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High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days −6, –3, +1, and +4 and melphalan (200 mg/m2 IV) on day –2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM–treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.

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.

Despite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high-dose therapy (HDT) consolidation on overall survival (OS) or progression-free survival (PFS) in patients who have high-risk cytogenetics. The authors performed a meta-analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk.All RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard-dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard-risk and high-risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic-risk subgroup using a random-effects model, and heterogeneity (IAfter screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow-up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard-risk and high-risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70-1.17; IThe magnitude of OS benefit with upfront HDT is cytogenetics-dependent. Patients with high-risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation.Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high-risk cytogenetics.

The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis.In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs3) and aged (75 vs ≥75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting.Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection).Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing.Sanofi.

Background: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival. Methods: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0–2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1–2, once every 2 weeks in cycles 3–6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1–21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172. Findings: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7–59·9), median progression-free survival was not reached (95% CI 54·8–not reached) in the daratumumab group versus 34·4 months (29·6–39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43–0·66]; p15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group. Interpretation: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation. Funding: Janssen Research & Development.

NEW THERAPIES IN MULTIPLE MYELOMA Multiple myeloma is the second most common hemopathy in Western countries. The development of the therapeutic arsenal has significantly improved patients' prognosis. In the early 2000s, autograft, the addition of immunomodulatory drugs and proteasome inhibitors have undoubtedly changed the face of the disease. In the last decade, a new chapter has opened, targeted therapies led by anti-CD38 and more recently the introduction of CAR T-cells and bispecific antibodies. Because of the survival improvement, quality of life is now a major concern as well as personalized treatment (adapted to cytogenetic risk or treatment response [minimal residual disease]) to overcome prognosis heterogeneity.NOUVEAUX TRAITEMENTS DU MYÉLOME MULTIPLE Le myélome multiple est la deuxième hémopathie la plus fréquente dans les pays occidentaux. Le développement de l’arsenal thérapeutique a amélioré significativement le pronostic des patients. Au début des années 2000, l’autogreffe, l’introduction des immunomodulateurs et des inhibiteurs du protéasome ont indubitablement changé le visage de la maladie. Cette dernière décennie s’est ouvert un nouveau chapitre : celui des thérapies ciblées avec, en chef de file, les anti-CD38 et, plus récemment, l’arrivée des CAR-T cells et des anticorps bispécifiques. Du fait de l’amélioration de la survie, la qualité de vie est désormais au coeur des préoccupations, de même que le traitement personnalisé (adapté au risque cytogénétique ou à la réponse au traitement [minimal residual disease]) afin de réduire l’hétérogénéité pronostique.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P

PURPOSE 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in patients with multiple myeloma (MM). This study aimed to define criteria for PET complete metabolic response after therapy, jointly analyzing a subgroup of newly diagnosed transplantation-eligible patients with MM enrolled in two independent European randomized phase III trials (IFM/DFCI2009 and EMN02/HO95). PATIENTS AND METHODS Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes. RESULTS At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS < 4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively) CONCLUSION FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.

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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. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172., The studies were supported by Janssen Research & Development, LLC.

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC

The Intergroupe Francophone du Myelome 2009 trial (NCT01191060) assessed health-related quality of life (HRQoL) in patients with newly diagnosed multiple myeloma (NDMM) receiving lenalidomide/bortezomib/dexamethasone (RVd) induction therapy followed by consolidation therapy with either autologous stem cell transplantation (ASCT) plus RVd (RVd-ASCT) or RVd-alone; both groups then received lenalidomide maintenance therapy for 1 year. Global HRQoL, physical functioning, and role functioning scores significantly improved for both cohorts from baseline to the end of consolidation and were sustained during maintenance and follow-up, with clinically meaningful changes (RVd-alone

CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM.

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.

Background: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. Methods: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18–65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0–2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. Findings: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2–39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]–NE) with daratumumab versus 46·7 months (40·0–NE) with observation only (hazard ratio 0·53, 95% CI 0·42–0·68, p

Introduction: Daratumumab (DARA) is a human, CD38-targeting, IgG1κ monoclonal antibody approved as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard of care for RRMM and NDMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently improved progression-free survival (PFS) and led to deep and durable responses, including higher rates of minimal residual disease (MRD) negativity compared with standard of care. In the primary analysis of the phase 3 MAIA study (median follow-up, 28.0 mo), D-Rd vs Rd significantly improved PFS and MRD-negativity rates in transplant-ineligible NDMM (Facon T, N Engl J Med 2019). With longer follow-up (36.4 mo), D-Rd maintained a PFS benefit and deeper and more durable responses vs Rd alone (Bahlis N, Blood 2019. 134[Suppl 1]:1875). Here, we report updated efficacy and safety findings from MAIA after approximately 4 years of follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age ( Results: A total of 737 patients were randomized (D-Rd, n = 368; Rd, n = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 47.9 months, 176 (48%) and 273 (75%) patients discontinued study treatment in the D-Rd vs Rd groups, respectively, with 85 (23%) and 113 (31%) patients discontinuing treatment due to progressive disease. PFS remained improved for D-Rd vs Rd (median, not reached [NR] vs 34 mo; HR, 0.54; 95% CI, 0.43-0.67; P Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (53%/37%), pneumonia (18%/11%), anemia (16%/21%), lymphopenia (16%/11%), hypokalemia (12%/10%), leukopenia (11%/6%), and cataract (11%/10%); grade 3/4 infection rates were 40%/29%. The most common serious TEAE was pneumonia (17%/11%). 11% of patients in the D-Rd arm and 22% in the Rd arm discontinued treatment due to an adverse event. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion : After 48 months follow up, the addition of DARA to Rd continues to demonstrate a superior PFS benefit. More patients continued to have deeper and more durable responses with D-Rd vs Rd alone. No new safety concerns were observed with longer follow-up. These results continue to support the use of D-Rd in the first line of treatment for patients with transplant-ineligible NDMM. Disclosures Kumar: Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; MedImmune: Research Funding; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Adaptive Biotechnologies: Consultancy. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Usmani:Abbvie: Consultancy; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; GSK: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding. Plesner:Janssen: Consultancy. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Goldschmidt:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Incyte: Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding. O'Dwyer:Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Weisel:Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Karlin:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Preis:Janssen: Other: for factor XI inhibitor. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Krevvata:Janssen: Current Employment. Wang:Janssen: Current Employment. Van Rampelbergh:Janssen: Current Employment. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Uhlar:Janssen: Current Employment, Current equity holder in publicly-traded company. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding.

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; PCONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

IF 15.132 (2017); International audience; The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7 center dot 5 vs 3 center dot 7 months; HR, 0 center dot 66; 95% CI, 0 center dot 33-1 center dot 28) and overall response rate (ORR, 50 center dot 0% vs 16 center dot 7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11 center dot 2 vs 4 center dot 6 months; HR, 0 center dot 50; 95% CI, 0 center dot 28-0 center dot 88) and ORR (53 center dot 6% vs 27 center dot 6%). More grade >= 3 adverse events occurred in high-risk patients receiving isatuximab (95 center dot 7%) versus the control group (67 center dot 6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.

