Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma

Abstract

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.

Graphical abstract

Figure 1.

CONSORT diagram. Patient enrollment and disposition throughout the study.

Figure 2.

PFS by independent review of the ITT population. (A) Kaplan-Meier analysis of PFS by independent review of the ITT population. (B) Forest plots of PFS in prespecified subgroups based on patient and disease characteristics of the ITT population. *Expanded high-risk category includes del(17p), t(4;14), t(14;16), and amp(1q21) abnormalities; standard (std) risk category includes normal results as well as all types of abnormalities other than t(4;14), t(14;16), del(17), or amp(1q21); unclassifiable for expanded high risk is defined as patients who do not have cytogenetic data that can be categorized to expanded high risk or std risk corresponding to expanded high-risk group, because of either missing, unknown or indeterminate results. †High-risk category includes del(17p), t(4;14), or t(14;16) abnormalities; std risk category includes normal results as well as all types of abnormalities other than t(4;14), t(14;16), or del(17); unclassifiable for high risk is defined as patients who do not have cytogenetic data that can be categorized to high risk or std risk corresponding to high risk group, either because of missing, unknown, or indeterminate results. BPI-SF W P, Brief Pain Inventory-Short Form worst pain; CI, confidence interval; Exp., expanded; NE, not evaluable; R-ISS, revised ISS.

Figure 3.

Kaplan-Meier analysis of OS by independent review on the ITT population. OS distributions in the ixazomib-Rd and placebo-Rd arms.