Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study

Abstract

Background: The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide-dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies.

Methods: Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles. Randomization was stratified according to number of prior therapies, disease stage, and prior proteasome inhibitor exposure. The primary endpoint was progression-free survival (PFS). In total, 115 Chinese patients were randomized (57 ixazomib-Rd, 58 placebo-Rd).

Results: At the preplanned final analysis for PFS, after median PFS follow-up of 7.4 and 6.9 months, respectively, PFS was improved with ixazomib-Rd versus placebo-Rd (median 6.7 vs 4.0 months; HR 0.598; p = 0.035). At the preplanned final analysis of overall survival (OS), after median follow-up of 20.2 and 19.1 months, respectively, OS was improved with ixazomib-Rd versus placebo-Rd (median 25.8 vs 15.8 months; HR 0.419; p = 0.001). On the ixazomib-Rd and placebo-Rd arms, respectively, 38 (67%) and 43 (74%) patients reported grade ≥3 adverse events (AEs), 19 (33%) and 18 (31%) reported serious AEs, and 4 (7%) and 5 (9%) died on-study. The most frequent grade 3/4 AEs were thrombocytopenia (18%/7% vs 14%/5%), neutropenia (19%/5% vs 19%/2%), and anemia (12%/0 vs 26%/2%).

Conclusions: This study demonstrated that PFS and OS were significantly improved with ixazomib-Rd versus placebo-Rd, with limited additional toxicity, in patients with RRMM.

Trial registration: ClinicalTrials.gov, NCT01564537.

Keywords: China; Ixazomib; Multiple myeloma; Oral; Overall survival; Progression-free survival; Proteasome inhibitor; Relapsed/refractory.

Fig. 1

CONSORT diagram of patient disposition and flow through the study

Fig. 2

PFS (time from randomization to first documentation of PD or death) with ixazomib-Rd and placebo-Rd at data cut-off for primary and final analysis of PFS (median follow-up for PFS of 7.4 and 6.9 months, respectively). a Kaplan–Meier analysis of PFS by IRC assessment in the intent-to-treat population. b Forest plot of PFS in prespecified patient subgroups

Fig. 3

OS with ixazomib-Rd and placebo-Rd at data cut-off for final analysis of OS (median follow-up of 20.2 and 19.1 months, respectively). a Kaplan–Meier analysis of OS in the intent-to-treat population. b Forest plot of OS in prespecified patient subgroups

Fig. 4

Summary of individual predicted ixazomib systemic exposure for patients receiving ixazomib 4.0 mg. Ixazomib systemic exposures (AUC) were calculated for individual patients in the China Continuation study who underwent pharmacokinetic sampling, as well as for individual patients enrolled in other ixazomib studies (including the TOURMALINE-MM1 study), using the previously reported population pharmacokinetic model [26]. Red- and black-filled circles indicate the mean exposure in White patients and in other race categories, respectively. Numbers (brackets) at the top of the plot show the percent change in mean AUC (with 95% confidence intervals) in other race categories relative to White patients. Numbers at the bottom of the plot show the number of patients in each category