Simple Summary With the development of modern therapies in multiple myeloma, prognosis stratification is becoming an indispensable tool for the choice of treatment between patients. Many factors influence the prognosis in multiple myeloma; scores, mainly based on biochemical parameters and cytogenetics, have been proposed to discriminate patients. However, these scores are not perfect and fail to predict some patients’ outcomes. In this review, we describe current evaluated factors and their limitations. In the second part, we address factors with an impact on treatment escape and prognosis, but which are not available routinely yet. Abstract Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of tumor plasma cells (PCs) in the bone marrow (BM). Despite considerable advances in terms of treatment, patients’ prognosis is still very heterogeneous. Cytogenetics and minimal residual disease both have a major impact on prognosis. However, they do not explain all the heterogeneity seen in the outcomes. Their limitations are the result of the emergence of minor subclones missed at diagnosis, detected by sensible methods such as single-cell analysis, but also the non-exploration in the routine practice of the spatial heterogeneity between different clones according to the focal lesions. Moreover, biochemical parameters and cytogenetics do not reflect the whole complexity of MM. Gene expression is influenced by a tight collaboration between cytogenetic events and epigenetic regulation. The microenvironment also has an important impact on the development and the progression of the disease. Some of these determinants have been described as independent prognostic factors and could be used to more accurately predict patient prognosis and response to treatment.

Background Multiple Myeloma (MM) disease course is a succession of remissions and relapses, which define lines of treatment. For each line, several regimens can be used. This study provides a comprehensive overview of the evolution through treatment lines of MM patients, based on the nationwide French National Health Insurance (NHI) databases, called SNDS (“Systeme National des Donnees de Sante”). These databases include hospital records, primary and secondary care, and death records of 66 million people. Methods This is a retrospective observational cohort study including all cases of multiple myeloma from 2014 to 2019 identified through the French NHI databases (SNDS). Cases were detected using a validated algorithm which was expanded to consider recent evolution of MM therapeutic management. Incident patients of 2014 and 2015 were extracted and followed up until December 31st, 2019. Treatment lines were reconstructed from 2014 to 2019 through ATLAS, an artificial intelligence algorithm adapted from the Smith-Waterman alignment sequence. Time To Next Treatment (TTNT) for each line has been estimated with a Kaplan Meier method. Results 40,747 prevalent treated patients with MM were identified in the SNDS from 2014 to 2019. This analysis involved more specifically 7,118 of these patients, including 3,557 incident patients from 2014 and 3,561 from 2015. Patients were followed until December 31st, 2019, or death. For the frontline treatment, 76% [N=5,409] had a frontline without transplant (L1 NTE) and 24% [N=1,709] had a frontline with transplant (L1 TE). Among patients with L1 NTE (resp. TE), 15% [N=827] (resp. 33% [N=560]) stayed in frontline until the end of the follow-up, 31% [N=1,682] (resp. 4% [N=71]) died after their frontline, and 54% [N=2,900] (resp. 63% [N=1,078]) switched to L2. Among patients with a L1 NTE (resp. TE) and a L2, 26% [N=764] (resp. 35% [N=378]) stayed in L2 until the end of the follow-up, 29% [N=841] (resp. 12% [N=124]) died after their L2, and 45% [N=1,295] (resp. 53% [N=576]) switched to L3. Among patients with a L1 NTE (resp. TE) and a L3, 24% [N=316] (resp. 28% [N=159]) stayed in L3 until the end of the follow-up, 28% [N=367] (resp. 19% [N=111]) died after their L3, and 47% [N=612] (resp. 53% [N=306]) switched to L4. The median TTNT for L1 NTE (resp. TE) was 2.4 (resp. 3.3) years. The overall survival rate at 5 years for patients with a L1 NTE (resp. TE) was 41% (resp. 75%). Regarding treatment sequencing, the main course of patients was as follows: frontline: V-based regimen (VMP for NTE, VTd for TE); L2: Rd; L3: Pom-dex; L4: Dara mono. Conclusions This study shows the flow of patients from frontline to L4+ and their survival rates. The study also showed that real-world data are a powerful tool to study treatment lines at a national scale and lead the way to more precise analyses of optimal therapeutic sequences, including their impact on the overall survival.

PURPOSE To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study. PATIENTS AND METHODS PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs. RESULTS A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 ( P = .0007 v Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score. CONCLUSION D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.

Multiple myeloma (MM) is rare in young patients, especially before age 40 years at diagnosis, representing

Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes.At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively).FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.

Simple Summary Therapeutic strategies in multiple myeloma have been adapted only to age and comorbidities for a long time. Given the currently available therapeutic and technologic arsenal, the time may have come to refine this adaptation. First, high-risk patients should benefit from the most intensive and efficient combinations from diagnosis. Here, we review these different strategies and how to define and identify high-risk myeloma patients in current clinical practice. In addition, the advent of technologies detecting minimal residual disease gives us this opportunity to define the quality of response to treatment with an unpreceded sensitivity and adapt treatment accordingly. Finally, even if molecular targeting is still nascent in myeloma, some molecular features are interesting to detect at relapse to determine optimal salvage treatments. Abstract Myeloma therapeutic strategies have been adapted to patients’ age and comorbidities for a long time. However, although cytogenetics and clinical presentations (plasmablastic cytology; extramedullary disease) are major prognostic factors, until recently, all patients received the same treatment whatever their initial risk. No strong evidence allows us to use a personalized treatment according to one cytogenetic abnormality in newly diagnosed myeloma. Retrospective studies showed a benefit of a double autologous transplant in high-risk cytogenetics according to the International Myeloma Working Group definition (t(4;14), t(14;16) or del(17p)). Moreover, this definition has to be updated since other independent abnormalities, namely gain 1q, del(1p32), and trisomies 5 or 21, as well as TP53 mutations, are also prognostic. Another very strong predictive tool is the response to treatment assessed by the evaluation of minimal residual disease (MRD). We are convinced that the time has come to use it to adapt the strategy to a dynamic risk. Many trials are ongoing to answer many questions: when and how should we adapt the therapy, its intensity and duration. Nevertheless, we also have to take into account the clinical outcome for one patient, especially adverse events affecting his or her quality of life and his or her preferences for continuous/fixed duration treatment.

Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called “double-hit” population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in > 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the “double hit” situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying “double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd,n = 67; D-VMP,n = 67; D-Rd,n = 65). The primary endpoints were met for all cohorts: the >= very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71 center dot 6% [90% confidence interval (CI) 61 center dot 2-80 center dot 6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88 center dot 1% (90% CI 79 center dot 5-93 center dot 9%) and 90 center dot 8% (90% CI 82 center dot 6-95 center dot 9%). With longer median follow-up for D-VMP and D-Rd (14 center dot 3 and 14 center dot 7 months respectively), responses deepened (ORR: 89 center dot 6%, 93 center dot 8%; >= VGPR: 77 center dot 6%, 78 center dot 5%), and minimal residual disease-negativity (10(-5)) rates were 16 center dot 4% and 15 center dot 4%. Infusion-related reactions across all cohorts were infrequent (

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

Introduction: The 2-part phase 3 CASSIOPEIA study (NCT02541383) investigated the combination of DARA with VTd (D-VTd) in transplant-eligible NDMM pts. D-VTd induction/consolidation (ind/cons) led to increased rates of MRD negativity and prolonged progression-free survival (PFS) compared with VTd (Moreau P, et al. Lancet. 2019;394(10192):29-38). In Part 2, DARA as post-autologous stem cell therapy (ASCT) maintenance significantly improved PFS in pts who received VTd ind/cons. Most common (≥2.5%) grade 3/4 adverse events included pneumonia (DARA: 2.5%; observation [OBS]: 1.4%), lymphopenia (3.6%; 1.8%), and hypertension (3.0%; 1.6%; Moreau P, et al. J Clin Oncol. 2021;39(no. 15_suppl):8004). Here, we present results from a detailed analysis of MRD negativity. Methods: Eligible pts were 18-65 years of age, had NDMM and were ASCT eligible. Pts were randomized 1:1 to 4 (28-day) cycles of pre-ASCT induction and 2 (28-day) cycles of post-ASCT consolidation with D-VTd or VTd (bortezomib, 1.3 mg/m 2 SC on Days 1, 4, 8, 11; thalidomide, 100 mg PO daily; dexamethasone, 20-40 mg IV/PO; ± DARA, 16 mg/kg IV weekly (QW) in Cycles 1-2, Q2W in Cycles 3-6). Pts who completed consolidation and achieved partial response or better were re-randomized 1:1 to maintenance DARA at reduced intensity (DARA, 16 mg/kg Q8W) for a maximum of 2 years, or OBS. Samples were collected for MRD analysis at predefined timepoints from all pts regardless of response to ind/cons and in pts with very good partial response or better during maintenance. The primary MRD assessment methodology was multiparametric flow cytometry during ind/cons and next-generation sequencing during maintenance, each at the 10 -5 threshold. MRD negativity is reported here for pts who achieved complete response or better. Results: 1,085 pts were randomized to ind/cons (D-VTd, n=543 or VTd, n=542) and 886 pts were re-randomized for post-ASCT maintenance (DARA, n=442 or OBS, n=444). The rate of MRD negativity was higher with D-VTd than with VTd following induction (9.2% vs 5.4%; odds ratio [OR], 1.79; P=0.0150) and consolidation (33.7% vs 19.9%; OR, 2.06; P During maintenance, the rate of MRD negativity significantly favored DARA over OBS (58.6% vs 47.1%; OR, 1.80; P=0.0001). In pts who received D-VTd ind/cons, the MRD-negativity rates with DARA and OBS were 64.2% and 57.6% respectively (OR, 1.43; P=0.1037). In contrast, pts who had received VTd ind/cons showed significantly higher MRD-negativity rates during DARA maintenance vs OBS (52.6% vs 35.8%; OR, 2.26; P=0.0002). The rates of sustained MRD negativity in the D-VTd group were not significantly different with DARA vs OBS (1yr sustained: 48.5% vs 41.0%; OR, 1.41; P=0.0885; 2yr sustained: 28.8% vs 21.8%; OR, 1.47; P=0.0789). In the VTd group, the 1-year sustained MRD-negativity rate was significantly higher with DARA vs OBS (35.7% vs 21.4%; OR, 2.22; P=0.0006) but no difference was observed in the 2-year sustained MRD rate (11.3% vs 13.0%; OR, 0.83; P=0.5481). Conclusion: In CASSIOPEIA, the highest and most durable rates of MRD negativity were achieved after D-VTd ind/ASCT/cons and DARA maintenance. Reduced intensity (Q8W) DARA maintenance did not significantly improve MRD negativity compared to OBS in patients treated with D-VTd. In patients treated with VTd, DARA maintenance did improve MRD negativity, but this effect was not long lasting. Longer follow-up is required to assess the potential long-term benefits of sustained MRD negativity for DARA vs OBS after D-VTd. Figure 1 Figure 1. Disclosures Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Moreau: Amgen: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. van der Velden: Janssen: Other: Service Level Agreement; BD Biosciences: Other: Service Level Agreement; Navigate: Other: Service Level Agreement; Agilent: Research Funding; EuroFlow: Other: Service Level Agreement, Patents & Royalties: for network, not personally. Hulin: abbvie: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Arnulf: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Karlin: Janssen: Honoraria, Other: member of advisory board, travel support; Abbvie: Honoraria; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; GSK: Honoraria, Other: member of advisory board; oncopeptide: Honoraria. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Perrot: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van De Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Krevvata: Janssen: Current Employment. Rigat: Janssen: Current Employment, Current equity holder in publicly-traded company. Yang: Janssen: Current Employment. Vanquickelberghe: Janssen: Current Employment. de Boer: Janssen: Current Employment. Kampfenkel: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria; Sanofi: Honoraria; Bristol-Meyer Squibb: Honoraria; Amgen: Honoraria. OffLabel Disclosure: The specific regimen combination is not yet approved in the maintenance setting.

