Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after six patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I/II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days to 4.1 years), median progression-free survival of 4.4 months (95% confidence interval [CI]: 3.0–18.4), and median overall survival of 34.3 months (95% CI: 19.2 to not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side-effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM.
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