The triplet combination of the oral proteasome inhibitor (PI) ixazomib and the immunomodulatory drugs lenalidomide and dexamethasone resulted in longer progression-free survival (PFS) than placebo and lenalidomide/dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results from the phase III Tourmaline-MM1 study presented at the 2015 ASH Annual Meeting.
“This all-oral regimen may become one of the new standards of care in the relapse setting of multiple myeloma. It has a very safe profile, is a very effective combination, and is simple and convenient,” said principal investigator, Philippe Moreau, MD, from the University of Nantes in France.
The current trial was designed based on a previous phase I/II study in which this three-drug combination resulted in an objective response rate (ORR) of 90 percent, as well as a safety profile similar to that of the lenalidomide/dexamethasone combination, for patients with newly diagnosed MM. The investigational, randomized, double-blind, placebo-controlled, international, multicenter Tourmaline-MM1 study examined the safety and efficacy of ixazomib plus lenalidomide and dexamethasone in patients with relapsed and/or refractory MM.
Patients were eligible if they had received one to three prior lines of therapy and were not refractory to prior lenalidomide or PI-based therapy.
A total of 722 patients were randomized to receive either:
- Ixazomib (4 mg) 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 (n=360)
- Placebo plus lenalidomide (25 mg) on days 1-21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 in 28-day cycles (n=362)
The median patient age was 66 (range = 30-91 years). The majority of patients had been previously treated with bortezomib (69%), and 45 percent and 12 percent had received thalidomide and lenalidomide, respectively.
Patients were treated until disease progression or unacceptable toxicity. Tourmaline-MM1 is ongoing, with three interim analyses and one final analysis planned. Dr. Moreau presented findings from the first interim analysis.
The study met its primary endpoint – an improvement in PFS – at the cut-off time for the first interim analysis. Patients receiving the ixazomib combination were followed for a median of 14.8 months; those receiving lenalidomide and dexamethasone alone were followed for 14.6 months. Patients treated with the ixazomib combination had a 35-percent improvement in PFS over the placebo group (hazard ratio = 0.742; p=0.012). ORR, complete response, and duration of response were also improved in the ixazomib-treated group:
- ORR: 78.3% vs. 71.5% (OR=1.44; p=0.035)
- Complete response: 11.7% vs. 6.6% (OR=1.87; p=0.019)
- Median duration of response: 20.5 months vs. 15 months
The Tourmaline-MM1 investigators also looked specifically at the efficacy of the ixazomib combination in the 19 percent of patients who had high-risk cytogenetics. High-risk patients receiving ixazomib achieved a similar HR for PFS as the entire study population (HR=0.596 and 0.543, respectively), “indicating ixazomib may overcome the negative impact of cytogenetic alterations,” Dr. Moreau reported.
Data for determining overall survival (OS), a secondary endpoint, were not yet mature at the time of presentation.
At the time of the first interim analysis, 55 percent of patients in the ixazomib-treated group and 52 percent of patients in the placebo group remained on treatment, with patients receiving a median of 13 (range = 1-26) and 12 (range = 1-25) cycles of treatment, respectively.
The safety profile of the ixazomib combination was similar to the placebo and lenalidomide/dexamethasone treatment. Grade ≥3 adverse events (AEs) occurred in 68 percent in the ixazomib group versus 61 percent in the placebo group; this adverse event rate was “largely driven by thrombocytopenia and was consistent with reported safety profiles for the individual agents,” Dr. Moreau added, however the higher rate of thrombocytopenia in the ixazomib arm did not affect the number of transfusions needed or severe bleeding events. These events included: neutropenia (19% with ixazomib + lenalidomide/dexamethasone vs. 16% with lenalidomide/dexamethasone); anemia (9% vs. 13%); thrombocytopenia (13% vs. 5%), and pneumonia: (6% vs. 8%).
Rates of serious AEs (40% vs. 44%), AE-related study discontinuation (13% vs. 11%), and on-treatment death (3% vs. 5%) were similar between both arms.
“If approved, this all-oral treatment regimen may become one of the new standards of care in the relapsed setting, as a very effective combination that is safe and convenient,” Dr. Moreau said. Ixazomib was recently approved by the U.S. Food and Drug Administration (in combination with lenalidomide/dexamethasone) to treat patients with MM who have received at least one 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). Abstract #727. Presented at the ASH Annual Meeting, December 7, 2015; Orlando, Florida.