Background: The role of maintenance lenalidomide in myeloma, following autologous stem cell transplantation (ASCT) or not, is well established. However, 29% of patients discontinue the treatment with a median duration of less than 2 years with an increased rate of secondary primary malignancies (SPM). Pomalidomide could provide alternative maintenance therapy. Methods: This was a single arm phase II study of pomalidomide/dex (PD) maintenance therapy for MM patients (pts) in first relapse after treatment in the IFM 2009 trial. At first relapse, 100 pts received pomalidomide/cyclophosphamide/dex (PCD) for 4 cycles, after which half underwent ASCT (if no first line transplant) followed by 2 cycles of PCD consolidation (Arm A), or 5 cycles of PCD (if previously transplanted) (Arm B). All pts then received maintenance therapy consisting of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dex 20 mg once a week until progression (Blood 2018). The primary objective was to establish the safety and efficacy of PD as maintenance therapy. Results: A total of 75 pts were enrolled in the maintenance phase from January 2015 to November 2017 (Table 1) and the database was locked on 07/07/2021. The median age was 60 (range 39-70); 67% (50/75) were male. 53 pts had ISS stage I, 10 stage II and 3 stage III disease (9 missing). Infectious prophylaxis was antiviral in 94%, sulfamethoxazole/trimethoprim in 76%, penicillin in 69% and fluoroquinolone in 38%. A granulocyte colony stimulating factor was administered in 15 (20%) pts and immunoglobulins in 13 (17%). One quarter had thromboprophylaxis. The median follow-up was 73 months (95% CI: 68-75). Among the 75 pts, 63 (84%) left the study, 34 (54%) due to progressive disease, 19 (30%) due to AE/SAE, 7 (11%) on investigator (PI) discretion and 3 (5%) after consent withdrawal. 12 (16%) remained on therapy in July 2021.The median duration of maintenance was 23.7 months (IQR: 14.5-44). Pts received a median of 26 cycles (range 1-80) and 17 (23%) had 50 or more cycles. The reasons for pomalidomide discontinuation were progression or death in 54%, AE/SAE in 30%, PI decisions in 11% and patient decisions in 5%. 56 (75%) pts required a reduction in the dose of pomalidomide due to AE/SAE in 50%, omission in 19%, resumption of treatment in 11%, PI decisions in 16% and patient decisions in 2.7%. The reasons for dex discontinuation were progression or death in 30%, AE/SAE in 43%, PI decisions in 22% and patient decisions in 3%. 57 (76%) pts required a reduction in the dose of dex due to AE/SAE in 54%, omission in 3.4%, resumption of treatment in 0.3%, PI decisions in 38.7% and patient decisions in 3.1%. 31 SAE were reported in 22 pts: 13 (42%) infections, 5 tumors, 1 case of thrombosis, 1 diabetic ketoacidosis and 12 others. Grade 3/4 hematologic AE included neutropenia (51%), lymphopenia (35%), anemia and thrombocytopenia (0%). G3/4 drug-related non-hematologic AE (>5%) comprised 13% infections (5% pneumonia). G1/2 AE included 69% infections (49% bronchitis), 49.3% gastrointestinal disorders (20% diarrhea, 20% constipation), 48% fatigue, 31% skin disorders, 25% muscle spasms, 24% insomnia and 14.7% eye disorders (6.7% cataracts, 4% dry eyes). Concerning peripheral neuropathy, one patient had G3/4 and 45% G1/2. Eight pts developed SPM: 4 basocellular carcinoma, 1 epidermoid carcinoma, 1 melanoma, 1 colon carcinoma and 1 non small cell bronchial carcinoma. We observed an improvement in the response from the initiation of treatment: PR: 32.4 to 17.4%, VGPR: 56.8 to 49.3%, CR: 9.5 to 28%, sCR: 0 to 5.3% (at initiation to best response, respectively). A total of 33.4% of pts improved their response. The median PFS was 33.2 months (95% CI: 25.6-53.3). 41 pts died and the median OS was not reached (95% CI: 70.7-NR). All deaths were related to myeloma progression except 2 due to pulmonary infection, 1 lung carcinoma and 1 colorectal cancer. Conclusions: In the first relapse PCD trial, 75% initiated maintenance therapy. Long term administration of pomalidomide/dexamethasone as maintenance therapy is feasible. Thirty percent stopped pomalidomide because of SAE/AE, mostly related to hematologic AE, but this could be managed with dose reductions. There was generally G1/2 neuropathy, rare SPM and no other unexpected toxicity. One third of the pts improved their depth of response. The combination is safe, feasible and well tolerated and experience to date supports its further exploration with monoclonal antibodies. Figure 1 Figure 1. Disclosures Garderet: Amgen: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Roussel: Amgen: Consultancy; BMS: Honoraria; GSK: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Leleu: Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Karlin: Takeda: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Abbvie: Honoraria; oncopeptide: Honoraria; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Celgene-BMS: Honoraria, Other: member of advisory board. Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Macro: abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; takeda: Honoraria; janssen: Honoraria. Jourdan: Novartis: Consultancy; Abbvie: Consultancy; bms/celgene: Consultancy. Jaccard: Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Mohty: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria. Hulin: Celgene/BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. OffLabel Disclosure: pomalidomide as maintenance treatment

Introduction: Multiple myeloma (MM) is a chronic hematologic malignancy with a high symptom burden that can have a substantial negative impact on patients' (pts) health-related quality of life (HRQoL). The introduction of novel triplet regimens for newly diagnosed MM (NDMM) has extended progression-free survival (PFS) and overall survival (OS); however, adverse events and demanding administration and monitoring schedules have a further negative effect on HRQoL, especially among pts who are transplant ineligible (TIE) due to older age and/or frailty. Optimizing initial treatment is particularly important in older pts, many of whom receive only 1 line of therapy. The phase 3 MAIA trial compared daratumumab, lenalidomide, and dexamethasone (D-Rd) vs lenalidomide and dexamethasone (Rd) in TIE pts with NDMM. At a median follow-up of 28 months, D-Rd significantly prolonged PFS and was associated with faster and sustained clinically meaningful improvements in patient-reported outcomes (PROs) vs Rd. Results of an updated analysis with longer follow-up recently confirmed a significant benefit in OS with D-Rd vs Rd as well as a continued significant PFS benefit and higher rates of complete response or better and very good partial response or better. Here we present an update of the HRQoL analysis with additional follow-up. Methods: MAIA (NCT02252172) is a randomized, open-label, active controlled, multicenter, phase 3 study of TIE pts with NDMM who were randomly assigned 1:1 to receive D-Rd or Rd until disease progression (PD) or unacceptable toxicity. PROs were recorded using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EQ-5D-5L visual analog scale. EORTC QLQ-C30 has 30 items comprising 5 functional scales (physical, role, emotional, cognitive, and social functioning), 1 global health status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Questionnaires were completed at baseline, on day 1 of cycles 3, 6, 9, and 12 for year 1, and every 6 months thereafter until PD. Analyses were conducted on all pts with a baseline and ≥1 post-baseline PRO assessment. Pts were censored at PD or discontinuation of study treatment. Thresholds for meaningful improvement and worsening were defined a priori based on published literature (≥10-point change). Treatment effect was analyzed using a mixed-effects model for repeated measurements including baseline value, visit, treatment, visit by treatment interaction, and randomization stratification factors as fixed effects and individual subject as random effect. Results: At a median follow-up of 56.2 months, discontinuation rates were lower with D-Rd than Rd (56.8% vs 80.8%). For GHS, physical functioning, fatigue, pain, and dyspnea, PROs that are particularly relevant to pts with MM, a numerically greater proportion of pts achieved a meaningful improvement with D-Rd vs Rd (Table 1). Differences were significant for physical functioning, fatigue, and dyspnea. The proportion of pts achieving a meaningful worsening on therapy was similar in both treatment groups (Table 1). The median time to improvement was numerically shorter with D-Rd vs Rd for physical functioning and pain and with Rd vs D-Rd for GHS and fatigue; differences were not significant (Table 2). The median time to worsening of fatigue was similar between groups, numerically longer for D-Rd vs Rd for GHS, and significantly longer with D-Rd than Rd for physical functioning, pain, and dyspnea (Table 2). Median time to worsening of pain with D-Rd vs Rd was 39.43 vs 17.97 months, reflective of an additional ~21 months without worsening pain among pts treated with D-Rd. Between-group differences for least squares mean change from baseline for these 5 PROs favored D-Rd vs Rd at all assessment time points except cycle 3 for physical functioning and cycle 6 for fatigue; differences were significant at ≥1 timepoint for each scale. Conclusions: These updated PRO analyses from the MAIA study demonstrate sustained and clinically meaningful improvements in HRQoL with D-Rd vs Rd with almost 5 years of follow-up. These results are consistent with the clinical benefits of superior PFS, OS, and deep responses observed with D-Rd compared with Rd and support the use of D-Rd in older pts. Figure 1 Figure 1. Disclosures Perrot: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Takeda: Research Funding; Oncopeptides: Other: Advisor, Research Funding; Genentech: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; AbbVie: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Janssen: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Oncopeptides: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Bahlis: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; abbvie: Honoraria. Quach: CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldschmidt: Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; GSK: Honoraria; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. O'Dwyer: ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Bristol Myers Squibb: Research Funding. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Weisel: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Leleu: Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria. Liu: Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau: Janssen: Current Employment, Current equity holder in publicly-traded company. Gries: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Ho: DRG Abacus: Consultancy; Janssen: Consultancy; Emalex Biosciences: Consultancy. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Usmani: Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau.

