Abstract: 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 ( & lt;75 vs ≥75 years). All patients received 28-day cycles of Rd (R: 25 mg orally once daily on Days 1-21; d: 40 mg orally on Days 1, 8, 15 and 22). In the D-Rd arm, DARA (16 mg/kg intravenously) was given weekly for Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. Patients were treated until disease progression or unacceptable toxicity in both treatment arms. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), MRD-negativity rate (10‒5 sensitivity, clonoSEQ® version 2.0), and safety. PFS on the next line of therapy (PFS2), defined as the time from randomization to progression on the next subsequent line of therapy or death, was also measured. 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 & lt;0.0001; Figure). The estimated 48-month PFS rate was 60% with D-Rd vs 38% with Rd. The PFS benefit of D-Rd in prespecified subgroups, including patients with high cytogenetic risk, was generally consistent with overall results. Adding DARA to Rd continued to result in deeper responses with higher rates of ≥CR and ≥very good partial response (VGPR; Table). Median duration of response among responders was NR with D-Rd vs 44 months with Rd. Median PFS2 was NR vs 51 months with D-Rd vs Rd, respectively (HR, 0.65; 95% CI, 0.52-0.83; P=0.0005); follow up is ongoing. 107 (29%) patients in the D-Rd group and 132 (36%) in the Rd group have discontinued the study due to death. 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.

Abstract: CMP is an effective induction regimen for transplant-ineligible MM patients. The CMP regimen is safe and well tolerated with a notable lack of peripheral neuropathy.

Abstract: Abstract 598 Background: Several biological parameters have been described, which define patients with multiple myeloma with a high-risk of progression. Nevertheless, apart from the International Staging System (ISS), no clear, simple and reliable prognostic index has yet been identified, especially for the classification of patients with very high-risk disease. We aimed to characterize the group of patients who have a high risk of early death from progression in the context of frontline therapy using novel agents-based induction therapy and autologous stem cell transplantation. Methods: We investigated prognostic parameters of patients enrolled in the IFM2005-01 trial, which compared bortezomib-dexamethasone versus VAD induction followed by ASCT (Harousseau et al, J Clin Oncol 2010;28:4621–4629). Results: In a multivariate logistic regression analysis, the risk of death from progressive disease (and not toxicity) (42 cases out of 482 patients) within the first 2 years from the start of therapy was related to 3 independent adverse baseline characteristics: high LDH 〉 normal value (p = 0.0014), ISS 3 (p = 0.0097) and cytogenetic abnormalities defined by the presence of either t(4;14) or 17p deletion (p = 0.0002). These 3 variables enabled the definition of a simple scoring system consisting of 4 categories (scores 0–3) that predicts for overall survival (OS). Score 0 was defined by the absence of adverse factors (neither high LDH, nor ISS 3, nor t(4;14) and/or del(17p)); in this group of patients, representing 57% of the overall population, the 4-year OS rate was 84%. A score of 1 was defined by the presence of only 1 adverse factor (either high LDH or ISS 3 or t(4;14) and/or del(17p)). The 4-year OS rate in this group of patients (32% of the overall population) was 73%. A score of 2 defined by the presence of high LDH plus ISS 3 in the absence of t(4;14) and/or del(17p), was found in 6% of the overall population. The 4-year OS rate in this group was 68%. Score 3 was defined by the presence of t(4;14) and/or del(17p) in addition to either ISS 3 or high LDH. In this group of patients, representing 5% of the overall population, the median OS was only 19 months (Figure). Conclusion: We have defined a new and simple scoring system that allows the identification of a small group of patients with very high-risk disease and a shortened survival despite the use of intensive novel agents-based therapy. These preliminary findings require confirmation using data from a large number of patients enrolled in the most recent prospective clinical trials investigating triplet induction regimens prior to ASCT. The subgroup of patients with a score of 3, which is associated with a detrimental outcome, might benefit from innovative therapeutic approaches. Disclosures: Moreau: janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Attal:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Hulin:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Facon:millenium: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees. Kolb:celgene: Honoraria; janssen: Honoraria. Roussel:janssen: Honoraria; celgene: Honoraria. Leleu:celgene: Honoraria; janssen: Honoraria. Avet-Loiseau:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract: Multiple myeloma (MM) is rare in young patients, especially before age 40 years at diagnosis, representing & lt;2% of all patients with MM. Little is known about the disease characteristics and prognosis of these patients. In this study, we examined 214 patients diagnosed with MM at age ≤40 years over 15 years, in the era of modern treatments. Among them, 189 patients had symptomatic MM. Disease characteristics were similar to older patients: 35% had anemia, 17% had renal impairment, and 13% had hypercalcemia. The staging was ISS-1 in 52.4%, ISS-2 in 27.5%, and ISS-3 in 20.1%. Overall, 18% of patients had high-risk cytogenetics [del 17p and/or t(4;14)]. Ninety percent of patients received intensive chemotherapy followed by autologous stem cell transplant, and 25% of patients had allogeneic stem cell transplant predominantly at time of relapse. The median follow-up was 76 months, the estimated median overall survival was 14.5 years, and the median progression free-survival was 41 months. In multivariate analysis, bone lesions (hazard ratio [HR] , 3.95; P = .01), high ISS score (HR, 2.14; P = .03), and high-risk cytogenetics (HR, 4.54; P & lt; .0001) were significant risk factors for poor outcomes. Among predefined time-dependent covariables, onset of progression (HR, 13.2; P & lt; .0001) significantly shortened overall survival. At 5 years, relative survival compared with same age- and sex-matched individuals was 83.5%, and estimated standardized mortality ratio was 69.9 (95% confidence interval, 52.7-91.1), confirming that MM dramatically shortens the survival of young patients despite an extended survival after diagnosis.

Abstract: Introduction The use of autologous haematopoietic cell transplantation (auto-HCT) in the treatment of myeloma (MM) has greatly increased over the last twenty-five years. There are, however, few large datasets detailing the overall trends in transplant use, patient selection, induction regimen, choice of mobilisation regimen, stem cell yield, response to transplant and survival. We performed a retrospective analysis of all patients who underwent first auto-HCT for MM in EBMT centres between 1993 and 2017 and analysed these trends over consecutive five-year cohorts: (1) 1993-1997, (2) 1998-2002, (3) 2003-2007, (4) 2008-2012 and (5) 2013-2017. Methods Data on patients with MM who underwent a first auto-HCT at EBMT centres between 1993 and 2017 were obtained from the EBMT registry. Med-A forms consist of registration and follow-up forms. More detailed information in captured in Med-B forms. Results A total of 103,032 patients in 568 centres in 54 countries were included in this analysis. The number of transplants increased seven-fold between the first and fifth cohorts: (1) 5,246, (2) 12,554, (3) 21,153, (4) 28,390 and (5) 35,689. The gender breakdown has been consistent over time: 58% Male, 42% Female. Over these years, the median patient age at transplant has increased significantly, as follows: (1) 54, (2) 57, (3) 58, (4) 59, and (5) 61 years. The percentage of patients 〉 65 years at transplant has also increased: (1) 3%, (2) 9%, (3) 14%, (4) 14%, and (5) 22%. Between 1993 and 1997, IgG, IgA and Light Chain (LC) MM constituted 58%, 22% and 16%, respectively. The corresponding percentages between 2013 and 2017 were 52%, 18% and 27%, respectively. Data on the choice of first induction regimen was available in 19,882 (21%) cases (Med-B forms) though only cohorts 4 (2008-2012) and 5 (2013-2017) had specific data in more than 80% of cases. The trends in the percentage use of these regimens in the two cohorts since 2008 are as follows: VTD: 11% to 32%; VCD: 5% to 20%; CTD 15% to 10%; VD: 19% to 7%; PAD 5% to 4%; VRD 2% to 3%; VAD: 8% to 3%. The CR rates pre-ASCT have improved: (1) 16% (2) 14% (3) 13% (4) 20% and (5) 21%; 〉 PR rates pre-ASCT also reveal deeper responses over time: (1) 65%, (2) 68%, (3) 70%, (4) 72%, and (5) 73%. Stem cell mobilisation regimen data was available in 19,882 (19%) cases. In these centres, the use of cyclophosphamide has steadily increased: (1) 31%, (2) 54%, (3) 63%, (4) 64%, and (5) 65%. Conversely, the use of single agent G-CSF has declined: (1) 69%, (2) 45%, (3) 36%, (4) 31%, and (5) 28%. G-CSF + Plerixafor was used in 3.5% of cases from 2008-2012 and 5% in 