Background:Multiple myeloma (MM) is an incurable hematological malignancy with increasing prevalence. While randomized controlled trials have demonstrated survival improvements, they underrepresent older and comorbid patients. Real-world data from observational cohorts are therefore essential. Objective:To assess the comparability of patient, hospitalization and center characteristics for patients treated in centers included in the French Epidemiology of Multiple MYeloma (EmmY) cohort with those treated in centers of the French-speaking Intergroupe Francophone du Myélome (IFM) network (including EmmY) and those treated in all centers treating MM in France between 2017-2023. Methods:We analyzed French national hospital discharge data (PMSI) to identify adults hospitalized with MM (ICD-10 C90) between August 2017 and December 2023. Patient demographics, comorbidities, hospitalization characteristics, and center profiles were compared between the three cohorts using standardized differences. Results:We identified 69,276 patients (including 50,243 IFM and 33,785 EmmY), 1,871,369 hospitalizations (including 1,484,288 IFM and 1,022,462 EmmY), and 323 centers (including 118 IFM and 70 EmmY). EmmY centers were larger and treated a higher mean proportion of MM patients (2.7%) per center than IFM (2.4%) and all MM centers (1.3%). No clinically meaningful differences were observed between EmmY and IFM centers regarding patient age, sex, comorbidities, treatment patterns, or hospitalization outcomes. Conclusions:The EmmY cohort is highly comparable to patients treated in specialized MM centers and those within the broader French MM population, supporting its validity as a robust real-world data source. It is well-suited for evaluating treatment pathways and outcomes in real-world MM populations, including patients underrepresented in randomized controlled trials.

Background Waldenström macroglobulinemia (WM) is a rare, indolent B-cell neoplasm characterized by bone marrow (BM) infiltration by lymphoplasmacytic cells producing monoclonal IgM. A distinct inflammatory subset (iWM) has recently been described, defined by persistent elevation of C-reactive protein (CRP ≥20 mg/L) in the absence of infection or autoimmune disease. This phenotype is observed in ~33% of symptomatic cases, is more frequent at relapse (42%), and remains rare in asymptomatic patients (<10%). iWM has been associated with 6q deletion, clonal hematopoiesis, and a lower frequency of CXCR4 mutations. Clinically, it correlates with shorter time to next treatment (TTNT) following immunochemotherapy, but improved TTNT in patients receiving BTK inhibitors. However, its underlying pathophysiology remains poorly understood. Methods We prospectively collected blood and BM samples from 36 individuals with symptomatic WM. Based on CRP levels, patients were classified as having iWM (n = 20, median age 76 years) or non-inflammatory WM (nWM, n = 16, median age 74 years). Patients with elevated IgM levels but concurrent malignancies or inflammatory disorders—including Schnitzler syndrome—were excluded. Ederly healthy donors (HD, n = 13, median age 58 years) served as controls. Serum concentrations of inflammatory cytokines, including IL-1β, IFN-α2, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33, were measured using multiplex ELISA. High-dimensional immune profiling by 40-marker spectral flow cytometry and single-cell RNA sequencing (scRNA-seq) were performed on peripheral blood to characterize immune cell populations. Results iWM was not associated with tumor burden at the symptomatic phase, as assessed by IgM levels and BM infiltration. However, plasma cytokine analysis at steady state revealed significantly higher levels of inflammasome-related cytokines in iWM compared to nWM and HD. IL-1β showed the strongest difference, with median concentrations threefold higher in iWM (2630 fg/mL) compared to nWM (976 fg/mL, p = 0.02). IL-18 levels were also significantly higher in iWM (1205 pg/mL) versus nWM (500 pg/mL, p = 0.006). IL-6 levels were elevated in iWM (median 37 pg/mL vs 11 pg/mL) but did not reach statistical significance (p = 0.11). No correlation with age was observed for IL-1β (r = 0.14, p = 0.31) or IL-18 (r = 0.05, p = 0.77), and cytokine levels were similar between nWM and healthy donors. In peripheral blood, spectral cytometry (n = 7 per group; 100,000 cells/patient) and scRNA-seq (n = 3 per group; 43,000 cells total) revealed a higher proportion of intermediate and non-classical monocytes in iWM compared to nWM (p < 0.001). Overall, IL-1β expression was significantly increased in iWM relative to both nWM and HD (p < 0.001), with monocytes identified as the principal source. Subclustering revealed a population of cytokine-producing classical monocytes in iWM as the main IL-1β producers, with upregulation of inflammasome-related genes compared to their counterparts in nWM. In the bone marrow (n = 4 per group; 100,000 cells/patient), spectral cytometry showed an increased abundance of monocytes/macrophages in iWM compared to nWM. Mast cell density did not differ between groups. Discussion iWM represents a biologically distinct inflammatory subset of WM, independent of tumor burden, and seems to be associated with alterations in the immune microenvironment. Cytokine-producing monocytes, more transcriptionally active in iWM and functionally suppressed in nWM, may be key contributors to the inflammatory profile. Given the role of BTK in inflammasome regulation—and the superior clinical responses observed in iWM under BTK inhibitor therapy—these findings highlight potential therapeutic strategies targeting IL-1β signaling and monocyte–B-cell interactions. Additional investigations are ongoing, including BM scRNA-seq and monocyte stimulation assays, to further characterize the inflammatory mechanisms underlying iWM.