Introduction: CC-92480 is a potent, novel CELMoD ® compound designed for rapid and maximal degradation of Ikaros and Aiolos, that has shown immunostimulatory effects and enhanced tumoricidal activity in myeloma cells, including those resistant to lenalidomide (LEN) and pomalidomide (POM). CC-92480 has demonstrated potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) (Wong L, et al. Blood 2019;134[suppl 1]:1815). In pts with RRMM, CC-92480 in combination with DEX demonstrated a manageable safety profile with promising preliminary efficacy (Richardson PG, et al. J Clin Oncol 2020;38[suppl 15]:8500). CC-92480-MM-002 (NCT03989414) is an ongoing phase 1/2 study evaluating CC-92480 in combination with standard treatments in pts with RRMM. Here we report preliminary results from the CC-92480 + BORT + DEX cohort. Methods: Pts with RRMM who had received 2-4 prior regimens, including prior treatment with LEN, and had documented disease progression during or after their last myeloma therapy were eligible. CC-92480, at specified cohort doses (0.3 mg, 0.6 mg, and 1.0 mg), was administered orally on days (D) 1-14 with subcutaneous BORT (1.3 mg/m 2) on D1, 4, 8, and 11 in cycles (C) 1-8 and on D1 and 8 after C8, over a 21-day cycle; DEX (20 mg/day or 10 mg/day if > 75 years of age) was given on D1, 2, 4, 5, 8, 9, 11, and 12 in C1-8 and on D1, 2, 8, and 9 after C8. Primary objectives were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and to evaluate safety and preliminary efficacy. Pharmacodynamics (PD), Ikaros/Aiolos protein levels, and immunophenotyping were also assessed. Results: As of May 26, 2021, 19 pts had received CC-92480 + BORT + DEX. Median age was 66 (50-83) years, median time since initial diagnosis was 4.8 (1.9-17.1) years, and median number of prior regimens was 3 (2-4). Prior therapies included stem cell transplantation (57.9%), BORT (78.9%), carfilzomib (CFZ, 21.1%), LEN (100%), POM (47.4%), and anti-CD38 mAbs (36.8%); 21.1% of the pts had extramedullary disease and 21.1% were triple-class refractory (refractory to immunomodulatory drug, PI, and anti-CD38 mAb). Median follow-up was 8 (1.0-19.2) months, with a median number of 10 (1-28) cycles received and 9 (47.4%) pts continue on treatment. Main reason for discontinuation was progressive disease, reported in 5 pts. All pts experienced ≥ 1 treatment-emergent adverse events (TEAEs) and grade (Gr) 3-4 TEAEs were reported in 18 (94.7%) pts. Most frequent (≥ 10% of pts) Gr 3-4 TEAEs were neutropenia (36.8%, no febrile neutropenia reported), thrombocytopenia (21.1%, no bleeding reported), anemia (10.5%), hyperglycemia (10.5%), and insomnia (10.5%). Gr 3-4 infection was reported in 1 (5.3%) pt. Eight (42.1%) pts had Gr 1-2 peripheral neuropathy. Five (26.3%) pts had serious TEAEs, none considered related to study treatment. Five (26.3%), 7 (36.8%), and 8 (42.1%) pts had dose reductions of CC-92480, BORT, and DEX, respectively; 4 (21.1%) pts had dose reductions due to TEAEs. Two (10.5%) pts discontinued due to TEAEs (dysgeusia and colon neoplasm [pre-existing]). No pt experienced dose-limiting toxicity and the MTD was not reached. Two deaths were reported (due to myeloma progression and colon neoplasm). The overall response rate across all doses per investigator assessment was 73.7% (14/19 pts), including 3 stringent complete responses and 1 complete response. Responses were observed at all dose levels. Median duration of response was 10.4 (5.5-not reached) months and median time to first response was 0.95 (0.7-3.3) months. Plasma exposures of CC-92480 + BORT + DEX were consistent with previous pharmacokinetic (PK) analysis of CC-92480 + DEX. Consistent with CC-92480 mechanism of action, PD studies showed potent degradation of substrates 3-6 hours post treatment and a reduction of mature B cells with CC-92480 + BORT + DEX treatment. Based on safety, efficacy, and PK/PD data, a 1.0 mg dose of CC-92480 was selected as the RP2D. Conclusions: CC-92480 in combination with BORT and DEX appears to be safe and well tolerated with encouraging preliminary efficacy in pts with RRMM. These results support further development of CC-92480 in combination regimens in RRMM. In the CC-92480-MM-002 study, a CC-92480 + BORT + DEX expansion cohort is ongoing at the RP2D, as well as a CC-92480 + CFZ + DEX cohort. Updated data will be presented at the meeting. Disclosures Richardson: Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Ocio: Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy; MSD: Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. White: Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Forus: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sandhu: Celgene/BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Raab: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. LeBlanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Rodriguez: BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau. Trudel: Sanofi: Honoraria; Roche: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Genentech: Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Wäsch: Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Perrot: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria. Bahlis: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Zhou: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lamba: Bristol Myers Squibb: Current Employment; Pfizer: Current equity holder in publicly-traded company. Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Civardi: Bristol Myers Squibb: Current Employment. Katz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Maciag: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Amgen: Honoraria.

