ALBERT

Description: 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

Description: Key Points Pom-Dex is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p). Pom-Dex prolonged OS in adverse cytogenetic patients with early RRMM.

Description: Abstract 1817 Poster Board I-843 Deletion of the short arm of chromosome 17 [del(17p)] is known to confer a poor prognosis in multiple myeloma (MM). However, no large study has been specifically dedicated to this purpose, especially in the novel drug era. We analyzed a series of 1324 patients with MM at diagnosis, treated within or according to IFM trials, and analyzed for del(17p). Most of the patients were under 65 years of age (1122 of the 1324 patients), and were treates either with a VAD-based induction or a Velcade®/Dexamethasone-based induction, followed by one or two courses of high-dose melphalan. Del(17p) was correlated to the major other prognostic parameters, both for event free survival and overall survival. Del(13) was observed in 71% of the patients with del(17p). A significant association was observed with anemia 〈 10g/dl (p=.05), with thrombocytopenia 〈 130 G/l (p3.5 mg/l (p=.006). No specific association was observed with t(4;14) (17% of the del(17p)-positive patients displayed t(4;14)). Del(17p) was observed in 10% of the patients. Del(17p) was associated with a very poor outcome, both in young and elderly patients. Actually, the prognostic value was observed only in patients displaying del(17p) in at least 70% of their plasma cells. The median EFS and OS were 18 and 28 months respectively, versus 30 and 69 months for patients lacking the del(17p). A particularly poor outcome was observed in patients presenting both del17p and t(4;14), with a median EFS of 4.5 months and a median OS of 12 months. Of particular importance, none of the treatment modality (high-dose melphalan, thalidomide, bortezomib) overcame the poor prognosis associated with del(17p), although patients lacking del(17p) displayed a better outcome when treated with Vel/Dex or MP-Thalidomide. In conclusion, del(17p) is associated with an especially poor outcome, independently of the type of treatment, including novel drugs. Disclosures No relevant conflicts of interest to declare.

Description: Melphalan-Prednisone + bortezomib (MPV) is one of the standard of care for the frontline treatment of patients with symptomatic multiple myeloma non eligible for high-dose therapy. In the pivotal VISTA trial for approval of MPV, the main toxicity was grade 3-4 peripheral neuropathy (PN) described in 14% of the cases. Carfilzomib (CFZ), the second-in-class proteasome inhibitor has shown promising activity and a favorable toxicity profile with low PN rates. Therefore, the option of combining CFZ with MP (CMP) is an attractive one. Therefore we designed a phase I/II study to determine the maximum tolerated dose (MTD) of CMP and to assess safety and efficacy. In the phase I portion of the trial, CFZ was started at 20mg/m2, then escalated to 27, 36, and 45mg/m2, administered IV over 30 minutes in 42-day cycles on D1/2/8/9/22/23/29/30 for 9 cycles. Melphalan 9mg/m2 and prednisone 60mg/m2 were given PO D1–4 of every 42-day cycle. MTD was based on dose-limiting toxicity (DLT) in cycle 1 defined as any grade 4 (G4) hematologic adverse event (AE), any hematologic AE preventing aministration of ≥ 2 CFZ doses except G4 thrombocytopenia without bleeding or G4 neutropenia ≤ 7days, ≥ G3 febrile neutropenia, or any ≥G3 nonhematologic AE. As of July 6, 2013, 24 pts have been enrolled in phase I: 6 for each dose level. There were 2 DLTs at 45mg/m2 (fever plus hypotension) resulting in a MTD of 36mg/m2. In Phase II, 44 additional patients received CMP at 36mg/m2 CFZ for N=68 total PhI/II patients (50 patients overall treated at the dose pf 36mg/m2). The median age of the series was 72 years, with 36% of the patients presenting with ISS3. Overall response rate was 89.5% including 56% ≥ very good partial response. With a median follow-up of 12 months, the projected 2y OS was 87%, and the median event-free survival was 22 months. CMP was well tolerated and only 1 patient developed grade 3 PN. These promising results compare favorably to those of MPV, MP+Thalidomide, MP+lenalidomide (R), and R+dex in similar pts. CFZ 36mg/m2 + MP is tolerable and effective in elderly patients with symptomatic newly diagnosed MM. Treatment is ongoing, 20% of the patients are receiving their last cycles of CMP. Final safety and efficacy data will be presented during the meeting. Disclosures: Moreau: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE TREATMENT WITH CARFIZOMIB. Hulin:CELGENE: Honoraria; JANSSEN: Honoraria. Leleu:CELGENE: Honoraria; JANSSEN: Honoraria. Roussel:CELGENE: Honoraria; JANSSEN: Honoraria. Attal:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Facon:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

Description: It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.

Description: Abstract 812FN2 On behalf of IFM (Intergroupe Francophone du Myélome) Background. The interim analysis of this phase 2 randomized open label trial was presented at ASH last year. It aimed to determine the impact of the combination of pomalidomide (oral 4 mg daily) and dexamethasone (oral 40 mg weekly) in pts characterized with advanced myeloma (MM) following lenalidomide and bortezomib. The response rate (ORR, PR and better), and the median PFS were similar in the 2 arms, pomalidomide on days 1–21 vs. 1–28 of each 28-day cycle. The final analysis of IFM 2009-02 will be fully presented at ASH 2011. We have also studied subgroups characterized with refractory MM, in order to further demonstrate that the combination of pomalidomide and dexamethasone might benefit pts that have progressed after multiple novel agents. Method. This study was addressed to MM pts who had at best a stable disease with the last course of bortezomib and the last course of lenalidomide, or who were refractory to bortezomib and lenalidomide (as per IMWG criteria). The primary objective was ORR (PR and better). The responses were assessed centrally in Lille, and reviewed by an independent committee (all data reported herein are based on the IRC). FISH cytogenetic analysis was performed in Nantes on bone marrow plasma cells. All pts had received prophylaxis against venous thromboembolism. Data are presented for the overall population when there was no difference between the 2 arms. The analysis is performed on ITT. Results. Eighty four pts (57 male and 27 female) were enrolled; 43 in arm 21/28 and 41 in arm 28/28. The median (min-max) age was 60 (42–83) years. The median time from diagnosis to enrolment in IFM 2009-02 was 70.5 months (9–277). The median number of prior lines of therapy was 5 (1–13), and 100% of the pts had received bortezomib and lenalidomide as per protocol, 70% had received alkylating agents and 71% thalidomide. Overall, 21 (37.5%) pts had loss of 17p (n=15) or t(4;14) (n=6). At the cut-off of March 1st 2011 the median follow-up for alive pts was 10.4 months (1.6–14.3), the median number of cycles administered was 8 (1–18) in arm 21/28 and 6 (1–18) in arm 28/28. The ORR was 34.9% in arm 21/28 and 34.1% in arm 28/28, including 4.7% and 7.3% VGPR, respectively. Overall, 40 (47.6%) pts had stable disease (including minor response) and 3 pts reached CR. The median (95%CI) PFS was 6.3 (4.1–9.1) months in either arm, and the median duration of response was 11.4 (3.7–13.6) months and 7.9 (4.0–) months in arm 21/28 and 28/28, respectively. The median PFS was 4.2 (3.3–6.9) months for pts with SD as compared to 12.6 (9.9–14.8) months in pts that had a response. A summary of subgroups characterized with refractory MM is presented in the table below. Survival and toxicity will be updated at ASH 2011. Conclusion. Pomalidomide and dexamethasone is active and well tolerated in these heavily pre-treated MM pts. This study provides further evidence that pomalidomide has no-cross resistance with lenalidomide and suggests that it can provide benefit for pts who have relapsed after other novel therapies. Disclosures: Leleu: LeoPharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Roussel:Celgène: Honoraria; Janssen: Honoraria. Hulin:Celgene: Honoraria; Janssen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Description: Stem cell factor (SCF) has been shown to synergize with filgrastim to mobilize CD34+ cells into the peripheral blood. To determine if addition of SCF to chemotherapy and filgrastim reduces the number of leukaphereses required to achieve a target yield of 5 × 106 CD34+ cells/kg, 102 patients with multiple myeloma were randomized to receive mobilization chemotherapy with cyclophosphamide (4 g/m2) and either SCF (20 μg/kg/d) combined with filgrastim (5 μg/kg/d) or filgrastim alone (5 μg/kg/d), administered daily until leukaphereses were completed. After collection, patients were treated with myeloablative therapy supported by autologous peripheral blood progenitor cell (PBPC) infusion and filgrastim (5 μg/kg/d). There was a significant difference between the treatment groups in the number of leukaphereses required to collect 5 × 106 CD34+ cells/kg (median of 1 v 2 for SCF + filgrastim and filgrastim alone, respectively, P = .008). Patients receiving the combination of SCF plus filgrastim had a 3-fold greater chance of reaching 5 × 106 CD34+ cells/kg in a single leukapheresis compared with patients mobilized with filgrastim alone. The median CD34+ cell yield was significantly increased for the SCF group in the first leukapheresis (11.3 v 4.0 × 106/kg, P = .003) and all leukaphereses (12.4v 8.2 × 106/kg, P = .007). Total colony-forming unit–granulocyte-macrophage (CFU-GM) and mononuclear cell counts were also significantly higher in the SCF group in the first leukapheresis and in all leukaphereses. As expected for patients mobilized to an optimal CD34+ cell yield, the time to engraftment was similar between the 2 treatment groups. Cells mobilized with the combination of SCF plus filgrastim were thus considered effective and safe for achieving rapid engraftment. Treatment with SCF plus filgrastim was well tolerated, with mild to moderate injection site reactions being the most frequently reported adverse events. There were no serious allergic-like reactions to SCF. The addition of SCF to filgrastim after cyclophosphamide for PBPC mobilization resulted in a significant increase in CD34+cell yield and a concomitant reduction in the number of leukaphereses required to collect an optimal harvest of 5 × 106CD34+ cells/kg.

