Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 Tourmaline-MM3 Trial

Abstract

Introduction Maintenance therapy following ASCT can delay disease progression and prolong survival in multiple myeloma (MM). To date, lenalidomide is the only agent approved as post-ASCT maintenance. While bortezomib-based maintenance has shown promising activity post-ASCT, the benefit of PI-based maintenance has not been demonstrated in a phase 3 trial vs placebo. Ixazomib, currently approved for relapsed/refractory MM, is ideally suited for maintenance therapy given its efficacy, convenient once-weekly oral dosing, and low toxicity profile. Methods The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) randomized (3:2) NDMM patients to receive ixazomib or matched placebo following induction, high-dose therapy and transplantation on days 1, 8, and 15 of 28-day cycles for 2 years, until progressive disease or unacceptable toxicity, whichever came first. The primary endpoint was PFS. Here, we report data from the final analysis for PFS (data cut-off: April 16, 2018). Results 656 patients were randomized (395 ixazomib; 261 placebo). Patient demographics were balanced between groups; for the overall population, median age was 58 years (range, 24–73), 37% vs 63% had International Staging System (ISS) disease stage I vs II or III, 18% had high-risk cytogenetics, 59%/11%/30% had received PI without immunomodulatory drug (IMiD)/IMiD without PI/PI+IMiD induction therapy, and 79%/21% had achieved complete or very good partial response/partial response following induction+HDT-ASCT. After a median follow-up of 31 months, with 54% of patients having had a PFS event, there was a 28% reduction in the risk of progression/death with ixazomib vs placebo (median 26.5 vs 21.3 months; hazard ratio [HR] 0.72; 95% CI: 0.582, 0.890; p=0.002; Figure). Ixazomib maintenance led to higher rates of deepened response vs placebo (relative risk 1.41; 95% CI: 1.10, 1.80; p=0.004). Conversion from documented minimal residual disease (MRD) positivity at study entry to MRD negativity occurred at a higher rate with ixazomib vs placebo (12% vs 7%). PFS benefit was seen broadly across subgroups, including patients with ISS III (HR 0.661), high-risk cytogenetics (HR 0.625), PI-exposed (HR 0.750) and PI-naive (HR 0.497) patients. With ixazomib vs placebo, discontinuation due to adverse events (AEs) was low (7% vs 5%); 42% vs 26% of patients had grade ≥3 AEs; 27% vs 20% had serious AEs; and 1 patient vs 0 died on treatment. Common grade ≥3 AEs were infections (15% vs 8%), gastrointestinal disorders (6% vs 1%), neutropenia (5% vs 3%), and thrombocytopenia (5% vs Conclusions This study demonstrated a 28% reduction in the risk of progression/death with ixazomib maintenance, supporting ixazomib as a valuable option for maintenance therapy in responding patients post-ASCT.