Analyzing Survival Outcomes With Ixazomib-Rd in Relapsed/Refractory Multiple Myeloma

While treatment with ixazomib, lenalidomide, and dexamethasone (ixazomib-Rd) was shown to improve progression-free survival, recent long-term findings from the phase III TOURMALINE-MM1 trial published in the Journal of Clinical Oncology show the triple combination therapy may not prolong overall survival (OS) compared with only Rd in patients with relapsed or refractory multiple myeloma (MM).

According to the study’s senior author, Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, the median OS values reported in both arms of the study are the longest reported in phase III studies where lenalidomide and dexamethasone are used in this patient population. “This just points to the remarkable clinical benefit of the immunomodulatory platform in these patients,” he said.

However, Dr. Richardson suggests, the lack of OS benefit with ixazomib-Rd isn’t necessarily a negative finding. “I think it points to the real equipoise of these trials in the modern setting because obviously patients get outstanding salvage therapies, so that impacts on OS,” he said. “It doesn’t mean that ixazomib has ‘failed,’ it means that the impact of subsequent therapies has dramatically improved outcome.”

Patients with MM were eligible for enrollment in the multicenter, late-stage TOURMALINE-MM1 trial if their disease had relapsed, become refractory, or relapsed and become refractory after one to three prior therapies. Randomization was stratified by number of prior therapies (one vs. two or three), prior exposure to a proteasome inhibitor (yes vs. no), and International Staging System disease stage (I or II vs. III).

Treatment consisted of randomly assigned ixazomib-Rd (n=360) or placebo-Rd (n=362). Ixazomib 4 mg or a matching placebo was administered on days one, eight, and 15. In both arms, patients also received lenalidomide 25 mg on days one through 21 as well as dexamethasone 40 mg on days one, eight, 15, and 22. Treatment was administered in 28-day cycles until either disease progression or unacceptable toxicity.

At the time of data cutoff, a total of 16 patients in the ixazomib-Rd arm and 15 patients in the placebo-Rd group were still on their assigned treatment. Approximately 71.4% (n=257) and 69.9% of patients in the intention-to-treat (ITT) analysis received subsequent therapy in the ixazomib-Rd and placebo-Rd arms, respectively.

With a median follow-up of approximately 85 months in both arms, the median OS was 53.56 months for ixazomib-Rd and 51.6 months placebo-Rd in the ITT analysis.

Overall, there was no significant difference in OS between the two arms (hazard ratio [HR] = 0.939; 95% CI 0.784-1.125; p=0.495).

Treatment with ixazomib-Rd demonstrated a treatment benefit in prespecified subgroups, including patients with del(17p) (HR=0.916; 95% CI 0.516-1.626), high-risk cytogenetics (HR=0.870; 95% CI 0.580-1.305), and expanded high-risk cytogenetics (HR=0.862; 95% CI 0.660-1.124). (See FIGURE)

There was also a larger OS benefit with ixazomib-Rd compared with placebo-Rd in patients who:

  • were refractory to any (HR=0.794; 95% CI 0.538-1.172) or last (HR=0.742; 95% CI 0.460-1.198) treatment line
  • were between 65 and 75 years old (HR=0.757; 95% CI 0.559-1.027)
  • had International Staging System stage 3 disease (HR=0.779; 95% CI 0.487-1.247)
  • had two or three prior therapies (HR=0.845; 95% CI 0.642-1.114)

The researchers found no new or additional safety concerns associated with the treatments during the study’s seven-year follow-up period. The only grade ≥3 treatment-emergent adverse events that occurred with a ≥5% higher incidence in patients treated with ixazomib-Rd versus placebo-Rd were thrombocytopenia (21.3% vs. 10.3%) and diarrhea (10.0% vs. 3.1%). No differences were found between the two treatment arms in terms of quality of life.

Study authors report relationships with Millennium Pharmaceuticals, which sponsored this trial.


Richardson PG, Kumar SK, Masszi T, et al. Final overall survival analysis of the TOURMALINE-MM1 phase III trial of ixazomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma [published online ahead of print, 2021 Jun 11.] J Clin Oncol. doi:10.1200/JCO.21.00972.