Description: The IFM99-03 and IFM99-04 trials were conducted from April 2000 to August 2004. Patients younger than 66 years with high-risk (b2microglobulin 〉 3 and chromosome 13 deletion by FISH analysis at diagnosis) de novo multiple myeloma (MM) were included and prospectively treated. In both protocols, induction regimen consisted of VAD (4 courses) followed by melphalan 200 mg/m2 (HDM200) plus autologous peripheral blood stem cell transplantation (ASCT). When a HLA-sibling donor was available, ASCT was followed by reduced-intensity conditioning regimen (RIC) allograft (fludarabine, antithymocyte globulin and low dose busulfan): IFM9903 protocol (Garban et al, Blood2006;107:3474–3480). When no donor was available, patients were randomised to receive a second ASCT with HDM220 +/− anti-IL6 monoclonal antibody (BE-8, 250 mg total dose, Diaclone Besançon, France): IFM99-04 protocol (Moreau et al, Blood2006;107:397–403).284 patients met eligibility criteria and received at least one course of VAD. 65 had an available HLA-identical sibling donor and were included in the IFM99-03 trial, and 219 were included in the IFM 99-04 trial. Patients were older in the tandem ASCT trial (median age, 58 vs 54 years; P = .006) and the b2-microglobulin level was also higher in the latter group (median, 4.9 mg/L vs 4.1 mg/L; P = .049). At the reference date of July 1st, 2008, on an intent-to-treat basis, considering the entire population of 284 patients, with a median follow-up of 56 months, the EFS did not significantly differ from tandem ASCT to single autograft followed by allo-RIC (median 22 vs 19 months, P = 0.58). Nevertheless, there was a trend for a superior OS in the double ASCT trial (median 48 vs 34 months, P = 0.07). When considering the comparison of the results of the 166 patients /219 who completed the whole tandem ASCT protocol with those of the 46 patients /65 who underwent the entire auto/allo-RIC program, no difference was observed regarding EFS (median 25 vs 21 months, P = 0.88), but there was again a trend for a superior OS in favour of double ASCT (median OS, 57 vs 41 months, P = 0.08), due to a longer survival after relapse in the tandem ASCT arm. These long-term results indicate that, in a subgroup of high-risk patients with de novo MM, a tandem autologous transplant procedure is at least equivalent or even superior to a combination of autologous followed by RIC allogeneic stem cell transplantation.

