As reported in the Journal of Clinical Oncology by Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens, Greece, and colleagues, the phase III TOURMALINE-MM4 trial has shown that postinduction maintenance with ixazomib prolonged progression-free survival vs placebo in patients with newly diagnosed multiple myeloma who were not undergoing autologous stem cell transplantation (ASCT).1
Meletios A. Dimopoulos, MD
As stated by the investigators: “Maintenance therapy prolongs progression-free survival … in patients with newly diagnosed multiple myeloma … not undergoing ASCT but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed.”
Study Details
In the double-blind trial, 706 patients from sites in 34 countries who had achieved a partial response or better after 6 to 12 months of standard induction therapy were randomly assigned 3:2 between April 2015 and October 2018 to receive the oral proteasome inhibitor ixazomib (n = 425) or placebo (n = 281) on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. Randomization was stratified by induction regimen, preinduction International Staging System level, age at randomization (< 75 vs ≥ 75 years), and response to initial therapy at screening. The primary endpoint was progression-free survival from the time of randomization in the intent-to-treat population.
Progression-Free Survival
Median follow-up for progression-free survival was 21.1 months. Median progression-free survival was 17.4 months in the ixazomib group vs 9.4 months in the placebo group (hazard ratio [HR] = 0.659, 95% confidence interval [CI] = 0.542–0.801, P < .001).
Among the 62% of patients in each group who had a complete or very good partial response postinduction, median progression-free survival was 25.6 months vs 12.9 months (HR = 0.586, 95% CI = 0.449–0.765, P < .001). Among patients with a partial response, the hazard ratio was 0.756 (95% CI = 0.566–1.010). Among the 35% vs 36% of patients with stage III disease as assessed by the International Staging System, the hazard ratio was 0.695 (95% CI = 0.499–0.967, P = .030). Among the 38% vs 39% of patients aged ≥ 75 years at randomization, the hazard ratio was 0.738 (95% CI = 0.537–1.014, P = .060).
Median time to disease progression was 17.8 vs 9.6 months, and response improvements during maintenance were observed in 14.6% vs 8.2% of patients. Second progression-free survival and overall survival data were not mature at the time of the current analysis. The study remains blinded, with follow-up for progression-free survival–2 and overall survival continuing.
Adverse Events
Grade ≥ 3 adverse events occurred in 36.6% of the ixazomib group vs 23.2% of the placebo group. Pneumonia occurred in more than 3% of patients (16 patients, 3.8%) in the ixazomib group. Adverse events of any grade for which the incidence was at least 5% higher in the ixazomib group included nausea (26.8% vs 8.0%), rash (25.6% vs 10.5%), vomiting (24.2% vs 4.3%), diarrhea (23.2% vs 12.3%), peripheral neuropathy (19.5% vs 10.9%), and pyrexia (11.3% vs 5.1%).
Serious adverse events occurred in 22.1% vs 16.7% of patients. Treatment was discontinued due to adverse events in 12.9% vs 8.0%. New primary malignancies occurred in 5.2% vs 6.2% of patients. The rate of on-study deaths was 2.6% vs 2.2%.
KEY POINTS
- Ixazomib maintenance significantly prolonged progression-free survival vs placebo.
- Marked benefit of ixazomib was observed in patients with a very good partial response or better after induction.
The investigators concluded: “Ixazomib maintenance prolongs [progression-free survival] with no unexpected toxicity in patients with [newly diagnosed multiple myeloma] not undergoing ASCT. To our knowledge, this is the first proteasome inhibitor demonstrated in a placebo-controlled randomized clinical trial to have single-agent efficacy for maintenance and is the first oral proteasome inhibitor option in this patient population.”
DISCLOSURE: The study was supported by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. Dr. Dimopoulos has received honoraria from Amgen, Beigene, Takeda, Janssen-Cilag, and Bristol Myers Squibb and has served as a consultant or advisor to Amgen, Janssen-Cilag, Takeda, Beigene, and Bristol Myers Squibb. For full disclosures of all study authors, visit ascopubs.org.
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