Ixazomib is an oral investigational proteasome inhibitor that is undergoing advanced clinical testing, both as a single agent and in combination, and is under regulatory review for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM). As combination therapy, ixazomib in combination with the lenalidomide and dexamethasone (Rd) backbone was shown to produce an overall response rate (ORR) of 90% with a manageable safety profile in patients with newly diagnosed multiple myeloma.1 These encouraging results provided the rationale for phase 3 investigation of ixazomib in combination with Rd (IRd) versus placebo plus Rd in patients with RRMM. Moreau and colleagues presented results of the first interim analysis of this trial at the 2015 ASH meeting.2 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 (362) weekly plus lenalidomide (25 mg orally) and dexamethasone (40 mg). The primary end point was progression-free survival (PFS); key secondary end points were overall survival (OS) and OS in the high-risk del(17) patient subgroup. At the first prespecified interim analysis (and final analysis for PFS), the study met its 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 control. 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% vs 71.5%) and longer median duration of response (20.5 vs 15.0 months) compared with standard Rd treatment. OS data are not yet mature. Grade 3/4 adverse events (AEs; 68% vs 61%), serious AEs (40% vs 44%), and treatment discontinuations due to AEs (13% vs 11%) were similar between the 2 treatment arms. Common grade 3/4 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Incidence of peripheral neuropathy (all grades) was slightly higher with IRd therapy (28% vs 21%); incidence of grade 3 events was similar. The authors concluded that addition of ixazomib to the standard lenalidomide/dexamethasone regimen was associated with a significant PFS benefit that extended to patients with high-risk cytogenetics without substantial increases in toxicity, with the potential to becoming a new standard of care in this setting.