Description: High dose chemotherapy plus autologous transplantation (ASCT) is considered a standard of care for newly diagnosed myeloma patients younger than 65 years of age. The high complete response rate (CR) achieved with the triplet combination of immunomodulatory drugs + proteasome inhibitors + dexamethasone has led investigators to propose this strategy upfront without immediate ASCT. The aim of this study was to determine if, in the era of new drugs, ASCT was still required in the initial management of young patients. We conducted a randomized trial comparing conventional dose treatment (RVD arm= 8 cycles of Lenalidomide, Bortezomib and Dexamethasone, plus stem cell mobilization after 3 cycles of RVD utilizing high dose cyclophosphamide and G-CSF) to RVD with ASCT (Transplant arm= 3 induction cycles of RVD, followed by stem cell collection, and then ASCT conditioned with Melphalan 200 mg/m2, followed by 2 cycles of RVD as consolidation). Maintenance treatment with Lenalidomide (10 to 15 mg/d) was used in both arms for one year. In the RVD arm, ASCT was planned at time of relapse. From November 2010 to November 2012, 700 previously untreated French and Belgian patients were equally randomized between arms. Randomization was stratified according to ISS stage (I vs II vs III) and FISH analysis (standard vs high risk = del 17p or t(4;14) or t(14;16)). The primary study end point was progression-free survival (PFS). Two pre-specified interim analysis were to be performed at 33% and 69% of the estimated total number of events. The second interim analysis was performed in June 2015 (346 events= 197 in the RVD arm, 149 in the transplant arm). These results were submitted to an independent data management and safety committee, who recommended completing the trial, and continuing follow-up (without cross over before progression), since the difference in PFS between the 2 groups had reached the pre-specified level of significance for stopping the study. As of June 8, 2015, median follow up was 39 months. All patients had discontinued treatment (completion of planned therapy= 66%, disease progression= 16%, adverse events= 10%). Patient characteristics of each group were similar and no significant differences were found with regard to age (median=58 years), ISS stage (I=233, II=341, III=126), Ig isotype, beta-2-microglobulin (median=3.5 mg/L), and cytogenetics (high risk=90 patients). In the transplant arm, 93% of patients underwent ASCT and 5 toxic deaths occurred during mobilization or in the actual transplant phase (1.4%). ASCT was found to improve PFS (stratified p value for log-rank test 〈 0.0002; HR= 1.5, 95% CI= 1.2-1.9). The 3-year post-randomization PFS rate was 61% in the transplant arm versus 48% in the RVD arm. The PFS benefit observed in the transplant arm was uniform across all the following subgroups: age (≤ or 〉 60 years), sex, Ig isotype (IgG or others), ISS stage (I or II or III), cytogenetics (standard or high risk), and response after the 3 first cycles of RVD (complete response or not). The 3-year post randomization rate of overall survival was extremely high (88%) and similar between the 2 study groups (stratified p value for log rank test=0.25). The complete response rate was significantly higher in the transplant arm compared to the RVD arm: 58% versus 46%, respectively (p

Description: Autologous stem cell transplantation (ASCT) is recommended for younger patients with newly diagnosed multiple myeloma. Achieving complete response (CR) or at least very good partial response (VGPR) is a major prognostic factor for survival with 20% to 30% of patients achieving CR after ASCT. Bortezomib has shown synergistic effects with melphalan and no prolonged hematologic toxicity. In this Intergroupe Francophone du Myélome (IFM) phase 2 study, 54 untreated patients were enrolled between July and December 2007 to receive bortezomib (1 mg/m2 × 4) and melphalan (200 mg/m2) as conditioning regimen (Bor-HDM). Overall, 70% of patients achieved at least VGPR, including 17 patients with CR (32%) after ASCT. No toxic deaths were observed. Bortezomib did not increase hematologic toxicity. Only 1 grade 3 to 4 peripheral neuropathy was reported. A matched control analysis was conducted comparing our cohort with patients from the IFM 2005-01 trial (HDM alone). Patients were matched for response to induction therapy and type of induction: CR was higher in the Bor-HDM group (35% vs 11%; P = .001), regardless of induction therapy. These results suggest that Bor-HDM is a safe and promising conditioning regimen. Randomized studies are needed to assess whether this conditioning regimen is superior to HDM alone. This trial was registered at www.clinicaltrials.gov as NCT00642395.