Background In recent years, large clinical trials have shown the superiority of L1 RD (lenalidomide-dexamethasone) over MPT, and then L1 VRD (lenalidomide, bortezomib and dexamethasone) over RD in Multiple Myeloma (MM) patients ineligible for autologous stem cell transplantation (ASCT). The EMMY study, a large-scale epidemiological study to assess the epidemiology and real-life management of multiple myeloma (MM), describes the real-life use and efficacy of RD and VRD regimens in first-line patients not eligible for ASCT (non ASCT-L1). Methods EMMY is a descriptive, multicenter, national, non-interventional study conducted in 72 IFM (Intergroupe Francophone du Myélome, sponsor) centers in France. Any patient initiating treatment for MM over a 3-month observation period, from October to December, is included, since 2017. It is a dynamic cohort with the inclusion of 1000 additional patients each year (2765 patients included at the end of 2019). Data are updated annually from hospital records up to 2020. The sample of patients receiving RD or VRD therapy in the non ASCT-L1 patient group, over the 2017-2019 period, was extracted to describe patient characteristics. The time to next treatment (TNT), and overall survival (OS) were estimated. The strategies were compared in the subgroup of patients aged of [65-75[ year-old (Wilcoxon test). Results Among the 773 EMMY patients initiating a non ASCT-L1 treatment during the period 2017-2019, 162 (21%) received RD and 158 (20%) VRD. The median follow-up was 22 months (RD) and 11 months (VRD). Other patients received MPV (26%, n=204), VCD (13%, n=101), VD (8%, n=61), VTD (5%, n=37) or other combinations (7%, n=50). Median age was 79.6 [73.7-83.1] and 69.3 [64.7-73.2] years at initiation of RD and VRD. When available, other characteristics were similar between the 2 groups: ECOG ≥ 2 for 31% (RD) (n= 23/ 74) and 26% (VRD) (n=17/65), high cytogenetic risk for 13% (RD) (n=9/67) and 12% (VRD) (n=9/77), ISS at 1/2/3 for 32, 28, and 40% (RD) (n= 83) and 33, 23, and 44% (VRD) (n= 87) of patients. ASCT was initially planned for 23 of 82 patients initiating VRD in late 2019. The mTNT was 29.1 months 95%IC [20.1-37.7] in RD patients and 34.1 months 95%IC [24.1 - NA] in VRD patients. For patients who received other combinaison in non ASCT-L1, mTTNT varied from 5.2 months 95%IC [3.6 - 12.6] (VRD) and 5.3 months 95%IC [3.9 -15.3] (VD) to 13 months 95%IC [9.2 - 24.7] (VCD), 13 months 95%IC [9.2 - 20.3] (other) and 20.3 months 95%IC [17.2 - 24] (MPV) (p The mTNT by age ( OS at 24 months was 86% [78; 91] and 85% [75; 91] for the RD and VRD groups, respectively. Of the 55 RD patients who relapsed and initiated L2, 46 (84%) received bortezomib (MPV 26%, DVD 16%, VD 18%, and VCD 11%). The 39 VRD patients with initiated L2 received IMID (72%) and/or anti CD38 (50%) in various strategies (DPomDex 17%, DRD 14%, DVD 6%). By focusing on the [65-75[ year old patient group (n=135, including 48 RD and 87 VRD patients), the 12 and 24 month TTNT rates were respectively 67% [54;85] and 55% [40;71] in the RD group (n=48) vs 85% [77-92] and 71% [58-84] in the VRD group (n=87) (p.0,01). In this subgroup RD patients were slightly older (72 vs 70 year-old) with ECOG≥2 in 41% vs 18%. Conclusion RD and VRD stragegies improve TTNT in non ASCT L1 patients. RD is predominantly prescribed to patients ≥75 years of age in whom it remains highly effective. For patients ≥75 years of age, prescription of VRD does not appear to provide significant benefit vs. RD. For those Figure 1 Figure 1. Disclosures Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Perrot: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria. Moreau: Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Leleu: Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support; Amgen: Honoraria; AbbVie: Honoraria. Sanhes: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jaccard: Abbvie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Boccaccio: celgene: Current holder of individual stocks in a privately-held company. Hulin: Celgene/BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria.

Introduction: The introduction of new treatments over the past 2 decades has improved survival outcomes in patients with multiple myeloma (MM), yet MM remains incurable. Despite therapeutic advances, most patients with MM eventually relapse and/or become refractory to treatment, and cycle through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs), becoming triple-class exposed. These triple-class exposed patients represent a population with an urgent unmet clinical need and are a major focus for the development of new therapies. There are currently no prospective data outside of clinical trials on standard-of-care (SOC) in MM patients who progress after these treatment regimens. LocoMMotion (NCT04035226) is the first prospective study to assess the efficacy and safety of real-life SOC treatments in triple-class exposed patients with relapsed/refractory MM (RRMM). Initial analysis at a median follow-up of 3.7 months (range: 0.0-12.7) showed an overall response rate (ORR) of 20.1% (95% CI: 15.0-26.0), with only 5% of patients achieving very good partial response or better. Here, we report updated results from LocoMMotion with a longer median duration of follow-up (7.8 months), along with progression-free survival (PFS) and overall survival (OS) data. Methods: LocoMMotion is a non-interventional study of 246 patients across 10 countries (the US and 9 in Europe) and 75 sites. Patients (aged ≥18 years) with a documented diagnosis of MM were included if they received ≥3 prior lines of therapy or were double-refractory to a PI and IMiD; had measurable disease at screening; received at least a PI, an IMiD, and anti-CD38 mAb with documented progressive disease since their last line of therapy; and had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Patient-level data and the most common SOC treatments were collected and analyzed during the study period (August 2019 through October 2020). Real-life SOC treatments were defined as those used in local clinical practice. Responses were assessed per International Myeloma Working Group response criteria. A review committee assessed the ORR (primary objective) of real-life current SOC as well as disease progression for the determination of PFS. Secondary objectives included evaluation of additional efficacy endpoints, including OS, and safety. Results: As of the data cut-off date of March 9, 2021, 246 patients were included with a median follow-up of 7.8 months (range: 0.1-16.9); 23 (9.3%) patients were from the US and 223 (90.7%) were from Europe. Median age was 68 years (range: 41-89), 133 (54.1%) were male, 180 (73.8%) had a baseline ECOG PS score of 1, and median time since initial MM diagnosis was 6.3 years (range: Conclusions: Updated results of this first, prospective study of real-life SOC treatment in triple-class exposed patients with RRMM confirm rapid disease progression after application of salvage therapy and poor outcomes with currently available treatments. New treatment approaches with novel therapies are needed to improve outcomes in this patient population. Disclosures Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria. Weisel: Roche: Honoraria; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Goldschmidt: Incyte: Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; GSK: Honoraria; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Mohty: Novartis: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Cavo: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Dytfeld: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Current Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Perrot: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Benjamin: Servier: Honoraria, Research Funding; Allogene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Gileai: Honoraria, Research Funding. Van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Ocio: MSD: Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Scheid: Roche: Consultancy; Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clínica Universidad de Navarra: Current Employment; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria. Broyl: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria; Sanofi: Honoraria; Bristol-Meyer Squibb: Honoraria; Amgen: Honoraria. Potamianou: Janssen: Current Employment, Current holder of stock options in a privately-held company. Sakabedoyan: Janssen: Current Employment. Semerjian: Janssen: Current Employment. Keim: Janssen Research & Development: Current Employment. Strulev: Janssen Pharmaceutica NV: Current Employment. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Wapenaar: Janssen: Current Employment; Johnson & Johnson: Current holder of individual stocks in a privately-held company. Nesheiwat: Legend Biotech USA: Current Employment. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld: SkylineDx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Mateos: Oncopeptides: Honoraria; GSK: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Induction therapy followed by autologous stem cell transplantation (ASCT) before maintenance is the standard of care for transplant eligible NDMM patients. The addition of daratumumab to bortezomib, thalidomide, and dexamethasone (VTD) improved response rates and reduced the risk of progression or death compared to VTD alone (Moreau et al, Lancet 2019). Other quadruplet combinations such as carfilzomib, lenalidomide, dexamethasone and daratumumab have also been evaluated, showing high response rates and high levels of MRD negativity (Landgren et al, JAMA Oncol 2021), which seems particularly suitable to high-risk patients. The replacement of bortezomib with ixazomib in an all-oral combination with lenalidomide and dexamethasone (IRD) has been demonstrated to be safe, convenient, and effective in induction and consolidation before and after ASCT (Moreau et al, Blood 2017). The more progressive response kinetics and the very safe profile of ixazomib led to consider daratumumab plus IRD (D-IRD) extended induction and consolidation in standard-risk NDMM patients. We evaluated its safety and efficacy before and after ASCT followed by lenalidomide maintenance as frontline therapy for patients with standard-risk NDMM younger than 66 years (NCT03669445). Methods Patients with standard-risk cytogenetic MM (defined by FISH at diagnosis according to IMWG criteria) received six 21 days-cycles of induction therapy with daratumumab 16 mg/Kg IV at days 1, 8, 15 (cycles 1-4) and days 1 and 15 (cycles 5-6) plus ixazomib 3 mg on days 1, 4, 8 and 11 plus lenalidomide 25 mg on days 1 through 14 and dexamethasone 40 mg on days 1, 8 and 15. Peripheral blood stem cells were collected after cyclophosphamide mobilization, followed by Melphalan 200 mg/m2 and ASCT. D-IRD consolidation started 2 to 3 months after ASCT and consisted in four 28 days-cycles with daratumumab at days 1 and 15, ixazomib 4 mg on days 1, 8 and 15, lenalidomide 25 mg on days 1 to 21 and dexamethasone 20 mg on days 1, 8, 15 and 22 (cycles 7-8) and days 1 and 15 (cycles 9-10). Single agent lenalidomide maintenance was administrated at 10 mg on days 1 through 21 of a 28 days-cycle during 26 cycles. The primary endpoint was the MRD-negativity after consolidation and before maintenance. MRD-negativity was assessed using NGS method with a sensitivity threshold of detection of MM cells up to 10 -6. Secondary objectives were toxicity according to NCI-CTCAE version 5.0, MRD-negativity rates at other timepoints, response rates according to 2016 IMWG criteria as well as PFS, TTP and OS. Results From 12/2018 to 09/2019, 45 patients were enrolled in 10 IFM centers. Median age was 57 years [28-65] and 66.7% were male. Since it was an eligibility criteria, there was no t(4;14), t(14;16) or del(17p). The distribution of ISS scores 1, 2 and 3 was as follows: 40.9%, 38.6% and 20.5%. On 45 patients who initiated the treatment, 43 completed induction, ASCT and consolidation and 42 started maintenance. All patients responded (ORR 100% [CI 92.1-100.0]) and the best response was sCR or CR in 53.4%, VGPR in 40% and PR in 6.7% of the patients. For the primary endpoint 38 patients were evaluable at 10 -6 after consolidation and the MRD-negativity rate was 39.5% ([CI 26.1-54.1]; p=0.137). At a sensitivity of 10 -5 (IMWG criteria) the MRD negativity rate was 51.4% ([CI 36.8-65.7]; p=0.005). Response rates deepen with time, regarding IMWG categories as well as MRD-negativity rates (Figure). After a median follow up of 23.6 months, 2 patients experienced disease progression. The PFS rate at 24 months was 95.2% [CI 82.1-98.8]. Serious adverse events occurred in 15 (33.3%) patients and grade 3/4 event in 28 (62.2%). The most common grade 3-4 toxicities were neutropenia (28.9%), thrombocytopenia (11.1%) and infections (15.6%). Moderate peripheral neuropathy (35.6%; no grade 3-4), gastrointestinal disorders (4.4% grade 3-4) and rash (28.9%; no grade 3-4) were also described. No deaths or secondary primary malignancies were reported to date. Conclusion D-IRD as extended induction prior to, and as consolidation following ASCT was safe and allows gradually deepening responses in standard-risk MM, with 39.5% of patients with MRD negativity at 10 -6 after consolidation, 2-year PFS at 95.2% and 2-year OS at 100%. MRD-negativity rates are lower than those obtained with D-VTD or D-KRD; more follow-up is needed to confirm PFS and OS data. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Hulin: Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; abbvie: Honoraria. Macro: Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Karlin: Abbvie: Honoraria; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Janssen: Honoraria, Other: member of advisory board, travel support; oncopeptide: Honoraria. Roussel: Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; BMS: Honoraria; Takeda: Consultancy; Amgen: Consultancy. Guillemot: Takeda: Honoraria. Avet-Loiseau: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Janssen: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria. OffLabel Disclosure: The quadruplet Dara-Ixa-Len-Dex is not approved in newly diagnosed multiple myeloma.

