Overall Survival With the Addition of Ixazomib to Lenalidomide/Dexamethasone in Relapsed or Refractory Multiple Myeloma

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As reported in the Journal of Clinical Oncology by Paul G. Richardson, MD, and colleagues, the final overall survival analysis of the phase III TOURMALINE-MM1 trial showed no overall survival benefit with the addition of ixazomib to lenalidomide/dexamethasone (Rd) in relapsed or refractory multiple myeloma.

The trial supported the November 2015 approval of ixazomib in combination with Rd in this setting based on significantly prolonged progression-free survival with the triplet therapy.

Paul G. Richardson, MD

Paul G. Richardson, MD

Study Details

The double-blind trial included 722 patients who had been treated with one to three prior therapies from sites in 26 countries. They were randomly assigned between August 2012 and May 2014 to receive ixazomib at 4 mg (n = 360) or placebo (n = 362) on days 1, 8, and 15, both in combination with lenalidomide at 25 mg on days 1 to 21 and dexamethasone at 40 mg on days 1, 8, 15, and 22 in 28-day cycles until disease progression or unacceptable toxicity. Overall survival in the intent-to-treat population was a key secondary endpoint of the trial.

Key Findings

With a median follow-up of 85 months, median overall survival was 53.6 months (95% confidence interval [CI] = 49.25­­–62.95 months) in the ixazomib/Rd group vs 51.6 months (95% CI = 44.78–59.14 months) in the Rd group (hazard ratio [HR] = 0.939, 95% CI = 0.784–1.125, P = .495).

In analyses of prespecified subgroups, those for which hazard ratios were nonsignificantly lower for ixazomib/Rd vs Rd included the following subgroups:

  • Refractory to any (0.794) or last (0.742) treatment line
  • Aged > 65 to 75 years (0.757)
  • With International Staging System stage III disease (0.779)
  • With two to three prior therapies (0.845)
  • With high-risk cytogenetics (0.870)
  • With high-risk cytogenetics and/or 1q21 amplification (0.862).

After study therapy, 71.7% of patients in the ixazomib/Rd group vs 69.9% of the Rd group received one or more subsequent anticancer therapy; those with a ≥ 5% difference between groups included daratumumab (24.7% vs 33.9%), bortezomib (56.8% vs 61.8%), and carfilzomib (27.0% vs 33.5%); overall, 47.5% vs 55.8% received a proteasome inhibitor–based next-line therapy.

In an exploratory analysis, median time to next treatment in the intent-to-treat population was 29.7 months vs 26.9 months (HR = 0.917, 95% CI = 0.769–1.094).

In an exploratory analysis, median overall survival was 54.3 months vs 58.1 months among the 510 patients who received subsequent therapy (HR = 0.985, 95% CI = 0.800–1.213) and 50.4 months vs 31.5 months among the 212 who did not receive subsequent therapy (HR = 0.877, 95% CI = 0.603–1.275).

Among patients receiving daratumumab in any subsequent line of therapy, median overall survival was 78.9 months vs 83.4 months (HR = 1.15, 95% CI = 0.73–1.81); in those not receiving subsequent daratumumab, median overall survival was 49.2 months vs 35.5 months (HR = 0.83, 95% CI = 0.68–1.01). Among patients receiving proteasome inhibitor–based next-line therapy, median overall survival was 52.0 months vs 56.9 months (HR = 1.04, 95% CI = 0.78–1.4); in the remaining patients in the intent-to-treat population, median survival was 54.6 months vs 48.8 months (HR = 0.90, 95% CI = 0.71–1.13).

New primary malignancies were observed in 10.3% vs 11.9% of patients.

The investigators concluded, “Median overall survival values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib/Rd vs placebo/Rd did not translate into a statistically significant overall survival benefit on intent-to-treat analysis. Overall survival benefit was greater in subgroups with adverse prognostic factors. Overall survival interpretation was confounded by imbalances in subsequent therapies received, especially [proteasome inhibitors] and daratumumab.”

Dr. Richardson, of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.