia); Schjesvold, F.; Oriol, A. ; et al.
    Revista: THE LANCET. HAEMATOLOGY
    ISSN 2352-3026 Vol.6 N° 9 2019 págs. e448 -e458
    Resumen
    Background: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). Methods: KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-ass
  • Autores: Rosinol, L. ; Oriol, A. ; Rios, R. ; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.134 N° 16 2019 págs. 1337 - 1345
    Resumen
    Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged <= 65 years with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and post-transplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 x 10(-6) sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade >= 3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade >= 2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment.
  • Autores: Attal, M. (Autor de correspondencia); Richardson, P. G. (Autor de correspondencia); Rajkumar, S. V. ; et al.
    Revista: LANCET
    ISSN 0140-6736 Vol.394 N° 10214 2019 págs. 2096 - 2107
    Resumen
    BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ¿75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (<75 years vs ¿75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab-pomalidomide-dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338. FINDINGS: Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab-pomalidomide-dexamethasone, and 153 to pomalidomide-dexamethasone. At a median follow-up of 11·6 months (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) in the pomalidomide-dexamethasone group; hazard ratio 0·596, 95% CI 0·44-0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab-pomalidomide-dexamethasone group and 14 (9%) in the pomalidomide-dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection). INTERPRETATION: The addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor. FUNDING: Sanofi. VIDEO ABSTRACT.
  • Autores: Terpos, E. (Autor de correspondencia); Kostopoulos, I. V.; Kastritis, E.; et al.
    Revista: HEMASPHERE
    ISSN 2572-9241 Vol.3 N° 6 2019 págs. e300
    Resumen
    Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (>= 2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10(-5); 17% at 10(-6). All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts' and tumor-associated monocytes/macrophages' predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10(-6).
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Laubach, J. P.; Gutierrez, M. A. E.; et al.
    Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
    ISSN 0902-4441 Vol.102 N° 6 2019 págs. 494 - 503
    Resumen
    Objectives To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. Methods Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. Results A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received >= 1 dose of ixazomib maintenance. Grade >= 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in <= 2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. Conclusions Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.
  • Autores: Walker, B. A.; Mavrommatis, K.; Wardell, C. P. ; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.33 N° 1 2019 págs. 159 - 170
    Resumen
    Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R-2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R-2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (>= 4 copies) of CKSJB (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
  • Autores: Richardson, P. G. (Autor de correspondencia); Oriol, A.; Beksac, M.; et al.
    Revista: LANCET ONCOLOGY
    ISSN 1470-2045 Vol.20 N° 6 2019 págs. 781 - 794
    Resumen
    Background As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged >= 18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of beta(2) microglobulin at screening. Bortezomib (1.3 mg/m(2)) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1,4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings Between Jan 7, 2013, and May 15,2017,559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15.9 months (IQR 9.9-21.7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11.20 months [95% CI 9.66-13-73] vs 7.10 months [5.88-8-48]; hazard ratio 0.61, 95% CI 0.49-0-77; p<0-0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%1 of 270 patients; nine p.m vs no patients had febrile neutropenia), infections (86 [31%] vs 48 118%1), and thrombocytopenia (76 [27%1 vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=11) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia In=11, hepatic encephalopathy [n=1.]). Interpretation Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
  • Autores: Flores-Montero, J.; Grigore, G.; Fluxa, R.; et al.
