Based on encouraging results from early clinical studies, the randomized, placebo-controlled phase 3 Tourmaline-MM1 trial evaluated the combination of the oral proteasome inhibitor (PI) ixazomib plus lenalidomide and dexamethasone (IRd) versus placebo plus lenalidomide and dexamethasone (Rd) in patients with relapsed and/or refractory multiple myeloma (RRMM); Moreau and colleagues presented results of the first interim analysis of this trial.1
The feasibility of long-term treatment with current PIs is limited due to toxicities or the need for frequent clinic visits. Ixazomib is the first oral PI to be studied in patients with RRMM. In the phase 3 Tourmaline-MM1 study, a total of 722 eligible patients who were not refractory to either lenalidomide or PI therapy were randomized to receive either the all-oral regimen of ixazomib 4 mg (n = 360) or placebo (n = 362) weekly plus lenalidomide (25 mg daily) and dexamethasone (40 mg daily) in 28-day cycles until disease progression or unacceptable toxicity. This first interim analysis showed that the study met its primary end point by demonstrating a significant prolongation of progression-free survival (PFS) with IRd therapy (20.6 months vs 14.7 months; hazard ratio [HR], 0.742; P = .012) compared with Rd. This PFS benefit also extended to patient subgroups with high-risk cytogenetics, where IRd therapy resulted in a 40% decrease in risk of progression (HR, 0.596), suggesting that the addition of ixazomib to Rd overcomes the negative impact of unfavorable cytogenetics. Patients treated with IRd achieved higher overall response rates (78% vs 71.5%) and longer median durations of response (20.5 months vs 15.0 months) compared with standard Rd treatment.
Grade 3/4 adverse events (AEs; 74% vs 69%), serious AEs (47% vs 49%), and treatment discontinuations due to AEs (17% vs 14%) were similar between the 2 treatment arms. The most common grade 3/4 AE was thrombocytopenia (12% in the IRd group vs 5% in the Rd group). The incidence of peripheral neuropathy (all grades) was slightly higher with IRd therapy (27% vs 22%); incidence of grade 3 events was similar. Quality of life as measured on the EORTC-QLQ-C30 mean global health status scale was maintained with the addition of ixazomib to the standard doublet regimen. The authors concluded that addition of ixazomib to standard lenalidomide/dexamethasone backbone provided a significant PFS benefit that extended to patients with high-risk cytogenetics without exacerbating toxicity. The all-oral regimen of IRd may become the new standard of care for patients with RRMM. Largely on the strength of these data, the US Food and Drug Administration (FDA) approved on November 20, 2015, the combination of ixazomib/lenalidomide/dexamethasone for patients with MM who have received at least 1 prior therapy. Ixazomib is the first FDA-approved oral PI in this setting.
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