Progression-free survival failed to meet the threshold for statistical significance with the addition of ixazomib to lenalidomide and dexamethasone in patients with newly diagnosed, transplant-ineligible multiple myeloma in the phase III TOURMALINE-MM2 trial, not meeting the primary endpoint.
Progression-free survival (PFS) failed to meet the threshold for statistical significance with the addition of ixazomib (Ninlaro) to lenalidomide (Revlimid) and dexamethasone in patients with newly diagnosed, transplant-ineligible multiple myeloma in the phase III TOURMALINE-MM2 trial, not meeting the primary endpoint, according to a press release from Takeda.1
The median PFS for the combination was 35.3 months compared with 21.8 months with lenalidomide and dexamethasone alone, resulting in a 17% improvement in the risk of progression, but this was not considered to be statistically significant (HR, 0.83;P= .073).
“There is a need for treatment options in transplant-ineligible patients. We remain committed to advancing the field of multiple myeloma and continue to drive innovation through ongoing research and development,” said Christopher Arendt, head of the Oncology Therapeutic Area Unit, Takeda, in a statement. “We are confident there will be numerous learnings from this trial and look forward to sharing these data with the community.”
Further results from the phase III trial will be submitted for presentation at an upcoming medical meeting. The company also noted in the press release that continued treatment on the study regimen will be up to the physicians’ discretion.
TOURMALINE-MM2 is an international, randomized, double-blind, multicenter, placebo-controlled study (NCT01850524) that explored the safety and efficacy of the ixazomib triplet in the newly diagnosed setting. More than 700 adult patients with treatment-naïve, transplant-ineligible multiple myeloma were enrolled. They were randomized to receive either ixazomib with lenalidomide and dexamethasone or lenalidomide and dexamethasone plus placebo.
Eligible patients were not candidates for high-dose therapy followed by stem cell transplantation, had an ECOG performance status of 0 to 2, and were able to take concurrent aspirin. Evidence of another malignancy within the past 5 years; recent infection, surgery, or radiation; disease in the central nervous system; treatment with CYP1A2 or CYP3A inhibitors; active hepatitis B or C virus; and other comorbid illnesses were all criteria for exclusion from the trial.
In the investigational arm, patients received 4 mg of ixazomib on days 1, 8, and 15 of a 28-day cycle plus 25 mg of lenalidomide on days 1 through 21 and 40 mg of weekly dexamethasone. Each agent was administered as a single oral dose and was given for the first 18 cycles, after which both ixazomib and lenalidomide were to be reduced and the dexamethasone discontinued.
Secondary end points for the trial include complete response rate, overall survival rate, and pain response.
The most common adverse events (AEs) reported with the ixazomib triplet in comparison with the placebo regimen were diarrhea (42% vs 36%), constipation (34% vs 25%), thrombocytopenia (28% vs 14%), peripheral neuropathy (28% vs 21%), nausea (26% vs 21%), peripheral edema (25% vs 18%), vomiting (22% vs 11%), and back pain (21% vs 16%). Serious AEs included thrombocytopenia (2%) and diarrhea (2%).
The triplet combination was approved by the FDA in November 2015for use in the relapsed/refractory multiple myeloma setting. The approval was based on findings from the phase III TOURMALINE-MM1 trial.
In the MM1 study, the median PFS with the triplet was 20.6 months compared with 14.7 months without ixazomib. This resulted in a 26% improvement in the risk of progression (HR, 0.74; 95% CI, 0.59-0.94;P= .01).2
The overall response rate was 78.3% with the ixazomib regimen versus 71.5% in the control arm (P= .04). The median duration of response was 20.5 months with ixazomib versus 15.0 months in the control group.
Common all-grade AEs reported with the triplet regimen in the MM1 study included diarrhea, rash, constipation, neutropenia, thrombocytopenia, anemia, nausea, back pain, and vomiting.
The rate of grade 3 peripheral edema and peripheral neuropathy, both of which are associated with proteasome inhibitors, was 2%.