Ixazomib plus lenalidomide and dexamethasone (Rd) did not improve overall survival (OS), when compared with placebo plus Rd, in patients with relapsed or refractory multiple myeloma (RRMM), according to a study published in the Journal of Clinical Oncology.

The initial analysis of the phase 3 TOURMALINE-MM1 trial (ClinicalTrials.gov Identifier: NCT01564537) had shown that ixazomib plus Rd prolongs progression-free survival (PFS) in RRMM. The median PFS was 20.6 months with ixazomib-Rd and 14.7 months with placebo-Rd (hazard ratio [HR], 0.74; 95% CI, 0.59-0.94; P =.01). 

In the final analysis, researchers investigated whether this improvement in PFS would translate to a benefit in OS.

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The trial included 722 adults with RRMM who had received 1 to 3 prior therapies. Patients were randomly assigned to ixazomib-Rd (n=360) or placebo-Rd (n=362). The patients were stratified based on the number of prior therapies, previous proteasome inhibitor (PI) exposure, and disease stage.

At a median follow-up of more than 7 years, the median OS was 53.6 months in the ixazomib-Rd arm and 51.6 months in the placebo-Rd arm (HR, 0.939; 95% CI, 0.784-1.125; P =.495).

“[A]lthough the slight favorable trend in OS seen with ixazomib-Rd versus placebo-Rd … was not significant, these results were obtained in the context of the longest median OS reported to date in phase 3 studies of Rd-based therapy in RRMM,” the study authors noted.

Furthermore, ixazomib-Rd was associated with an OS benefit in some prespecified subgroups. Patients with del(17p), high-risk cytogenetics, or expanded high-risk cytogenetics had OS HRs of less than 1.

“OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab,” the authors noted.

Overall, the proportion of patients who received subsequent therapy was similar in both arms — 71.7% in the ixazomib arm and 69.9% in the placebo arm. Daratumumab was given to 24.7% of patients in the ixazomib arm and 33.9% of patients in the placebo arm. PI-based therapy was given to 71.8% and 76.9%, respectively.

There were no new safety concerns identified during the extended follow-up. The rate of new primary malignancies was similar between the treatment arms — 10.3% in the ixazomib arm and 11.9% in the placebo arm. 

Grade 3 or higher adverse events that were more common with ixazomib-Rd than with placebo-Rd were thrombocytopenia (21.3% and 10.3%, respectively) and diarrhea (10.0% and 3.1%, respectively).

“The impact of the evolving RRMM treatment landscape on the ability to demonstrate OS benefit in clinical trials warrants further consideration regarding randomized trial design and the utility of OS as an endpoint,” the study authors wrote. “Nonetheless, with a demonstrated PFS benefit, limited additional toxicity versus placebo-Rd, and the convenience of an all-oral triplet regimen, ixazomib-Rd continues to represent an important treatment option for patients with RRMM.”

Disclosures: This research was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Richardson PG, Kumar SK, Masszi T, et al. Final overall survival analysis of the TOURMALINE-MM1 phase III trial of ixazomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. Published online June 11, 2021. doi:10.1200/JCO.21.00972