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Adding Ixazomib to Lenalidomide and Dexamethasone Results in Longer Progression-Free Survival in Patients with Relapsed/Refractory Myeloma

December 30, 2021

Treatment with ixazomib plus lenalidomide and dexamethasone increased progression-free survival (PFS) by approximately six months – and with limited additional toxic effects – compared with lenalidomide and dexamethasone alone in patients with relapsed, refractory, or relapsed/refractory multiple myeloma (RRMM), according to results of the phase III TOURMALINE-MM1 trial published in The New England Journal of Medicine.

The study authors, led by Philippe Moreau, MD, the head of the Hematology Department at the University Hospital Hôtel Dieu in Nantes, France, also reported that the benefit with ixazomib was seen across pre-specified subgroups of patients with typically poor prognoses, including older patients and those with high-risk cytogenetic abnormalities.

"An increased focus on continuous therapy has heightened the need for regimens that have acceptable side-effect profiles, that allow quality of life to be maintained, and that are easy to administer," Dr. Moreau and colleagues wrote. "In consideration of its adverse-event profile and efficacy, this all-oral regimen provides an additional therapeutic option for patients with RRMM."

The randomized, double-blind, placebo-controlled, phase III TOURMALINE-MM1 trial compared the safety and efficacy of lenalidomide and dexamethasone plus placebo or the proteasome inhibitor (PI) ixazomib in 722 patients (median age = 66 years; range = 30-91 years) with RRMM.

Patients were excluded from the trial if they had grade >1 peripheral neuropathy or were refractory to prior lenalidomide therapy or PI–based therapy.

Randomization was stratified based on the number of prior therapies (1 vs. 2-3), previous exposure to PIs (not exposed vs. exposed), and International Staging System (ISS) disease stage (I or II vs. III).

All patients received a 28-day cycle of lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, and 22), with 360 patients receiving ixazomib 4 mg (days 1, 8, and 15) and 362 patients receiving placebo.

At the data cut-off point on October 30, 2014, the median follow-up was 14.8 months in the ixazomib combination group and 14.6 months in the placebo group. Progression-free survival (the study's primary endpoint) was significantly longer in the ixazomib-treated group: 20.6 months versus 14.7 months (hazard ratio [HR] = 0.74; 95% CI 0.59-0.94; p=0.01).

The PFS benefit was consistent across pre-specified subgroups, including those:

  • with ISS stage III disease: 18.4 months vs. 10.1 months
  • older than 75 years: 18.5 months vs. 13.1 months
  • who had received 2-3 prior therapies: 17.5 months vs. 14.1 months

Ixazomib also lengthened median PFS in patients with high-risk cytogenetic abnormalities (75 in the ixazomib group and 62 in the placebo group): 21 months versus 9.7 months (HR=0.54; 95% CI 0.32-0.92; p=0.02).

"Data on median PFS suggest that an ixazomib regimen may improve the prognosis for patients with high-risk cytogenetic features (including del17p, t[4;14], and t[14;16]), which have traditionally been associated with a poor prognosis by lengthening the PFS to a point that is similar to that among patients with standard-risk cytogenetic features," the authors wrote.

The overall response rate (a secondary endpoint) was 78.3 percent in the ixazomib group versus 71.5 percent in the placebo group (p=0.04). "The responses were durable and deepened with increasing duration of treatment," the authors noted.

Disease progression or death occurred less often in the ixazomib combination cohort (n=129 events) compared with the placebo group (n=157 events).

Based on the results of TOURMALINE-MM1, the U.S. Food and Drug Administration approved ixazomib in combination with lenalidomide and dexamethasone for MM patients who have received at least one prior therapy.

The safety profiles were similar between each treatment group, with comparable rates of serious adverse events (AEs), AE-related discontinuation of the study regimen, and death during the study period.

By 23 months, 171 deaths had occurred: 81 in the ixazomib combination group and 90 in the placebo group. "The only grade ≥3 AE for which there was at least a 5-percent difference between the ixazomib and placebo groups was thrombocytopenia, a known side effect of bortezomib and carfilzomib, for which there were no apparent clinical sequelae," they added.

The most common any-grade hematologic adverse events (AEs) occurring in both study cohorts included:

  • neutropenia (n=118; 33% vs. n=111; 31%)
  • thrombocytopenia (n=112; 31% vs. n=57; 16%)
  • anemia (n=103; 29% vs. n=48; 13%)

The most common any-grade non-hematologic AEs that occurred in both cohorts included: diarrhea (n=164; 45% vs. n=139; 39%), rash (n=131; 36% vs. n=82; 23%), and constipation (n=126; 35% vs. n=94; 26%).

Dr. Moreau and colleagues also found that ixazomib was well tolerated, with patients in the ixazomib group receiving a median of 17 treatment cycles (range = 1-34 cycles) and patients in the placebo group receiving a median of 15 cycles (range = 1-34 cycles). "The duration of therapy with the ixazomib regimen was notable; almost half the patients had received treatment for at least 18 cycles at the 23-month analysis," the authors wrote.

The authors reported that no AEs affecting quality of life were reported in the ixazomib combination cohort, although the tendency to overestimate the quality-of-life benefit in open-label trials was noted as a limitation of this study.

Overall survival was not reached in either treatment group, though follow-up is ongoing.


Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-34.


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