2013-2017. The median number of stem cells collected (CD34+cells x 10^6/kg) has gradually increased: (1) 5.1, (2) 5.2, (3) 6.3, (4) 6.6, and (5) 6.5, though the median cell dose infused has remained relatively constant: (1) 3.6, (2) 4.1, (3) 4.0, (4) 3.8, and (5) 3.8. Almost all (99%) patients received peripheral blood (PB) stem cells. The number of months from diagnosis to auto-HCT has been stable since 1998: (1) 8.9, (2) 7.7, (3) 7.4, (4) 7.4, and (5) 7.3. Finally, three-year overall survival (OS) post-transplant has risen from 65% to 81% and Progression-Free Survival (PFS) from 41% to 46% (Figure 1). Conclusions This very large dataset shows consistently increasing numbers of auto-HCT for MM in Europe over the last 25 years. Although it is still sometimes stated that 65 years is the upper age limit for auto-HCT in Europe, 22% of auto-HCT recipients in the most recent cohort were older. Analysis of MM subtypes shows an increasing rate of auto-HCT for patients with LC MM, possibly facilitated by the deeper responses which are now being achieved, overall CR rates having risen from 16% to 21% and 〉 PR rates from 65% to 73%. Most patients (59%) in the most recent cohort (2013-2017) received bortezomib-based triplet induction regimens: VTD: 32%; VCD: 20%; PAD 4%; VRD 3%. Data from a subset of centres confirm the use of cyclophosphamide-based stem cell mobilisation in two-thirds; only 5% used G-CSF + Plerixafor. The median stem cell yield has increased by a quarter. As the median cell dose infused remains unchanged, this most likely reflects increasing rates of storage for subsequent transplants. Finally, serial cohort analysis reveals rising rates of OS and PFS over the 25 years, reflecting the deeper responses achieved pre-transplant and the increasing availability of novel agents, whether in the setting of consolidation or maintenance. Figure 1 Disclosures Hayden: Alnylam: Honoraria; Amgen: Honoraria. Goldschmidt:MSD: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Benjamin:Gilead: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Eusapharm: Consultancy; Servier: Research Funding; Allogene: Research Funding; Pfizer: Research Funding. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gribben:Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Beksac:Celgene: Consultancy; Amgen: Consultancy; Janssen & Janssen: Consultancy; Takeda: Consultancy. Schönland:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant.

Abstract: Background Frontline ASCT is the standard of care for patients with symptomatic NDMM less than 66 years of age. 3-drug combinations are the standard induction regimens prior to ASCT. Consolidation therapy after ASCT is aimed at improving disease control through deepening responses. Maintenance therapy is administered with the objective of prolonging response duration. The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone (IRd) was recently evaluated in NDMM, was generally well tolerated and appeared active (Kumar et al, Lancet Oncology 2014;13:1503-12). We analyzed the safety and efficacy of the triplet IRd combination prior to, and as consolidation after ASCT followed by ixazomib maintenance in the initial management of MM in patients younger than 66 years in a phase 2 study (NCT01936532). Methods Patients received 3 cycles of induction therapy with Ixazomib 4 mg on days 1, 8 and 15 plus Lenalidomide 25 mg on days 1 through 21 and dexamethasone 40 mg on days 1-8-15 and 22 of a 28-day cycle followed by Melphalan 200 mg/m2 and ASCT. Two months after ASCT, patients received an early consolidation with 2 cycles of IRd identical to induction therapy followed by a late consolidation phase with 6 additional cycles of IR without dexamethasone. One month after the last consolidation cycle, patients received maintenance therapy with Ixazomib single-agent 4 mg on days 1, 8 and 15 of a 28-day cycle, during 12 months. The primary end-point was the complete response (CR) rate after extended consolidation therapy. The secondary objectives were to evaluate the overall response rate (ORR) after induction, after ASCT, after consolidation and after maintenance, to evaluate the safety of induction therapy, the feasibility of extended consolidation, the feasibility of maintenance with Ixazomib, the duration of response, progression-free and overall survival. Responses (central lab, Dr Dejoie, Nantes) were assessed according to the IMWG criteria. Toxicity was evaluated according to NCI CTCAE, version 4.03. Results From 11/2014 to 04/2015, 42 patients (21 males, 21 females, median age 60 years (43-65)) with NDMM were enrolled in 10 centers