Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination before and after Autologous Stem Cell Transplantation (ASCT) Followed By Ixazomib Maintenance Is a Safe and Effective Strategy in Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du MyéLome (IFM)

Background

Frontline ASCT is the standard of care for patients with symptomatic NDMM less than 66 years of age. Triplet combinations including a proteasome inhibitor and an IMiD can be administered before (induction) and after ASCT (consolidation, aimed at deepening response). The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone (IRd) was evaluated in NDMM and showed durable responses with a good safety profile (Kumar et al, Lancet Oncology 2014;13:1503-12). We evaluated the safety and efficacy of the triplet IRd combination prior to, and as consolidation after ASCT followed by ixazomib maintenance as frontine therapy for patients with NDMM 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 13 cycles (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 (median age 60 years) were enrolled in 10 centers from IFM. The last patient enrolled received the last dose of ixazomib maintenance in 08/2017. Response rates increased at each step of the strategy. On an intent-to-treat basis, the CR rate was 12% following 3 induction cycles of IRd, 19% following ASCT, 32% following early consolidation, 36% following late consolidation (primary end-point) and 48% following maintenance. With a median follow-up of 24 months, the 2-year progression-free-survival (PFS) rate is 83%, and 2-year overall survival (OS) rate is 95%. Seven patients (17%) relapsed or progressed: 2 during induction, 1 following ASCT, 2 during consolidation, 2 during maintenance, and 2 patients (5%) died from progressive disease. The overall strategy was well tolerated. Excluding ASCT, the number of adverse events leading to exclusion was very low: 1 rash during induction, 1 rash during late consolidation, 1 thrombocytopenia before maintenance, 1 infection during maintenance, 1 rash during maintenance; 12 cases of non-hematologic grade 3-4 toxicities were reported: infections (8 cases), abdominal pain (2), atrial fibrillation (1), and thrombosis (1). Overall, no renal or liver toxicity was reported. No cardiac failure and no ischemic heart disease was documented. The feasibility of the consolidation phase with IRd (2 cycles) and IR (6 cycles) was good: 32 / 37 patients (86%) who started consolidation completed the 8 planned cycles. The feasibility of the maintenance phase was very good as well: 26 / 31 patients (84%) who started maintenance therapy with Ixazomib following extended consolidation completed the 13 planned cycles.

Conclusions

The all-oral triplet combination IRd administered as induction prior to, and as consolidation following ASCT is safe, convenient, and effective, leading to 48% CR after maintenance, 2-year PFS rate of 83% and 2-year OS rate of 95%.