Introduction. A recent international genomic consensus staging has standardized the high-risk (HR) definition on the basis of an NGS-based definition plus serum beta-2-microglobulin level. Isa-VRd has become a standard-of-care for NDMM Transplant-Ineligible (TI). We studied the 12-24 months sustained MRD (sMRD) in high-risk patients using the genomic consensus staging in BENEFIT study. Methods. BENEFIT is a multicenter, phase 3 study, that randomized NDMM TI to receive Isa-VRd or IsaRd (ClinicalTrials.gov identifier: NCT04751877). Data are presented in intention-to-treat. IMS/IMWG new HR definition was assessed centrally by NGS on sorted plasma cells. Results. With a median follow-up of 33.4 months [95%CI, 33 - 34], 78 (29%) patients discontinued from the study, mostly for progressive disease. The HRMM (n=72, 27%) characterized 42/135 (31%) and 30/135 (22%) patients across Isa-VRd and IsaRd arms. The 18-month MRD negativity rate at 10-5, the primary end point, was similar across HRMM and non-HRMM within the same arm, and Isa-VRd remained superior for HRMM, OR 2.75 (95%CI, 1 to 7.5). Similar differences were observed at 10-6 at 18 months. The sustained MRD 12-24 months negativity rate at 10−5was higher for Isa-VRd than for IsaRd in HRMM, 31% and 13% respectively, OR 2.91 (95%CI, 0.8 to 10). There is no new safety signal observed across arms, including for HRMM. Conclusion. The results from the BENEFIT study continue to demonstrate meaningful benefit of the quadruplet-based Isa-VRd regimen in NDMM TI patients, including sMRD negativity rates. The benefits of the Isa-VRd regimen are observed in HRMM. This data supports Isa-VRd as a new SOC for NDMM TI aged of 65 to 79 patients, including for HRMM.

INTRODUCTION:Multiple myeloma patients aged 80 years and older are a population more prone to comorbidities and frailty. We aim to describe the real-life management and outcomes of this population. EMMY is a descriptive large-scale study. PATIENTS:Between 2017 and 2021 we included 4383 patients of which 894 (20.3%) were aged ≥ 80 years. Four cohorts of patients aged ≥ 80 years were analysed: line 1 (L1), line 2 (L2), line 3 (L3) or line 4+ (L4+). RESULTS:The proportion of patients ≥ 80 years old was 20.8% in L1, 21.3% in L2, 20.9% in L3 and 17.8% in L4+. L1 patients received more treatment including a proteasome inhibitor (PI) (42.9%), L2 patients received mainly an immunomodulator (IMID) (65.9%) or an anti-CD38 (31.5%). For L3, IMID was used in 71.4% than an anti-CD38 (33.5%). L4+ patients received a PI (40.6%), IMID (33.2%) or an anti-CD38 (29.1%). Regarding efficacy, the median progression-free survival was 18.4 months in L1, 15.1 months in L2, 10.4 months in L3 and 6.5 months in L4+. The median overall survival was 49 months in L1, 31.3 months in L2, 21.4 months in L3 and 13.6 months in L4+. CONCLUSION:EMMY cohort confirmed that patients ≥ 80 years of age represent an important proportion of MM patients, in the de novo or relapse setting. This study is an important step in improving our comprehension and management of treatment in elderly patients.

