Ixazomib, the first oral investigational proteasome inhibitor, was recently approved by the US Food and Drug Administration in combination with lenalidomide and dexamethasone (IRd) to treat patients with multiple myeloma (MM) who have received at least 1 prior therapy. In earlier studies, ixazomib in combination with IRd was shown to produce an overall response rate (ORR) of 92% with a manageable safety profile in patients with newly diagnosed MM (Kumar R, et al. Lancet Oncol. 2014;13:1503-1512). These encouraging results provided the rationale for phase 3 investigation of ixazomib in combination with Rd versus placebo plus Rd in patients with relapsed/refractory MM (RRMM).
In this trial, 722 eligible patients who were not refractory to either lenalidomide or proteasome inhibitor therapy were randomized to receive either ixazomib 4 mg (n = 360) or placebo (n = 362) weekly plus lenalidomide 25 mg orally and dexamethasone 40 mg. The primary end point was progression-free survival (PFS), and key secondary end points included overall survival (OS) and OS in high-risk del(17) patients.
The study met the primary end point by demonstrating a significant prolongation of PFS with IRd therapy (20.6 vs 14.7 months; hazard ratio [HR], 0.742; P = .012) compared with patients receiving Rd. In patients with high-risk cytogenetics, IRd therapy resulted in a 40% decrease in risk of progression (HR, 0.596), indicating that ixazomib may overcome the negative impact of cytogenetic alterations. IRd treatment was associated with higher ORRs (78.3% vs 71.5%) and longer median duration of response (20.5 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 mostly similar between the 2 treatment groups. Twenty-three percent and 24% of patients in the IRd and Rd arms, respectively, developed grade 3/4 neutropenia. The rate of grade 3/4 thrombocytopenia was somewhat higher in the IRd arm (19% vs 9%). Incidence of peripheral neuropathy (all grades) was slightly higher with IRd therapy (27% vs 22%); incidence of grade 3 peripheral neuropathy was similar.
Study results were encouraging, with IRd showing an improved efficacy profile and comparable safety compared with Rd alone, including patients with high-risk cytogenetics. The investigators concluded that addition of ixazomib to IRd treatment had the potential to become a new standard of care in the RRMM treatment setting.