Ixazomib Plus Lenalidomide-Dexamethasone (IRd) vs. Placebo-Rd for Newly Diagnosed Multiple Myeloma (NDMM) Patients Not Eligible for Autologous Stem Cell Transplant: The Double-Blind, Placebo-Controlled, Phase 3 TOURMALINE-MM2 Trial

Context: Continuous Rd-based regimens are among the standards of care in the diverse, transplant-ineligible NDMM patient population. An all-oral triplet may be useful for patients who cannot/prefer not to travel to the clinic frequently. Ixazomib, the first oral proteasome inhibitor (PI), has predictable, manageable toxicities, enabling an all-oral PI-Rd regimen for use in this setting. Objective: Compare IRd vs. placebo-Rd in transplant-ineligible NDMM patients. Interventions: Patients were randomized to ixazomib 4 mg (n=351) or placebo (n=354) plus Rd (28-day cycles). After 18 cycles, dexamethasone was discontinued and lower ixazomib and lenalidomide doses were administered until progression or unacceptable toxicity. Main Outcome Measure: Progression-free survival (PFS) - final analysis. Results: In the IRd vs. placebo-Rd arms, the median age was 73 vs. 74 years (43% vs. 44% ≥75 years), 16% vs. 17% had International Staging System stage III MM, and 38% vs. 41% had high-risk cytogenetics [t(4;14), t(14;16), del(17p), or amp(1q21)]. The median PFS was 35.3 vs. 21.8 months (hazard ratio [HR] 0.830, p=0.073; median follow-up 53.3 vs. 55.8 months). Overall response rates were 82% vs. 80%; depth of response was greater with IRd vs. placebo-Rd (26% vs. 14% complete response [CR], odds ratio [OR] 2.10, p Conclusions: IRd in NDMM demonstrated a strongly positive trend in PFS, improved TTP and CR rate, and improved the poor PFS associated with high-risk cytogenetics, as seen in the TOURMALINE-MM1 study of IRd in relapsed/refractory MM. Safety was consistent with the well-characterized toxicity profile of ixazomib/IRd. IRd is a feasible treatment option for certain transplant-ineligible patients who could benefit from an all-oral triplet combination.