To assess efficacy and safety of dapsone in adult immune thrombocytopenia (ITP), a multicenter randomized controlled trial (RCT) and a real-word study cohort were performed. Participants were adults with primary ITP, transient response to corticosteroids ± intravenous immunoglobulin, and a platelet count ≤ 30x109/L (or ≤ 50x109/L with bleeding). Patients in the RCT were randomized in arm A (prednisone x3weeks+dapsone for 12 months) or arm B (prednisone alone). The observational study involved dapsone initiation at 100 mg/d with standard follow-up. The primary endpoint was the response rate (platelet count >30x109/L and ≥2×baseline) at 52 weeks, with the response rate at 24 weeks and adverse events as secondary endpoints. The RCT enrolled 93 patients (54.8% female), median age 48.5 years (46 in arm A, 47 in arm B). In the intention-to-treat analysis, 78.3% of patients in group A discontinued dapsone after a median of 4.6 weeks due to adverse events (66.7%) or lack of efficacy (33.3%). The response rate at week 52 was 21.7% (95% CI:10.9%-36.4%) in group A versus 8.5% (95% CI:2.7%-18.6%) in group B (p=0.17). The observational study, which was conducted after the end of the RCT, included 46 patients (52.2% female), median age 50.7 years. Adverse events occurred in 30.4%, leading to discontinuation of dapsone in 23.9%, and 13.6% (95% CI: 5.2%-27.4%) met the primary efficacy endpoint. Results from both studies showed an unfavorable risk-benefit ratio for the use of dapsone in adult primary ITP and suggest that, whenever available, second-line options should be used. NCT02627417, NCT02877706

We report on the use of a daratumumab-CHOP regimen for treatment of gamma heavy chain disease (γHCD) in a 79-year-old woman. γHCD is a very rare hematological disease, often associated with an underlying lymphoproliferative disorder. Only a few cases are reported in the literature, and, therefore, strong evidence is lacking regarding new therapeutic strategies. We attempted a treatment with a monoclonal anti-CD38 antibody in association with conventional chemothorapy, due to CD38 expression by clonal cells. This is the first reported case in the literature, in a disease in which very few novel strategies have recently emerged.

Managing multiple myeloma (MM) patients receiving advanced (four or more) lines of treatment is a complex challenge. Therefore, real-world data are essential to better understand and address the medical need of this challenging population. We used the EMMY cohort, a French longitudinal real-world study, to describe the characteristics and outcomes of 2127 MM patients receiving advanced-line treatments between 2017 and 2020. A wide variety of treatments were used without a predominant combination showing an evolution over time. Patients exhibited median time to next treatment and overall survival ranging from 7.8 months (95% CI: 6.7-7.8) and 19.4 months (95% CI: 17.4-22.5) in Line 4 (L4) to 4.8 months (95% CI: 3.5-6) and 12.6 months (95% CI: 8.7-16.6) in L8, respectively. The EMMY study provides valuable insights into the real-world application of advanced-line treatments, demonstrating rapid disease progression and poor outcomes in these patients before the novel anti-B-cell maturation antigen (BCMA) directed therapies. These findings highlight the critical need for novel therapies in this population.

BACKGROUND:Primary plasma cell leukemia (PPCL) is the most aggressive disorder among plasma cell malignancies, with new diagnostic criteria recently established by the International Myeloma Working Group. Studies have shown that PPCL patients receiving a combination of novel agents, but not eligible for transplantation, may have a median survival up to 2 years, extended to 3 years or more in those undergoing transplant procedures. These findings remain unsatisfactory, particularly if compared with progresses obtained in multiple myeloma. DESIGN:A European Myeloma Network (EMN) expert panel reviewed the most recent literature and selected the areas of major concern in the management of PPCL by generating and rank ordering key questions using the criterion of clinical relevance. Multistep procedures were utilized to achieve a consensus on recommendations. The Delphi questionnaire method was used and a consensus of at least 80% was reached for all final statements. RESULTS:An extended overview of current biological, clinical, prognostic, and therapeutic aspects of PPCL, including ongoing and close to start clinical trials, is presented. Furthermore, updated guidelines for the management of PPCL and practical recommendations are provided, in the context of current knowledge about this disease, also looking at possible future perspectives to ameliorate the outcome of these patients. CONCLUSIONS:PPCL still remains an unmet clinical need. Notwithstanding, some not negligible progresses have been recently achieved. The European Myeloma Network panel strongly support ongoing and planned clinical trials, as well as biological studies based on novel technologies, strategies, and treatment options that could represent breakthroughs we have been waiting for too long.

