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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 ≥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 ≥CR. In MAIA, (D-Rd, n=368; Rd, n=369), and ALCYONE (D-VMP, n=350; VMP, n=356), the median duration of follow-up was 36.4 months 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 versus control groups. In a pooled analysis, patients who were MRD negative had improved PFS versus patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. ClinicalTrials.gov identifier NCT02252172 (MAIA); NCT02195479 (ALCYONE).

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 (

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.

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 over-lapped 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 BCMAxCD3-bispecific antibody increasednotably 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.

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 dys- plastic 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. (Blood. 2020;135(26):2375-2387)

Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment.

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Espanol de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM. (C) 2017 by American Society of Clinical Oncology

12 páginas, 2 figuras, 3 tablas.-- Presented in part at the annual meeting of the American Society of Hematology, Atlanta, December 10, 2007.-- et al., [Background]: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. [Methods]: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. [Results]: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P, Supported by Johnson and Johnson Pharmaceutical Research and Development and Millennium Pharmaceuticals.

This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodysplastic syndrome were excluded and 38 evaluable patients were included in the study (median age: 71 years; range: 65-83). Study patients received an induction with idarubicin (8 mg/m(2) iv days 1-3) plus cytarabine (100 mg/m2 iv days 1-7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19) that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. Complete remission rate was 64% with a time to relapse of 17.0 months (12.8-21.1). Median overall survival for the whole series was 17 months (5.5-28.4). Moreover, in 4 of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated. The most frequent adverse events were thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia (mainly grades 1/2). Five patients required dose reduction during this phase, but only one discontinued therapy due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and suggest further investigation is warranted, particularly in the context of maintenance therapy.

BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. METHODS: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P

We report the characteristics of relapse, treatment response, and outcomes of 145 elderly patients with multiple myeloma in first relapse after front-line treatment with VMP or VTP. Reappearance of CRAB symptoms (113 patients) and more aggressive forms of disease (32 patients) were the most common patterns of relapse. After second-line therapy, 75 (51.7%) patients achieved at partial response and 16 (11%) complete response (CR). Overall survival was longer among patients receiving VMP as front-line induction (21.4 vs. 14.4 months, P=0.037), in patients achieving CR (28.3 vs. 14.8 months; P=0.04), and in patients without aggressive relapse (28.6 vs. 7.6 months; P=0.0007).

This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P

Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these "second-generation" PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.

Introduction: A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particulary, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very diAerent outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined significance, Waldestron macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these diAerent subtypes of monoclonal gammopathies. Materials and methods: The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain significance, eight Waldenstrom Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and five primary plasma cell leukemia) using three diAerent assays (restriction enzymes and PCR or S-B and modification by sodium bisulphite). Results: Forty-one of 98 MM patients (41.8%) as well as four of the five (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined significance, Waldenstrom Macroglobulinemia or smoldering multiple myeloma displayed a methylation status. Conclusion: These findings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms. The Hematology Journal (2001) 2, 146-149

The aim of the present study was to assess which factors influence hematopoietic function long term after transplantation. For this purpose, we have analyzed a series of 79 patients who underwent autologous transplantation. None of them received any further chemotherapy or radiotherapy after transplant. All patients were disease-free 1 year after autologous transplantation. Late impairment of hematopoietic function was defined as the presence of non-transient peripheral blood cytopenias, detected 6 and 12 months after autografting. Before transplantion, 38.7% of patients showed peripheral blood cytopenias. Six and 12 months after transplantation, cytopenias presented in 44.2% and 42.4% of patients, respectively. Cases displaying cytopenias 6 months after transplantation had received a significantly lower dose of CFU-GM and CD34 + cells than patients without cytopenias (P = 0.012 and P = 0.04, respectively). The same correlation, with even higher statistical significance, was observed 12 months after transplant (P = 0.007 and P = 0.005). Alkylating agents and radiotherapy administered prior to transplantation and age did not seem to influence the presence of permanent cytopenias. The incidence did not vary significantly according to the stem cell source (bone marrow or peripheral blood). The number of CFU-GM and CD34 + cells infused was the most important factor for maintenance of adequate hematopoiesis.

Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P

For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention.

Melphalan 200 mg/m(2) (MEL200) is the standard conditioning regimen administered to newly diagnosed patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Few alternatives have been explored in order to improve the antimyeloma activity of this conditioning. We compare i.v. busulfan (BU) 9.6 mg/kg and MEL 140 mg/m(2) (MEL140) versus MEL200 mg/m(2) as a conditioning regimen before ASCT for newly diagnosed patients with MM. For this purpose, 51 patients receiving i.v. BU plus MEL were compared to 102 patients receiving MEL200 mg/m(2) in a 1:2 matched control analysis. Matching criteria included age, clinical stage at diagnosis, and response to induction therapy. No differences in the overall and complete response (CR) rates were observed after ASCT between both groups. After a median follow-up of 63 and 50 months in control and BU plus MEL groups, progression-free survival (PFS) was 24 and 33 months, respectively (P = .10). Most frequent toxicities included mucositis and febrile neutropenia in both groups. No case of sinusoidal obstruction syndrome was observed. Transplant-related mortality was 4% and 2% in BU plus MEL and control groups, respectively. ASCT conditioned with i.v. BU plus MEL may be considered an effective and well-tolerated alternative to a MEL-only approach as a conditioning regimen for patients with MM who are candidates for ASCT.

Smoldering myeloma is an asymptomatic plasma cell dyscrasia with a heterogeneous propensity to progress to active myeloma. In order to investigate the biology of smoldering myeloma patients with high risk of progression, we analyzed the genomic characteristics by FISH, SNP-arrays and gene expression profile of a group of patients with high-risk smoldering myeloma included in a multicenter randomized trial. Chromosomal abnormalities detected by FISH and SNP-arrays at diagnosis were not associated to risk of progression to symptomatic myeloma. However, the overexpression of four SNORD genes (SNORD25, SNORD27, SNORD30 and SNORD31) was correlated with shorter time to progression (P

Several studies have evaluated the prognostic value of the individual expression of certain genes in patients with myelodysplastic syndromes (MDS). However, none of them includes their simultaneous analysis by quantitative polymerase chain reaction (PCR). We evaluated relative expression levels of 14 molecular markers in 193 peripheral blood samples from untreated MDS patients using real-time PCR. Detectable WT1 expression levels, low TET2, and low IER3 gene expression were the only markers showing in univariate analysis a poor prognostic value for all treatment-free (TFS), progression-free (PFS), and overall survival (OS). In multivariate analysis, molecular parameters associated with a shorter TFS were: WT1 detection (p = 0.014), low TET2 (p = 0.002), and low IER3 expression (p = 0.025). WT1 detection (p = 0.006) and low TET2 (p = 0.006) expression were associated with a shorter PFS when multivariate analysis was carried out by including only molecular markers. Molecular values with an independent value in OS were: WT1 detection (p = 0.003), high EVI1 expression (p = 0.001), and undetectatable p15-CDKN2B (p = 0.037). WT1 expressers were associated with adverse clinical-biological features, high IPSS and WPSS scoring, and unfavorable molecular expression profile. In summary, detectable WT1 expression levels, and low TET2 and low IER3 expression in peripheral blood showed a strong association with adverse prognosis in MDS patients at diagnosis. However, WT1 was the only molecular marker displaying an independent prognostic value in both OS and TFS.