Abstract: The overall response rate following 4 induction cycles of VTD prior to ASCT is higher than that of 4 cycles of VCD.

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 Induction therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with symptomatic multiple myeloma less than 66 years old. The quality of response to the induction treatment is an important prognostic factor and is predictive of progression free survival (PFS) following ASCT. The triplet combinations bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) have demonstrated high response rates in prospective phase 2 and phase 3 clinical trials, they are 2 of the most commonly used induction regimens prior to ASCT, and are both recommended in the International guidelines. To date, no comparative data from prospective randomized trials of the safety and efficacy of VTD vs VCD are available. This provided the rationale for the phase 3 investigation of VTD vs VCD prior to ASCT in patients with de novo MM in this randomized multicenter study (NCT01564537). Methods Patients with de novo symptomatic MM less than 66 years old were prospectively randomized to receive either 4 cycles of VTD (arm A) or 4 cycles of VCD (arm B) followed by ASCT. The VTD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, subcutaneously (SC) D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Thalidomide 100 mg/d, PO D1 to D21. The VCD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, SC D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15. Patients were stratified according to ISS (1-2 versus 3) and cytogenetics (high-risk defined by 17p deletion and t(4;14) versus other).The primary endpoint was very good partial response (VGPR) rate following 4 cycles. Response was assessed in a central lab according to the IMWG criteria. Assuming a VGPR rate of 60% in the VTD arm versus 45% in the VCD arm (15% difference), the possibility to detect a statistically significant difference required the enrolment of 340 patients overall (170 per arm). Adverse events were graded using the NCI CTCAE catalogue, version 4.0. Results From 11/2013 to 02/2015, 358 patients were enrolled into the study. 18 were screening failures, and 170 were randomized each to arm A (VTD) and arm B (VCD). The median age was 60 years (range, 26-65), 62% of the patients were male, and overall, the patient characteristics were well-balanced across the 2 arms of the study. The median number of induction cycles administered in both arms was 4 (1-4). On an intent-to-treat basis, the overall response rate ( 〉 partial response [PR]) was 92.3% in arm A, including a 10.7% complete response (CR) rate and a VGPR rate of 66.7%, while in arm B the overall response rate was 84%, with a 9.5% CR and a 56.2% VGPR rate. VGPR and PR rates were significantly higher in the VTD arm with p-values of 0.04 and 0.02, respectively. Seven patients died during induction therapy (2%), 3 in arm A from infections (2) and pulmonary embolism (1), and 4 in arm B from progression to extramedullary myeloma (2) and infections (2). Grades 3 / 4 peripheral neuropathy occurred in 4% and 2.2% in Arm A and B, respectively. Grade 3/4 neutropenia was seen in 11.9% vs 22.5% in Arm A and B, respectively. Conclusion This trial is the first prospective randomized comparison of 4 cycles of VTD versus 4 cycles of VCD administered as induction therapy prior to ASCT. VTD was shown to be significantly superior to VCD in terms of VGPR and PR rates. Neuropathy rates low in both arms, while neutropenia was more frequent with VCD. Disclosures Moreau: Millennium: 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; Celgene: 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; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Garderet:Bristol-Myers Squibb: Consultancy. Stoppa:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Laribi:Hospira SAS: Research Funding. Avet-Loiseau:jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: 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; jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Attal:jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract: 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.

Abstract: 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%) & lt; 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.

Abstract: Abstract 3869 Poster Board III-805 Introduction The outcome of patients with plasma-cell leukemia (PCL) is poor. Avet-Loiseau reported on behalf the IFM, our first experience in PCL patients and showed that the median overall survival (OS) was 8 months (Avet-Loiseau, Blood, 2001). Since 1999, novel agents such as Thalidomide, Bortezomib (Velcade) or Lenalidomide (Revlimid) have been widely used in the treatment of multiple myeloma, both at the time of relapse or part of upfront therapy. Patients and methods In this retrospective analysis, we have looked at the outcome of PCL patients treated within the IFM since 1999 in order to study the impact of novel agents on survival. Results 31 cases, 20 males, 11 females, median age 55 years (34-78) were analyzed. Twenty one patients less than 65 years received high-dose therapy as part of frontline treatment : 19 autologous haematopoietic stem cell transplantation (HSCT) and 5 allogeneic transplantation. Novel agents were used part of induction therapy in 6 cases, at the time of relapse for 9 patients, for both induction and relapse in 16 cases. Thirteen patients received 1 novel agent, 11 received 2 and 7 patients received the 3 novel agents. The median number of lines of therapy was 2 (1 to 4). Bortezomib was used as up front treatment in 15 patients and at relapse for 9 patients. Overall response rate according the IMWG criterias was 70% (17/24) including 11 CR or VGPR (45%). PAD (Bortezomib, Adriamycin and Dexamethasone) and VTD (Bortezomib, Thalidomide, Dexamethasone) regimens provided the best response rates. Lenalidomide was used in 13 patients mostly at relapse. A response was obtained in 53% of patients including 2CR and 2 VGPR (30%). Nineteen patients were treated with Thalidomide-based regimens. Overall response rate was 52% (10/19) including 2 CR and 6 VGPR (31%). Overall, for the whole group of patients, the median progression-free survival was 8 months (0-26) and the median OS was 15 months (6-108). When comparing this survival with that described in our previous experience reported before 1999, we clearly showed that the use of novel agents improved the survival of patients with PCL. Conclusion In this retrospective study, novel agents improved the prognosis of P-PCL. Prospective IFM phase II studies are ongoing to confirm these results. Disclosures: No relevant conflicts of interest to declare.