Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination before and after Autologous Stem Cell Transplantation (ASCT) Followed By Ixazomib Maintenance in Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du MyéLome (IFM)
Authors: Moreau Philippe , Hulin Cyrille , Caillot Denis , Marit Gerald , Perrot Aurore , Garderet Laurent , Facon Thierry , Benboubker Lotfi , Karlin Lionel , Tiab Mourad , Arnulf Bertrand , Fermand Jean-Paul , Leleu Xavier , Touzeau Cyrille , Roussel Murielle , Planche Lucie , Minvielle Stephane , Bene Marie-Christine , avet-Loiseau Herve , Dejoie Thomas , Attal Michel 
Published: October 2019

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.