Introduction. Sustained minimal residual disease (sMRD) negativity has shown a stronger correlation with survival outcomes than MRD negativity at a single time point or at best response. We evaluated MRD negativity between 12 and 24 months in newly diagnosed multiple myeloma (NDMM) transplant-ineligible (TI) patients enrolled in the BENEFIT study. Methods. BENEFIT is a multicenter, phase 3 randomized trial comparing isatuximab-lenalidomide-dexamethasone with or without bortezomib (Isa-Rd ± V) in NDMM TI patients. In the Isa-VRd arm, bortezomib (V) was administered weekly for up to 18 months, dexamethasone was permanently discontinued after 12 months, and isatuximab-lenalidomide (Isa-R) was continued until progression. Data are presented in the intention-to-treat (ITT) population. Results.With a median follow-up of 33.4 months (95% CI, 33.0–34.0), 78 patients (29%) discontinued treatment, primarily due to progressive disease. At 24 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (odds ratio [OR] 2.26; 95% CI, 1.35–3.79; p=0.002). Sustained MRD negativity at 10⁻⁵ was also more frequent in the Isa-VRd arm (OR 2.73; 95% CI, 1.50–4.80; p=0.0007). Similar results were observed for sMRD at the 10⁻⁶ threshold. Importantly, MRD negativity at both 10⁻⁵ and 10⁻⁶ was evaluated in the t(11;14) NDMM TI subgroup. In this subgroup, MRD negativity rates were consistently lower at all time points up to 24 months, consistent with recent observations from the MIDAS study. Due to the small number of patients per group, no subgroup-specific analysis was feasible. Larger cohorts are required to determine whether t(11;14) MM in TI patients achieves delayed or less frequent MRD negativity, potentially reflecting a MGUS-like phenotype. No new safety signals were observed in either treatment arm, including in high-risk multiple myeloma (HRMM) patients. Conclusion. The BENEFIT study continues to support the efficacy of the quadruplet Isa-VRd regimen in NDMM TI patients, notably through improved sustained MRD negativity rates. These data support Isa-VRd as a new standard of care (SOC) for NDMM TI patients aged 65–79 years, including those with HRMM. ClinicalTrials.gov Identifier: NCT04751877

BACKGROUND:Patients with frailty and newly diagnosed multiple myeloma have worse outcomes due to higher rates of adverse events (AEs) and treatment discontinuation. This study evaluated a dexamethasone-sparing regimen of daratumumab plus lenalidomide versus lenalidomide plus dexamethasone in frail patients with newly diagnosed multiple myeloma. METHODS:In this prospective, randomised, open-label trial, conducted at 61 active Intergroup Francophone of Myeloma centres, patients aged 65 years or older with newly diagnosed multiple myeloma and an Eastern Cooperative Oncology Group proxy frailty score of 2 or more were randomly assigned 2:1 to receive daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of a 28 day cycle) and dexamethasone (20mg weekly) for two cycles (dexamethasone-sparing group) or lenalidomide (25 mg daily) and oral dexamethasone (20 mg weekly; control group), with stratification by International Staging System, age, and centre. The primary endpoint was progression-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients exposed to at least one dose of randomised intervention. This trial is registered with ClinicalTrials.gov, NCT03993912, and is complete. FINDINGS:From Oct 18, 2019 to July 20, 2021, 335 patients were screened, of whom 295 patients were randomly assigned (200 to lenalidomide plus daratumumab, 95 to lenalidomide plus dexamethasone). The median age was 81 years (IQR 77-84), with 180 (61%) aged older than 80 years, and 151 (51%) patients were female and 144 (49%) were male. Median follow-up was 46·3 months (IQR 46·0-52·7). Median progression-free survival was 53·4 months (95% CI 35·3-not reached) in the dexamethasone-sparing group versus 22·5 months (16·5-39·0) in the control group (hazard ratio [HR] 0·51, 95% CI 0·37-0·70, p<0·0001). The most common grade 3-5 AEs were neutropenia (110 [55%] of 200 patients in the dexamethasone-sparing group vs 23 [24%] of 95 patients in the control group), and infection (38 [19%] vs 20 [21%]). Serious adverse events occurred in 126 patients (63%) in the dexamethasone-sparing group and 66 patients (69%) in the control group. AEs leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, with 4 (2%) and 2 (2%) grade 5 treatment-emergent adverse events, respectively. INTERPRETATION:In the IFM2017-03 trial, use of lenalidomide plus daratumumab, with dexamethasone limited to the first 2 treatment cycles, reduced the risk of progression or death compared with lenalidomide plus dexamethasone, with no additional safety concerns. Lenalidomide plus daratumumab could therefore be considered as a treatment option for older patients with frailty and newly diagnosed multiple myeloma. FUNDING:The study was funded by Johnson & Johnson.