    Revista: JOURNAL OF IMMUNOLOGICAL METHODS
    ISSN 0022-1759 Vol.475 2019 págs. 112662
    Resumen
    In recent years the volume and complexity of flow cytometry data has increased substantially. This has led to a greater number of identifiable cell populations in a single measurement. Consequently, new gating strategies and new approaches for cell population definition are required. Here we describe how the EuroFlow Lymphoid Screening Tube (LST) reference data base for peripheral blood (PB) samples was designed, constructed and validated for automated gating of the distinct lymphoid (and myeloid) subsets in PB of patients with chronic lymphoproliferative disorders (CLPD). A total of 46 healthy/reactive PB samples which fulfilled predefined technical requirements, were used to construct the LST-PB reference data base. In addition, another set of 92 PB samples (corresponding to 10 healthy subjects, 51 B-cell CLPD and 31 T/NK-cell CLPD patients), were used to validate the automated gating and cell-population labeling tools with the Infinicyt software. An overall high performance of the LST-PB data base was observed with a median percentage of alarmed cellular events of 0.8% in 10 healthy donor samples and of 44.4% in CLPD data files containing 49.8% (range: 1.3-96%) tumor cells. The higher percent of alarmed cellular events in every CLPD sample was due to aberrant phenotypes (75.6% cases) and/or to abnormally increased cell counts (86.6% samples). All 18 (22%) data files that only displayed numerical alterations, corresponded to T/NK-cell CLPD cases which showed a lower incide
  • Autores: Facon, T. (Autor de correspondencia); Lee, J. H.; Moreau, P.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.133 N° 18 2019 págs. 1953 - 1963
    Resumen
    The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1: 1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m(2): C1D1, C1D2; 36 mg/m(2) thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m(2); D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m(2)) and prednisone (60 mg/m(2)) were administered on D1-4. The primary endpoint was progression-free survival (PFS). Nine hundred fifty-five patients were randomized (intention-to-treat population: KMP, n = 478; VMP, n = 477). Median PFS was 22.3 months with KMP vs 22.1 months with VMP (hazard ratio [HR], 0.906; 95% confidence interval [CI], 0.746-1.101; P = .159). Median overall survival was similar and not reached in either group (HR, 1.08; 95% CI, 0.82-1.43). Overall response rate was 84.3% for KMP and 78.8% for VMP. Complete response rate was 25.9% for KMP and 23.1% for VMP. Minimal residual disease-negative rates were 15.7% (KMP) and 15.5% (VMP). Adverse events (AEs) of interest (any grade) occurring with a >= 5% higher patient incidence in the KMP arm were acute renal failure (13.9% [KMP] vs 6.2% [VMP]) and cardiac failure (10.8% vs 4.3%). Grade >= 3 AE rates were 74.7% (KMP) and 76.2% (VMP). Grade >= 2 peripheral neuropathy was lower for KMP vs VMP (2.5% vs 35.1%). Treatment with KMP in CLARION did not yield a statistically significant difference in PFS vs VMP.
  • Autores: Moreau, P. (Autor de correspondencia); Sonneveld, P.; Boccadoro, M.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° 12 2019 págs. 2358 - 2360
    Resumen
    Adoptive cellular therapy using chimeric antigen receptor T-cell (CAR-T) therapy is currently being evaluated in patients with relapsed / refractory multiple myeloma (MM). The majority of CAR-T cell programs now being tested in clinical trials are targeting B-cell maturation antigen. Several recent phase I / II trials show promising preliminary results in patients with MM progressing on proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies targeting CD38. CAR-T cell therapy is a potentially life-threatening strategy that can only be administered in experienced centers. For the moment, CAR-T cell therapy for MM is still experimental, but once this strategy has been approved in relapsed/refractory MM, it will become one of the most important indications for this therapy in Europe and world-wide. This manuscript proposes practical considerations for the use of CAR-T cell therapy in MM, and discusses several important issues for its future development.
  • Autores: Lahuerta, J. J. (Autor de correspondencia); Jimenez-Ubieto, A. ; Paiva, Bruno; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.133 N° 25 2019 págs. 2664 - 2668
    Resumen
    Response criteria for multiple myeloma (MM) require monoclonal protein (M-protein)-negative status on both serum immunofixation electrophoresis (sIFE) and urine (uIFE) immunofixation electrophoresis for classification of complete response (CR). However, uIFE is not always performed for sIFE-negative patients. We analyzed M-protein evaluations from 384 MM patients (excluding those with light-chain-only disease) treated in the GEM2012MENOS65 (NCT01916252) trial to determine the uIFE-positive rate in patients who became sIFE-negative posttreatment and evaluate rates of minimal residual disease (MRD)-negative status and progression-free survival (PFS) among patients achieving CR, CR but without uIFE available (uncertain CR; uCR), or very good partial response (VGPR). Among 107 patients with M-protein exclusively in serum at diagnosis who became sIFE-negative posttreatment and who had uIFE available, the uIFE-positive rate was 0%. Among 161 patients with M-protein in both serumand urine at diagnosis who became sIFE-negative posttreatment, 3 (1.8%) were uIFE positive. Among patients achieving CR vs uCR, there were no significant differences in postconsolidation MRD-negative (< 10(-6); 76% vs 75%; P = .9) and 2-year PFS (85% vs 88%; P = .4) rates; rates were significantly lower among patients achieving VGPR. Our results suggest that uIFE is not necessary for defining CR in MM patients other than those with light-chain-only disease.
  • Autores: Usmani, S. Z. (Autor de correspondencia); Nahi, H.; Mateos, M. V.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.134 N° 8 2019 págs. 668 - 677
    Resumen
    Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV daratumumab in a similar patient population.
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