• Paul G Richardson, Craig C Hofmeister, Cara A Rosenbaum, Myo Htut, David H Vesole, Jesus G Berdeja, Michaela Liedtke, Ajai Chari, Stephen D Smith, Daniel Lebovic, Noopur Raje, Catriona Byrne, Eileen Liao, Neeraj Gupta, BaccoAlessandra DiADMillennium Pharmaceuticals Inc., Cambridge, MA, USA., Jose Estevam, Deborah Berg, and Rachid Baz.
• Dana-Farber Cancer Institute, Boston, MA, USA.
• Br. J. Haematol. 2018 Jul 1; 182 (2): 231-244.

AbstractWeekly ixazomib with lenalidomide-dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice-weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice-weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9-16) for up to sixteen 21-day cycles, followed by maintenance with twice-weekly ixazomib alone. No dose-limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression-free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug-related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug-related AEs. Thirteen patients discontinued due to AEs. Twice-weekly ixazomib-Rd offers substantial activity with promising long-term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib-Rd in this setting.© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd and British Society for Haematology.

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