ORLANDO – Adding ixazomib to lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma increased progression-free survival from 14.7 months to 20.6 months without a substantial increase in overall toxicity.1
“Outcomes in multiple myeloma have significantly improved over the last 15 years with the introduction of proteasome inhibitors and immunomodulatory drugs,” lead investigator Philippe Moreau, MD, of University of Nantes in France, said during his presentation at the American Society of Hematology annual meeting. “This has been associated with a shift in treatment patterns towards extended therapy.”
In a phase 1/2 trial that included 65 patients with newly diagnosed multiple myeloma, a triplet regimen consisting of ixazomib weekly plus lenalidomide and dexamethasone resulted in a 90% overall response rate with a manageable safety profile. Therefore, researchers sought to investigate the safety and efficacy of ixazomib vs placebo in combination with lenalidomide and dexamethasone in patients with relapsed/refractory myeloma.
“These data provided the rationale for the phase 3 TOURMALINE-MM1 study assessing IRd versus placebo plus lenalidomide-dexamethasone in patients with relapsed and/or refractory multiple myeloma,” Dr Moreau said.
For the international, double-blind, placebo-controlled, phase 3 TOURMALINE-MM1 trial, researchers enrolled 722 adult patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior lines of therapy but who were not refractory to prior lenalidomide or proteasome inhibitor-based therapy. Participants were randomly assigned 1:1 to receive ixazomib 4 mg weekly or placebo on days 1, 8, and 15, plus lenalidomide 25 mg orally on days 1 to 21 and dexamethasone 40 mg orally on days 1, 8, 15, and 22 in 4-week cycles.
Results of the final analysis showed that median progression-free survival was 20.6 months with ixazomib vs 14.7 months with placebo after a median follow-up of 14.8 months and 14.6 months, respectively, demonstrating a 35% improvement in progression-free survival with ixazomib (HR, 0.742; P = .012).
“This progression-free survival benefit was consistent across pre-specified patient subgroups,” Dr Moreau noted.
The confirmed overall response rate was 78.3% in the ixazomib arm and 71.5% in the placebo arm (P = .035) with a median duration of response of 20.5 months and 15.0 months, respectively.
Researchers found that in patients with high-risk cytogenetics, including those with del(17) and t(4;14), the median progression-free survival was similar to that observed in the overall ixazomib group, suggesting that ixazomib may overcome the negative effect of cytogenetic mutations.
Dr Moreau also noted that overall survival data were not yet mature.
In regard to safety, 74% of patients treated with ixazomib experienced grade 3 or higher adverse events compared with 69% of those in the placebo group. The most common grade 3 or higher adverse events associated with ixazomib plus lenalidomide and dexamethasone were neutropenia, anemia, thrombocytopenia, and pneumonia.
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“When focusing on other infrequent adverse events, no safety concerns were identified,” Dr Moreau said. There was no substantial increase in cardiac toxicity or peripheral neuropathy in the ixazomib arm compared with the placebo arm.
Furthermore, the study demonstrated that patient-reported quality of life was maintained during the study.
“The all-oral regimen of IRd may become a new standard of care for relapsed and/or refractory multiple myeloma,” Dr Moreau concluded.
Ixazomib was recently approved by the U.S. Food and Drug Administration in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.
- Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an investigational oral proteasome inhibitor (PI), in combination with lenalidomide and dexamethasone (IRd), significantly extends progression-free survival (PFS) for patients (Pts) with relapsed and/or refractory multiple myeloma (RRMM): The phase 3 Tourmaline-MM1 study (NCT01564537). Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL.