Jesus Gomez Navarro, MD
Ixazomib (Ninlaro) improved progression-free survival (PFS) compared with placebo as a maintenance therapy in adult patients with multiple myeloma who responded to high-dose therapy (HDT) and autologous stem cell transplant (ASCT), according to topline findings from the phase III TOURMALINE-MM3 study.
Takeda Pharmaceutical Company, the manufacturer of the proteasome inhibitor, did not provide any specific from the trial, but plans to submit the results for presentations at the 2018 ASH Annual Meeting in December.
“Within the maintenance setting, it is critical that we find agents that are efficacious, tolerable and convenient,” Jesús Gomez Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda.
“The results of the TOURMALINE-MM3 trial represent an important step toward the goal of expanding the use of Ninlaro as a maintenance therapy. This is the first and only phase III placebo-controlled study evaluating a proteasome inhibitor in this setting and we look forward to discussions with Health Authorities around the world.”
The double-blind phase III TOURMALINE-MM3 study included 656 patients with multiple myeloma who had at least a partial response to induction therapy followed by HDT and ASCT. Patients were randomized to ixazomib or placebo. Beyond the primary endpoint, overall survival (OS) was a key secondary outcome measure. In its press release, Takeda reported that there were no new safety signals with maintenance ixazomib, and toxicities were consistent with findings from previous studies of single-agent use of the proteasome inhibitor.
The FDA approved ixazomib in November 2015 for use in combination with lenalidomide (Revlimid) and dexamethasone as a treatment for patients with multiple myeloma who have received at least 1 prior therapy. The approval was based on data from the phase III TOURMALINE-MM1 trial, findings from which were published in the New England Journal of Medicine
) in April 2016.
In the study, adding ixazomib to lenalidomide and dexamethasone reduced the risk of disease progression or death by 26% compared with lenalidomide and dexamethasone alone for patients with relapsed/refractory multiple myeloma. The median PFS with the ixazomib triplet was 20.6 months compared with 14.7 months with lenalidomide and dexamethasone alone (HR, 0.74; 95% CI, 0.59-0.94; P
TOURMALINE-MM1 randomized 722 patients in a 1:1 ratio to receive lenalidomide and dexamethasone with placebo (n = 362) or ixazomib (n = 360). Ixazomib was given orally at 4 mg on days 1, 8, and 15 of a 28-day cycle. Patients received oral lenalidomide at 25 mg on days 1 to 21 and dexamethasone was administered orally at 40 mg on days 1, 8, 15, and 22.
The median age of patients was 66 years, and 12% had ISS stage III disease at baseline. The ECOG PS was primarily 1 or 2 (94%). The median creatinine clearance was 78.4 ml/min (range, 20-233) and 19% of patients had high-risk cytogenetics, including 10% with del17p.
A majority of patients had received 1 prior therapy (61%), with 10% having received 3. Overall, 57% of patients had received prior stem cell transplantation, 77% had relapsed multiple myeloma, and 12% were both relapsed and refractory. Prior therapies included bortezomib (69%), thalidomide (45%), and lenalidomide (12%). Twenty-three percent of patients had disease that was refractory to prior immunomodulatory agents.
The overall response rate was 78.3% with the ixazomib triplet versus 71.5% in the control arm (P
= .04). A very good partial response or better was achieved for 48% of those in the ixazomib arm versus 39% in the control (P
= .01). The complete response rate with the proteasome inhibitor was 12% versus 7% with placebo (P = .02). The median duration of response was 20.5 months with ixazomib versus 15.0 months in the control arm. The median time to progression was 21.4 months with ixazomib versus 15.7 months in the control arm (P
In those with high-risk cytogenetics, the median PFS with ixazomib was 21.4 months versus 9.7 months in the control arm (HR, 0.54; 95% CI, 0.32-0.92; P
= .02). Specifically for those with del17p (n = 69), the median PFS was 21.4 versus 9.7 months, with and without ixazomib, respectively (HR, 0.60; 95% CI, 0.29-1.24). In patients with t(4;14) without del17p or t(14;16), the median PFS with ixazomib was 18.5 versus 12.0 months in the control (HR, 0.65; 95% CI, 0.25-1.66).
At an analysis conducted in July 2015 after a median of 23 months of follow-up, the median OS had not yet been reached in either arm. The primary endpoint of the study was PFS, and the trial was halted upon meeting this endpoint in February 2015. Median OS was not assessed for individual subgroups.
At the 23-month analysis, the most frequently reported all-grade adverse events (AEs) for the ixazomib arm versus the control group, respectively, were diarrhea (45% vs 39%), rash (36% vs 23%), constipation (35% vs 26%), neutropenia (33% vs 31%), thrombocytopenia (31% vs 16%), anemia (29% vs 27%), nausea (29% vs 22%), and back pain (24% vs 17%), vomiting (23% vs 12%).
AEs traditionally associated with proteasome inhibition were generally mild. Peripheral neuropathy occurred in 27% of patients treated with ixazomib versus 22% with placebo; however, the rates of grade 3 AEs were similar in both arms, at 2%. Similar findings were seen for peripheral edema, with an all-grade rate of 28% and 20% and a grade 3 rate of 2% and 1%, with and without ixazomib, respectively.
Fewer cases of acute renal failure were seen with ixazomib (9% vs 11%). Cardiac events were similar between the arms, with heart failure experienced by 4% of patients in both arms. Thromboembolism was less common with ixazomib (8% vs 11%).
Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634