Pomalidomide in combination with dexamethasone is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM); however, its progression-free survival prolongation is suboptimal in a lenalidomide- and bortezomib-refractory patient population. Ixazomib is a novel, oral proteasome inhibitor that has demonstrated single-agent activity as a single agent in RRMM and in combination with lenalidomide/dexamethasone in newly diagnosed patients. The phase 1/2 Alliance study A061202 sought to evaluate the safety and preliminary efficacy of the combination of ixazomib, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone in patients with double-refractory multiple myeloma; Voorhees and colleagues reported on the phase 1 results of the study.1 In phase 1 of the study, using a 3+3 dose-escalation design, patients received pomalidomide (2?4 mg; days 1-21) plus ixazomib (3-4 mg; days 1, 8, and 15) and dexamethasone (40 mg; days 1, 8, 15, and 22) of a 28-day cycle on 4 dose cohorts. Of the 22 evaluable patients, all had received prior lenalidomide, bortezomib, and dexamethasone and 32% had received prior carfilzomib. Two dose-limiting toxicities of febrile neutropenia were reported, 1 each at dose levels 3 and 4. Grade 3/4 adverse events were hematologic, and included neutropenia, thrombocytopenia, anemia, thrombocytopenia, and lymphopenia; grade 3 infection was reported in 12% of patients. Treatment-related peripheral neuropathy occurred in 8 patients, and was ?grade 2 in severity. Dose reductions in at least 1 of the 3 drugs were reported in 50% of patients, whereas 50% experienced dose delays. To date, 2 patients have discontinued therapy due to adverse events; 1 due to grade 2 peripheral neuropathy and 1 due to grade 4 neutropenia. Of the 20 evaluable patients, the best overall response rate was 55%, including partial responses in 50% and very good partial response in 5%. Overall, these study results show encouraging preliminary efficacy with the combination of ixazomib, pomalidomide, and dexamethasone that is associated with an acceptable toxicity profile.