In multiple myeloma (MM), among the anomalies associated with shorter survival, it should be noted recurrent copy number variations (CNV), such as del(17p13), del(1p32), or 1q gains. These abnormalities are considered secondary, thus acquired during the course of the disease. Although they can be observed from diagnosis, they are only detected at the time of relapses in some patients. It is now clearly demonstrated that MM is a molecular subclonal disease, with the coexistence of different subclones of varying size. As in other cancers, it has also been shown that these different subclones can vary in size according to the different relapses, suggesting that an unnoticed minor subclone at diagnosis could become the major one at the time of relapse. Although subclonality has been largely reported at the mutational level, little is known about this phenomenon at the CNV level. Since a few CNV are associated with a poor outcome, and assuming they will impact the disease course, it would be clinically highly valuable to track these abnormalities at the time of diagnosis in minor subclones. Here, we report the first analysis at the single cell level of CNV of tumor cells from 81 patients with MM analyzed at the time of diagnosis, relapse or pre-symptomatic stages. A total of 52,176 single MM cells were analyzed. The number of analyzable tumor cells was variable from patients to patients, due to heterogeneity in the sample cellularity, but also variability in cell capture rate for the single cell analysis. The mean number of analyzable cells was 656 MM cells per patient (range=83-5192). To avoid possible false positive cases, we arbitrarily defined a subclone by at least 10 cells presenting the same CNV. In these 81 patients, at least one subclone was detected in 74 of them (91%). In this cohort, a subclonal high-risk CNV (not detected on the routine assessment) was observed in 19 patients (23.5%). We had the opportunity to also analyze at single cell level residual MM cells from one patient at the end of induction therapy, and early relapse. This patient displayed a 1q gain subclone at diagnosis (16 % of the analyzed cells), not detected in the bulk analysis. At the post-induction time (thus before high-dose melphalan and autologous stem cell transplantation), 70 % of the 202 analyzable tumor cells presented this high-risk feature. This patient did relapse only 18 months after diagnosis and at this time, 92% of the cells harbored the 1q gain (Figure 1). To address the question whether these high-risk subclonal features may impact outcome as soon as diagnosis, we explored our database. We found that 1q gains are observed in 34.1% of patients (1891/5539) at the time of diagnosis. When analyzing patients at relapse, 46.3% of them displayed a 1q gain (622/1341), thus a 12% increase. This increasing frequency reflects clonal selection of minor subclones already present at diagnosis but not detectable by conventional technique (found in comparable proportions), rather than actual acquisition after diagnosis during evolution of the disease. We then looked at the prognostic impact of 1q gain in patients displaying this CNV at diagnosis versus those presenting it only at the time of first relapse. Interestingly, the PFS and OS) curves were totally superimposable, suggesting that this subclonal 1q gain present from diagnosis in these latter patients impacts survival, possibly through early expansion. In order to go further in the molecular consequences of these high-risk subclones, we did perform single cell RNA-sequencing in 63 of the 81 patients. 1q gains defined specific subclones in the MM cells expression analyses from affected patients. Based on the expression of CDC28 protein kinase regulatory subunit 1B (CKS1B), located at 1q21, we found that high expression was restricted to specific subclones. In conclusion, our study highly suggests that high-risk CNVs are not acquired after, but are present from the diagnosis, and selected by the treatment. These findings may have implications in high-risk definition and patient's management, by reinforcing the therapeutic strategy in these patients as soon as the first line therapy to prevent the clonal selection of these aggressive subclones. Whether this finding could be extended to cancer in general but also in some pre-malignant stages is possible, but needs to be explored. Figure 1 Figure 1. Disclosures Perrot: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leleu: Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Other: Non-financial support; AbbVie: Honoraria. Manier: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Mohty: Novartis: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Jazz: Honoraria, Research Funding. Munshi: Novartis: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Adaptive Biotechnology: Consultancy; Legend: Consultancy; Pfizer: Consultancy.

