ORLANDO – The first all-oral drug combination for treatment of relapsed/refractory multiple myeloma significantly extended progression-free survival (PFS), based on the first of three planned interim analyses from a phase 3 trial.
The combination of the oral proteasome inhibitor ixazomib (Ninlaro, recently approved by the U.S. Food and Drug Administration) with lenalidomide and dexamethasone (len/dex) was associated with a 35% improvement in PFS, compared with len/dex and placebo, reported Dr. Philippe Moreau from Université Hospital of Nantes (France), Hôtel-Dieu.
The ixazomib combination also was associated with a significantly better median time to progression, at 21.4 vs. 15.7 months (P = .007). The time to response and duration of response were not significantly different, however, for the two groups in the placebo-controlled, randomized study of 722 patients.
“Ixazomib, when combined with len/dex for patients with relapsed and/or refractory multiple myeloma, was associated a significant and meaningful improvement in progression-free survival, significantly improved time to progression, and confirmed response rates,” Dr. Moreau said at a briefing at the American Society of Hematology annual meeting.
Dr. Moreau presented results of the phase III Tourmaline study, which compared len/dex plus weekly ixazomib or len/dex with weekly placebo in adults who have relapsed/refractory multiple myeloma following one to three prior lines of therapy and were not refractory to either prior lenalidomide or proteasome inhibitor–based therapy.
The study met its primary endpoint of a PFS advantage for the addition of ixazomib. The median PFS for ixazomib plus len/dex was 20.6 months, compared with 14.7 months for len/dex plus placebo. The hazard ratio for PFS with ixazomib-containing combination was 0.742 (P = .012).
The confirmed overall response rate (partial response or greater) was 78% with ixazomib vs. 71% with placebo (P = .035). The respective very good partial response or better rates were 48% vs. 39% (P = .014).
A total of 722 patients were randomized to either ixazomib 4 mg or placebo weekly on days 1, 8, 15 and 22 of each 28-day cycle, with oral lenalidomide 25 mg on days 1 through 21 (with dose reductions in patients with renal impairment at the investigator’s discretion) and oral dexamethasone 40 mg on days 1, 8, 15, and 22.
Patients were stratified at randomization by the number of prior therapies (one vs. two or three), previous proteasome-inhibitor exposure, and by International Staging System for multiple myeloma stage I or II vs. III. Cycles were repeated until disease progression or until patients experienced unacceptable toxicity.
The overall median age of patients was 66 (range, 30-91) years. In all, 70% had received a prior proteasome inhibitor, 88% had International Staging System stage I or II disease, and 59% had received just one prior line of therapy.
Dr. Moreau noted that the responses were rapid and durable with a median time to response of 1.1 months for ixazomib and 1.9 months for placebo, and a median duration of response of 20.5 months and 15 months, respectively. Neither difference was significant.
The incidence of grade 3 or greater adverse events was 68% for patients on ixazomib vs. 61% with placebo. A higher incidence of thrombocytopenia with ixazomib (19% vs. 9%) primarily accounted for the difference.
Dr. Moreau noted that peripheral neuropathy, a common problem with intravenous proteasome inhibitors, was low with ixazomib, and patients did not report significant changes in their quality of life.
The study was sponsored by Millennium Pharmaceuticals. Dr. Moreau disclosed receiving honoraria from the company.