The therapeutic management of patients with multiple myeloma (MM) is complex. Despite substantial advances, MM remains incurable, and management involves cycles of treatment response, disease relapse, and further therapy. Currently, evidence to support the therapeutic decision is limited. Thus, the EMMY longitudinal, real-world study was designed to annually assess therapeutic management of MM in France to provide evidence to support physicians. During an annual prespecified 3-month recruitment period, eligible patients will be identified from their medical records. Adults aged ≥18 years diagnosed with symptomatic MM and requiring systemic treatment will be eligible. The primary objective, the evolution of MM therapeutic management, will be described, as well as the impact on the following outcomes: time-to-next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). The study plans to recruit 5000 patients over 6 years: 700 to 900 patients annually. EMMY is a unique opportunity to collect real-world data to describe the evolving MM therapeutic landscape and record outcomes in France. These data will provide annual snapshots of various aspects of MM management. This knowledge will provide physicians with real-life, evidence-based data for therapeutic decision-making and ultimately improve treatment for MM patients.

Introduction: Isa-VRd significantly increased the MRD negative rate at 10-5 (NGS) at 18 months compared to IsaRd (OR for MRD negativity 3.16, 95%CI 1.89-5.28, p<0.0001), the primary endpoint of BENEFIT study, including in high-risk (HR) NDMM TI. HR was initially defined using the IFM linear predictor (LP) cytogenetic score(HR if LP >1)according to Perrot et al in BENEFIT. The IMS has recently attempted to standardize the HR definition based on several genomic abnormalities alone [deletion 17p in more than 20% of sorted plasma cells, TP53 mutation, del(1p32)del/del] or in combination [t(4;14) or t(14;16) or t(14;20) +gain/amp 1q or del(1p32)del/wt, gain/amp 1q +del(1p32)del/wt].We planned to investigate the efficacy of Isa-VRd over IsaRd in HR NDMM TI using the novel definition. Methods: BENEFIT is a prospective, multicenter, randomized, open-label, phase 3 study done at 68 IFM study sites in France. Patients were randomized 1:1 and stratified by age, centers and high-risk MM to receive Isa-VRd or IsaRd. Isa-VRd arm received V weekly for 12 months then day 1 and 15 up to 18 months; both arms received a classical IsaRd with d permanently discontinued at 12 months. At a median follow-up of 23.5 months, a total of 270 patients were enrolled with 135 assigned to either Isa-VRd or IsaRd arms, and received at least one dose of treatment. Data are presented in ITT. IMS new HR definition was defined based on targeted next generation sequencing of sorted plasma cells. Results: HR features characterized 32 (24%) patients and 24 (18%) across Isa-VRd or IsaRd arms using the IMS HR definition. Deletion 17p 10 (7%) and 7 (5%), TP53 mutation 6 (4%) and 5 (4%), del(1p32)del/del 1 (1%) and 0, t(4;14) or t(14;16) or t(14;20) +gain/amp 1q or del(1p32)del/wt 13 (10%) and 10 (7%), gain/amp 1q +del(1p32)del/wt 6 (4%) and 5 (4%), respectively across arms. Overall, the new IMS HR definition reclassified 30 (13%) NDMM TI patients in the HR category compared to the IFM LP score. Of note, the HR patients according to the IFM LP score were all considered HR by the new IMS definition.The 18-months MRD negativity rate at 10-5 was higher for Isa-VRd in high-risk NDMM TI with the IMS HR definition, 18 (56%) and 6 (25%) across arms, [odds ratio (OR) for MRD negativity in Isa-VRD group compared to IsaRd group was 3.86 (95%CI, 1.2 to 12.3)]. Similar data were observed at 10-6 at 18 months, 16 (50%) and 6 (25%) across arms [OR 3.00 (95%CI, 0,95 to 9.52)]. Higher MRD negativity rates were also observed at 12 months at both 10-5 and 10-6 and in patients with a response ≥ CR and MRD negative status in Isa-VRd in HR NDMM TI.The 18-month MRD negativity rate at 10-5 was higher for Isa-VRd also in NON high-risk NDMM TI (IMS HR definition) [OR 3.00 (95%CI, 1.7 to 5.3)], as well as at 10-6 [OR 2.61 (95%CI, 1.3 to 5.0)] and at 12 months at both 10-5 and 10-6 thresholds and in patients with a response ≥ CR and MRD negative status. Although no statistically significant interaction was detected across HR and NON HR, the greater benefit of IsaVRD vs. IsaRd for MRD negativity was systematically higher for HR patients, regardless of the timepoints (12 months, 18 months), MRD thresholds (10-5 or 10-6) and MRD negativity definition (≥CR or not) Conclusions: The results from the BENEFIT study demonstrated meaningful benefit of the quadruplet-based Isa-VRd regimen compared to IsaRd in all NDMM TI patients. Of importance, the benefit of the Isa-VRd regimen was greater in HR compared to NON HR NDMM TI patients. This data supports Isa-VRd as a new SOC for NDMM TI aged of 65 to 79 patients over the current triplet-based SOC DRd, particularly for HR NDMM TI.