from IFM. ISS was 1 in 12 cases (29%), 2 in 23 cases (54%) and 3 in 7 patients (17%), respectively. Adverse cytogenetics (17p deletion, and/or t(4;14); central lab, Dr Avet-Loiseau) was observed in 8 patients (19%). Induction with IRd was very well tolerated. Out of 120 cycles administered for 42 patients, only 13 cases of non-hematologic grade 3-4 toxicities were reported: infections (8 cases), abdominal pain (2), atrial fibrillation (1), thrombosis (1), and DRESS syndrome leading to study withdrawal (1). No renal or liver toxicity was reported. No cardiac failure and no ischemic heart disease was documented. No grade 3-4 peripheral neuropathy was described. Response rates increased at each step of the strategy. Following 3 induction cycles of IRd, the ORR was 81%, including 12% CR plus 24% very good partial response (VGPR), and 2 patients progressed (5%). Following ASCT, the VGPR rate or better was 78% including 38% CR. Following consolidation (early 2 cycles + extended 6 cycles), the VGPR rate or better was 80% including 44% CR. The feasibility of the consolidation phase with IRd (2 cycles) and IR (6 cycles) was excellent: 34 / 37 patients who started consolidation completed the 8 planned cycles (3 discontinuations: 2 patient decisions, 1 progression to plasma cell leukemia). 34/42 patients (81%) were able to receive maintenance therapy with Ixazomib following extended consolidation. Results of maintenance and of minimal residual disease evaluation will be presented during the meeting. At the cut-off date of June 30 2016, with a median follow-up of 16 months, 3 patients / 42 (7%) have progressed, 2 during induction and 1 during consolidation, and 2 (5%) died from progressive disease. Conclusions The all-oral triplet combination IRd administered as induction prior to, and as consolidation following ASCT is safe, convenient, and effective, leading to 80% VGPR and 44% CR before maintenance. Final results on response rates following maintenance and MRD data will be presented during the meeting. Updated results on PFS and OS will also be presented. Disclosures Moreau: takeda: Honoraria; celgene: Honoraria; janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Hulin:celgene: Honoraria; janssen: Honoraria; takeda: Honoraria. Facon:Millenium/Takeda: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Roussel:celgene: Honoraria; takeda: Honoraria; janssen: Honoraria. avet-Loiseau:takeda: Honoraria; janssen: Honoraria; celgene: Honoraria; amgen: Honoraria. Attal:sanofi: Consultancy; amgen: Consultancy, Research Funding; janssen: Consultancy, Research Funding; celgene: Consultancy, Research Funding.

Abstract: Despite the implementation of new therapeutic agents, management of relapsed multiple myeloma (MM) remains a challenge. Salvage autologous hematopoietic cell transplant (AHCT) remains a valid therapeutic option for eligible patients who achieve prolonged response after a first AHCT. However, a second graft is not always available, and these patients may need a second mobilization. Patients and Methods This prospective, non-interventional, multicenter study aimed to collect data on the feasibility of salvage AHCT using a plerixafor-based hematopoietic cell mobilization in relapsed MM, according to the plerixafor label in France. Adult patients with relapsed MM eligible for a second AHCT and mobilized using granulocyte- colony stimulating factor (G-CSF) and plerixafor were included. Results Of the 23 patients, 17 achieved a successful hematopoietic cell mobilization and 13 were able to proceed to a second AHCT. Median age was 62.9 years (min–max 51–71). Ten patients (77%) were male. Eleven (85%) received AHCT as a third-line treatment or more. Median time between first and second AHCT was 5.4 years (range, 2.6–16.3). Among 18 evaluable patients, mobilization was successful for 17 (94%) of them [95% CI 84–100], with no reported side effects. Among the 13 patients who underwent salvage AHCT, the median time to engraftment was 14 days (min–max 11–29). One-year progression-free and overall survival were 88.9% [95% CI 43.3–98.4] and 100%, respectively. Conclusion This study demonstrated that plerixafor allows safe and efficient mobilization in relapsed MM patients who are candidates for a salvage AHCT. Trial Registration NCT02439476 Registered 8 May 2015, https://clinicaltrials.gov/ct2/show/NCT02439476 .

Abstract: Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37–82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3–12). The median number of BM cycles administered was three (range, 1–22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.