Background EMMY is a large-scale epidemiological study to assess the epidemiology and real-life management of multiple myeloma (MM). Proteasome inhibitors (PI), immunomodulators (IMID) and anti-CD38, provide broad therapeutic solutions for the management of first-line Multiple Myeloma (MM). At more advanced stages, the therapeutic possibilities in patients already exposed to these 3 therapeutic classes are limited. The EMMY study allows to describe the characteristics and the real-life efficacy of treatments in tri-exposed patients. Methods EMMY is a descriptive, multicenter, national, non-interventional study conducted in 72 IFM (Intergroupe Francophone du Myélome, sponsor) centers in France. Any patient initiating treatment for MM over a 3-month observation period, from October to December, is included, since 2017. It is a dynamic cohort with the inclusion of 1000 additional patients each year (2765 patients included at the end of 2019). Data are updated annually from hospital records up to 2020. Patients with tri-exposure to the 3 classes IMID, IP and anti CD38 were identified, and the index date was defined as the initiation of the next line. The median time to next treatment (mTTNT), median progression-free survival (mPFS), and median overall survival (mOS) were estimated for these patients. Results are focused in patients refractory to the previous line (PL-Ref). Results After 3 years of data collection in EMMY, 491 patients (17.8%) were identified as tri-exposed in the cohort. The median age was 69.9 years [62.2-75.8] with 158 patients (32.2%) < 65 years and 63 (12.8%) ≥ 80 years. When available, patients had ECOG 0 or 1 for 59.3% (n=211), high cytogenetic risk for 29.5% (RD) (n=65), an ISS of 1/2/3 for 25.3, 28.5 and 46.2% and at least one comorbidity for 32% (n=157). The patients were tri-exposed at the end of L2, L3, L4, L5 and L6+ for respectively 2%, 16.9%, 26.9%, 26.3% and 27% of them with a median time from diagnosis to the index date of 54.9 months (mo) [32.9 -89.7]. The proportion of patients early tri-exposed as of L3 or L4 increased over the years with respectively 9.8% (L3) and 15.7% (L4) in 2017 (n=51), 11% and 18.9% in 2018 (n=127), 17.1% and 26.8% in 2019 (n=164) and 24.5% and 37.4% in 2020 (n=147). Time from diagnosis to the index line decreased from 64.6 mo (2017) and 62.8 mo (2018) to 54.5 mo (2019) and 49.5 mo (2020). Half patients (52.5%) had previously received ASCT. At the index date, patients had previously been treated with bortezomib (98%), carfilzomib (21.2%), ixazomib (10.4%), lenalidomide (90.4%), thalidomide (35.8%), pomalidomide (61,9%), daratumumab (96.5%) and isatuximab (3.5%). In overall, 86% were refractory to anti-CD38, 51% refractory to 3 classes, and 31% to 2 classes. Of them, 89.2% (438) were refractory to the line prior to the index line (PL-Ref). The mPFS was 5,1 mo 95%CI [4.4 - 6.3] and the mTTNT 6.9 mo 95%CI [6.1 -8.2] for the whole cohort (n=481). In the 438 PL-Ref patients, mPFS was 4.8 mo 95%CI [4.1-6] and mTTNT was 6.6 mo 95%CI [5.5; 7.8] (Figure 1). The mOS was 17.7mo 95%CI [14.2 - 20.2] for the whole cohort with mOS of 16.6 mo 95%CI [13.1 - 19.8] in PL-Ref patients. Conclusion Advances in the management of myeloma are leading to the increasingly early use of combination treatments with IMID, PI and anti-CD38 antibodies in the treatment of multiple myeloma. As a result, patients are increasingly early exposed to these 3 major classes. The EMMY cohort confirms that patients are triple exposed to PIs, IMID, and anti CD38 at an increasingly early stage in the management of MM. Most of them were refractory to the last line and to anti-CD38 antibodies. The majority remains healthy with ECOG less than 2 and few comorbidities. Median PFS and TTNTs are approximately six months, lower than those observed with modern anti-BCMA immunotherapies. These results underline the importance of developing new therapeutic strategies in triple-exposed patients such as novel immunotherapy including bi-specific antibody/CART cells. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin: Janssen: Honoraria; abbvie: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria. Macro: takeda: Honoraria; abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; janssen: Honoraria. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Leleu: Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support; Amgen: Honoraria; AbbVie: Honoraria. Manier: Novartis: Consultancy, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Karlin: Takeda: Honoraria, Other: member of advisory board; oncopeptide: Honoraria; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Abbvie: Honoraria; Janssen: Honoraria, Other: member of advisory board, travel support. Vincent: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Rigaudeau: Takeda: Membership on an entity's Board of Directors or advisory committees. Boccaccio: celgene: Current holder of individual stocks in a privately-held company. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria.

Introduction In the primary analysis of MAIA, daratumumab (DARA) plus lenalidomide and dexamethasone (D-Rd) reduced the risk of disease progression or death by 44% vs lenalidomide and dexamethasone (Rd) in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Here, we report the updated efficacy and safety of D-Rd vs Rd after almost 5 years of median follow-up from the prespecified interim overall survival (OS) analysis of MAIA (NCT02252172). Methods Pts with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to D-Rd or Rd. All pts received 28-day cycles of Rd (R: 25 mg PO once daily on Days 1-21; d: 40 mg PO on Days 1, 8, 15, 22) ± DARA (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter). All pts were treated until disease progression/unacceptable safety events. The primary endpoint was progression-free survival (PFS). Results 737 pts (D-Rd, 368; Rd, 369) enrolled and baseline characteristics were well balanced. Median age was 73 (range, 45-90) years. At a 56.2-month median follow-up, a significant 32% reduction in the risk of death was observed with D-Rd vs Rd. Median OS was not reached (NR) in either arm (HR, 0.68; 95% CI, 0.53-0.86; P=0.0013 [crossing the prespecified stopping boundary of P=0.0414]); estimated 5-year OS rates were 66.3% with D-Rd and 53.1% with Rd. The updated median PFS was NR with D-Rd vs 34.4 months with Rd (HR, 0.53; 95% CI, 0.43-0.66; PPP=0.2480); a PFS benefit was not observed with D-Rd vs Rd in pts who received P=0.3579). No new safety concerns were identified with longer follow-up. The most common grade 3/4 treatment-emergent adverse event was neutropenia (D-Rd, 54.1%; Rd, 37.0%). Conclusions After ~5 years of follow-up, D-Rd vs Rd showed a significant and clinically meaningful PFS and OS improvement in transplant-ineligible pts with NDMM. Additionally, D-Rd showed a greater PFS benefit vs Rd among pts treated for ≥18 months than among pts treated for shorter durations. Taken together with real-world data indicating that many transplant-ineligible pts do not receive a second line of therapy, the favorable benefit-risk profile observed in MAIA supports the frontline use of D-Rd in transplant-ineligible pts with NDMM.