Addition of Ixazomib to Lenalidomide/Dexamethasone Improves Progression-Free Survival in Relapsed/Refractory Multiple Myeloma

Making It the First Approved Oral Proteasome Inhibitor in Myeloma


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The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited.
— Philippe Moreau, MD, and colleagues

In the phase III TOURMALINE-MM-1 trial reported in The New England Journal of Medicine, Philippe Moreau, MD, of the University Hospital Hôtel Dieu, Nantes, France, and colleagues found that adding the oral proteasome inhibitor ixazomib (Ninlaro) to lenalidomide (Revlimid) and dexamethasone significantly prolonged progression-free survival among patients with relapsed, refractory, or relapsed and refractory multiple myeloma.1 The trial supported the recent U.S. Food and Drug Administration approval of ixazomib in previously treated multiple myeloma, making ixazomib the first approved oral proteasome inhibitor.

Study Details

In the double-blind trial, 722 patients from 147 sites in 26 countries were randomized between August 2012 and May 27 2014 to receive ixazomib (n = 360) or placebo (n = 362) plus lenalidomide/dexamethasone. Treatment consisted of 28-day cycles of oral ixazomib at 4 mg or placebo on days 1, 8, and 15; oral lenalidomide at 25 mg on days 1 through 21 (10 mg in those with creatinine clearance ≤ 60 or ≤ 50 mL/min/1.73 m2 according to local prescribing information); and oral dexamethasone at 40 mg on days 1, 8, 15, and 22. The primary endpoint was progression-free survival.

For the ixazomib vs placebo groups, median age was 66 years in both; 58% vs 56% were male; 86% vs 83% were white; Eastern Cooperative Oncology Group performance status was 0 or 1 in 95% vs 93%; International Staging System (ISS) stage was I in 63% vs 64%, II in 25% vs 24%, and III in 12% in both; 78% vs 72% had creatinine clearance ≥ 60 mL/min/1.73 m2; median time from initial diagnosis was 44 vs 42 months; 55% vs 60% had standard-risk and 21% vs 17% had high-risk cytogenetics; number of prior therapies was one in 62% vs 60%, two in 27% vs 31%, and three in 11% vs 9%. In addition, 59% of the ixazomib group vs 55% of the placebo group had prior stem cell transplantation; the disease category was relapsed in 77% in both, refractory in 12% vs 11%, relapsed and refractory in 11% vs 12%, and primary refractory in 7% vs 6%; prior proteasome inhibitor therapy was bortezomib (Velcade) in 69% in both; and prior immunomodulatory therapy was lenalidomide in 54% vs 56% and thalidomide (Thalomid) in 44% vs 47%, with 21% vs 25% having disease refractory to prior therapy.

Improved Progression-Free Survival, Response

After median follow-up of 14.7 months, median progression-free survival was 20.6 months in the ixazomib group vs 14.7 months in the placebo group (hazard ratio [HR] = 0.74, P = .01). Benefit of ixazomib was consistent across prespecified subgroups, including poor-prognosis subgroups such as those with high-risk cytogenetics (24.1 vs 9.7 months, HR = 0.54), ISS stage III disease (18.4 vs 10.1 months, HR = 0.72), those aged > 75 years (18.5 vs 13.1 months, HR = 0.87), and those who had received two (17.5 vs 14.1 months, HR = 0.75) or three (not estimable vs 10.2 months, HR = 0.37) prior therapies.

Benefit of Proteasome Inhibitor in Resistant Myeloma

  • The addition of ixazomib to lenalidomide/dexamethasone increased progression-free survival among patients with relapsed, refractory, or relapsed and refractory multiple myeloma.
  • The benefit was observed in poor-prognosis groups.

Overall response rates were 78% vs 72%, with rates of complete response plus very good partial response of 48% vs 39%. Median time to response was 1.1 vs 1.9 months. Median duration of response was 20.5 vs 15.0 months. At median follow-up of approximately 23 months, median overall survival had not been reached in either group.

Adverse Events

Adverse events of ≥ grade 3 occurred in 74% of the ixazomib group vs 69% of the placebo group, with the most common in the ixazomib group being neutropenia (23% vs 24%) and thrombocytopenia (19% vs 9%). Rash of any grade was more common in the ixazomib group (36% vs 23%), as were gastrointestinal adverse events (mostly low grade); 22% of ixazomib patients and 19% of placebo patients received antidiarrheal agents, and 21% and 13% received antiemetic drugs. Peripheral neuropathy of any grade occurred in 27% vs 22% (grade 3 in 2% in each).

Serious adverse events occurred in 47% vs 49%. Adverse events led to dose reduction of any drug in 56% vs 50%, discontinuation of any drug in 25% vs 20%, and discontinuation of the study regimen in 17% vs 14%. Death occurred during the study period in 4% vs 6%.

The investigators concluded:

The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. ■

Disclosure: The study was funded by Millennium Pharmaceuticals. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Moreau P, Masszi T, Grzasko N, et al: Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374:1621-1634, 2016.


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