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Ixazomib Maintenance in Patients With Newly Diagnosed Multiple Myeloma Who Did Not Receive ASCT


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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

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.

REFERENCE

1. Dimopoulos MA, Špička I, Quach H, et al: Ixazomib as postinduction maintenance for patients with newly diagnosed multiple myeloma not undergoing autologous stem cell transplantation: The phase III TOURMALINE-MM4 trial. J Clin Oncol. October 6, 2020 (early release online).


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