Prospective clinical trial of ixazomib, dexamethasone and rituximab as primary therapy in Waldenström macroglobulinemia

Introduction: Proteasome inhibition is of proven efficacy in patients with Waldenström macroglobulinemia (WM). However, WM remains incurable with standard treatments. Novel agents, safe and effective, are needed. Methods: We designed a prospective phase II study evaluating the combination of ixazomib, dexamethasone and rituximab (IDR) as primary therapy in symptomatic patients with WM. Protocol therapy consisted of oral ixazomib, 4 mg, with intravenous or oral dexamethasone, 20 mg, on days 1, 8 and 15 every 4 weeks for induction cycles 1 and 2, and in combination with intravenous rituximab, 375 mg/m2, on day 1, every 4 weeks for cycles 3 to 6. Maintenance therapy followed 8 weeks later with IDR given every 8 weeks for 6 cycles. Results: Twenty-six patients were enrolled. All patients had the MYD88 L265P mutation, and 15 patients (58%) had a CXCR4 mutation. The median time to response was 8 weeks, which was longer (12 weeks) in WM patients with CXCR4 mutations (p=0.03). The overall response rate was 96% and the major response rate was 77%. With a median follow-up of 22 months, the median progression-free survival was not reached. Grade ≥2 adverse events reported in >1 patient included infusion-related reactions (19%), rash (8%) and insomnia (8%). Conclusion: IDR offers a highly effective and well tolerated, neuropathy-sparing regimen for primary therapy in patients with WM. This trial is registered at www.clinicaltrials.gov under ID NCT02400437.

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