For the treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), the oral proteasome inhibitor ixazomib added to continuous lenalidomide-dexamethasone (Rd) treatment resulted in a nonstatistically significant increase in progression-free survival (PFS) and significantly higher response rates compared with placebo-Rd. The findings were reported in Blood.

Between May 17, 2013 and December 29, 2015, the double-blind, placebo-controlled phase 3 TOURMALINE-MM2 trial ( Identifier: NCT01850524) enrolled transplant-ineligible patients with NDMM. Patients were randomly assigned (1:1) to receive all-oral ixazomib (4mg; n=351) or placebo (n=354) plus Rd (25 mg and 40 mg) for 18 cycles, until progressive disease (PD), or unacceptable toxicity. Then dexamethasone was discontinued and reduced-dose treatment with ixazomib (3 mg) or placebo and lenalidomide (10 mg) was continued using until PD or unacceptable toxicity. The primary endpoint was PFS.

Patient and disease characteristics were well balanced between the arms. In the ixazomib-Rd arm and placebo-Rd arm, the median patient age was 73 and 74 years, respectively; 16.0% and 16.7% of patients had stage III disease; and 38.2% and 41.2% had high-risk cytogenetics.

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Median PFS was prolonged with ixazomib-Rd relative to placebo-Rd (35.3 vs 21.8 months, respectively); however, the difference was not statistically significant (HR, 0.830; 95% CI, 0.676-1.018; P =.073). Median follow-up duration was 53.3 months in the ixazomib-Rd arm and 55.8 months in the placebo-Rd arm. In a prespecified subgroup analysis, patients with high-risk cytogenetics had median PFS of 23.8 months in the ixazomib-Rd arm and 18.0 months in the placebo-Rd arm (HR, 0.690; P =.019).

Ixazomib-Rd resulted in higher complete response (26% vs 14%; odds ratio [OR], 2.10; P <.001) and at least very good partial response (63% vs 48%; OR, 1.87; P <.001) rates compared with placebo-Rd. At data cutoff (December 2, 2019), treatment had been discontinued in 84.6% and 83.9% patients in the ixazomib-Rd arm and placebo-Rd arm, due to PD in 35.0% and 46.9% and adverse events in 34.8% and 27.1%.

In both treatment arms, patients received a median number of 20 treatment cycles, and 55% of patients completed the initial 18 cycles. During the reduced-dose treatment, patients received a median of 44 and 39 cycles ixazomib-R and placebo-R, respectively.

Drug-related treatment-emergent adverse events (TEAEs) occurred in 96.6% and 92.6% of the ixazomib-Rd and placebo-Rd arm. In the ixazomib-Rd and placebo-Rd arms, grade ≥3 TEAEs occurred in 88% and 81% of patients and serious TEAEs occurred in 66% and 62% of patients. TEAEs resulted in treatment discontinuation in 35% and 27% of patients in the ixazomib-Rd arm and placebo-Rd arm, respectively, and 8% and 6% of patients died on study.

Limitations of the study were the primary PFS analysis, which was based on a stratified log-rank test, and the use of reduced-dose treatment after cycle 18.

“Collectively, these data suggest that median PFS in TOURMALINE-MM2 might have been marginally prolonged by continuing full-dose ixazomib and lenalidomide, and/or dexamethasone, for longer; however, at the time of study design, the tolerability of prolonged PI-based triplet therapy was unclear,” the authors wrote. “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.”

Disclosure: This research was supported by Millennium Pharmaceuticals, Inc, a wholly

owned subsidiary of Takeda Pharmaceutical Company Limited. Please see the original reference for a full list of authors’ disclosures. 


Facon T, Venner CP, Bahlis NJ, et al. Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2021;137(26):3616-3628. doi:10.1182/blood.2020008787