Abstract: Background: triplet combinations comprising a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) are current standard induction and consolidation regimens in NDMM. The all-oral combination of weekly ixazomib plus lenalidomide-dexamethasone (IRd) has been evaluated by several groups in NDMM and is approved in relapsed-refractory MM. The IFM 2014-01 phase 2 trial previously studied the weekly IRd regimen as induction and extended consolidation followed by single-agent ixazomib maintenance in frontline transplant eligible patients (Moreau et al ASH meeting 2016): IRd was well tolerated and overall response rate was 81%, including 38% very good partial response or better (≥VGPR) at the completion of induction (3 cycles). Responses further increased at each step of the program and 76% of patients (per protocole analysis) achieved ≥VGPR before maintenance with 6% CR and 38% sCR. To stay in line with current RVd regimen, and to increase dose intensity, we examined the efficacy and safety of twice-weekly ixazomib +Rd as induction prior to transplant, followed by weekly IRd consolidation and single-agent lenalidomide maintenance (NCT02897830). Methods: This is a phase II, single-arm, open-label, multicenter study. During induction, patients received three 21-day cycles of twice-weekly oral IRd: ixazomib (3 mg on days 1, 4, 8 and 11), lenalidomide (25 mg daily, days 1-14), and dexamethasone (40 mg on days 1, 4, 8 and 11) followed by transplant. Patients then received two 28-day cycles of weekly IRd early consolidation followed by 6 additional cycles of IR (no dexamethasone) as late consolidation (ixazomib 4mg on days 1-8 and 15; lenalidomide 25mg daily, days 1-21). Single-agent lenalidomide maintenance was administered for up to 1 year (10 mg daily, days 1-21). The primary endpoint was the stringent complete response (sCR) rate at the completion of consolidation. The secondary endpoints included assessments of overall response rate (ORR) and rates of response categories at each step of the program, progression-free survival (PFS), feasibility and safety. Responses were assessed in accordance with the IMWG uniform criteria. Toxicity was evaluated according to NCI CTCAE, version 4.03. Results Between 07/2016 and 08/2017, 50 patients with NDMM were screened at 10 IFM centers, 46 were enrolled with a median age of 59 years, and 59% were male. The percentages of patients with ISS stage I, II, and III were 41.5%, 41.5%, and 17%, respectively. High-risk cytogenetics, defined as t (4; 14), or del17p (central Lab, H. Avet-Loiseau), was observed in 9% of patients (6.5% FISH failure). As of July 1st 2019 (data cut-off), 10 patients prematurely discontinued therapy. Considering efficacy, 43/46 patients (94%) completed consolidation and 9 achieved sCR (20.9%; 90% CI [11.4 to 33.7]). This result did not meet the minimum efficacy threshold (40%) for the primary efficacy endpoint (p=0.998). Overall, at the completion of consolidation, ORR was 91% including 21% sCR, 30% ≥CR and 58%≥VGPR. Responses at each step of the program are described in the table 1. If we focus on twice-weekly IRd induction, at the completion of 3 cycles, ORR was 74%, including 33% ≥VGPR. The feasibility of the program was good and overall, 39/46 patients (85%) were able to receive maintenance therapy with single-agent lenalidomide. After a median follow-up of 22 months, 7 patients progressed and 3 patients died. Concerning safety: 31 serious treatment emergent AEs were reported in 20 patients (43.5%) comprising infections (8 patients), cardiac disorders (2 patients: ischemic heart disease and aortic valve incompetence), psychiatric, renal and respiratory disorders (2 cases each). No grade 3-4 peripheral neuropathy was described. Conclusions The all-oral Ixazomib-Lenalidomide-Dexamethasone (IRd) induction/consolidation regimen in the transplant setting is convenient, well tolerated, leading to 21% sCR before maintenance. Twice-weekly IRd induction does not seem superior to weekly IRd induction Results on response rates following maintenance and MRD data will be presented during the meeting. Table Disclosures Roussel: Celgene Corporation: Consultancy, Other: travel fees, lecture fees, Research Funding; takeda: Other: travel fees, lecture fees, Research Funding; Amgen: Other: travel fees, lecture fees, Research Funding; Janssen: Honoraria, Other: travel fees, lecture fees, Research Funding. Hebraud:celgene: Other: travel fees, lecture fees; takeda: Other: travel fees, lecture fees. Hulin:Janssen, AbbVie, Celgene, Amgen: Honoraria; celgene: Consultancy, Honoraria. Leleu:Oncopeptide: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Facon:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Touzeau:celgene: Other: travel fees, lecture fees, Research Funding; takeda: Other: travel fees, lecture fees. Perrot:jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; takeda: Honoraria. Stoppa:celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Attal:celgene: Consultancy, Other: travel fees, lecture fees, Research Funding; takeda: Consultancy, Other: travel fees, lecture fees, Research Funding. OffLabel Disclosure: Ixazomib is indicated in RRMM in association with Rd