IN PATIENTS with newly diagnosed multiple myeloma who responded well to induction therapy and underwent transplant, 2 years of maintenance therapy with ixazomib led to a 38% improvement in progression-free survival compared with placebo, according to the results of the phase III TOURMALINE-MM3 trial, presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1
Meletios A. Dimopoulos, MD
“This is the first randomized, double-blind, placebo-controlled trial of a proteasome inhibitor for maintenance treatment after transplant,” said Meletios A. Dimopoulos, MD, Professor and Chairman of Clinical Therapeutics at the University of Athens School of Medicine in Greece. “Ixazomib represents a new treatment option for maintenance after transplantation.”
Relapse after autologous stem cell transplant (ASCT) is “nearly unavoidable” in multiple myeloma, Dr. Dimopoulos said. “Maintenance therapy after ASCT may delay disease progression and prolong survival.”
Although lenalidomide is approved by the U.S. Food and Drug Administration in the maintenance setting, 29% of patients discontinue it due to treatment-related adverse events. “Ixazomib monotherapy may be well suited for maintenance therapy in the post-ASCT setting, given its convenient once-weekly oral dosing and manageable toxicity profile,” he suggested.
Ixazomib is currently approved for use in combination with lenalidomide and dexamethasone for patients who have received at least one prior therapy.
THE TOURMALINE-MM3 trial evaluated weekly treatment with single-agent ixazomib vs placebo in newly diagnosed patients who achieved at least a partial response to a proteasome inhibitor or immunomodulatory drug as induction therapy followed by single ASCT and 200 mg/m2 of melphalan. A total of 656 patients were randomly assigned to receive ixazomib at 3 mg (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles, for up to 26 cycles. After the first 4 cycles of treatment, the dose of ixazomib was increased to 4 mg. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival.
Baseline patient and disease characteristics were similar between the arms. The median age was 59 years, and one-third of the patients in both arms were minimal residual disease (MRD)-negative at study entry. For induction therapy, 59% received a proteasome inhibitor without an immunomodulatory drug, 11% received an immunomodulatory drug without a proteasome inhibitor, and 30% in each group received both agents. The most common immunomodulatory drug was thalidomide, and the most common proteasome inhibitor was bortezomib. The median duration of treatment at 4 mg was 15.2 months on the ixazomib arm and 16.2 months in the placebo group.
Improvement in Progression-Free Survival
THE MEDIAN progression-free survival was 26.5 months with ixazomib compared with 21.3 months with placebo (hazard ratio [HR] = 0.72; P = .002), meeting the study’s primary endpoint, Dr. Dimopoulos reported. The benefit was observed across patient subgroups. In patients with MRD-negative disease, the median progression-free survival reached 38.6 months and 32.5 months, respectively, whereas in MRD-positive patients, the median progression-free survival was 23.1 months with ixazomib and 18.5 months with placebo.
There was greater improvement in the depth of response with ixazomib over placebo. In 43% and 32%, respectively, patients with very good partial responses at study entry converted to complete responders, and 43% and 32%, respectively, improved from a partial response at study entry to a complete or very good partial response. Conversion from MRD-positive to MRD-negative was observed in 12% and 7%, respectively. The overall survival data were immature, but the median has not yet been reached in either arm.
“A progression-free survival benefit was observed in the ixazomib group irrespective of MRD status at study entry,” he said.
“IXAZOMIB MAINTENANCE was associated with low toxicity, with no increase in hepatic, cardiac, or renal adverse events,” Dr. Dimopoulos noted. “And at the current follow-up, there was no difference in the rate of a new primary, which was seen in 3% of each arm.”
For patients who did not discontinue therapy because of disease progression, 79% of those who received ixazomib vs 86% of those who received placebo completed the full 24 months of treatment. Quality of life was also preserved with ixazomib treatment, according to several validated instruments.
Additional studies of ixazomib combinations and treatment to disease progression are ongoing to further improve patient outcomes, Dr. Dimopoulos added. ■
DISCLOSURE: Dr. Dimopoulos has received honoraria from Takeda, Amgen, Celgene, and Bristol-Myers Squibb.
1. Dimopoulos MA, Gay F, Schjesvold FH, et al: Maintenance therapy with the oral proteasome inhibitor ixazomib significantly prolongs progression-free survival following autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Phase 3 TOURMALINE-MM3 trial. 2018 ASH Annual Meeting & Exposition. Abstract 301. Presented December 2, 2018.
Kenneth Shain, MD, PhD
KENNETH SHAIN, MD, PhD, Director of the Myeloma Working Group at Moffitt Cancer Center, Tampa, Florida, told The ASCO Post that ixazomib is “an effective drug,” but he is not ready to use it as maintenance therapy. He noted that the TOURMALINE-MM3 trial did meet its...