Zanubrutinib plus Ixazomib and Dexamethasone in Newly Diagnosed Symptomatic Waldenström Macroglobulinemia: A Phase II Study

PURPOSE: Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. Bruton's tyrosine kinase inhibitors have shown promising outcomes, yet achieving deep remission (very good partial remission or complete remission) remains challenging. and time-limited therapy with proteasome inhibition has not been reported. We conducted a phase II clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib, and dexamethasone (ZID) in patients with newly diagnosed WM. PATIENTS AND METHODS: A total of 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-day cycles, followed by consolidation therapy for a total of 24 cycles. The primary endpoint was the deep remission rate. RESULTS: Overall, 24 of the 27 enrolled patients completed induction treatment. One patient (4.2%) achieved complete remission. Ten patients (41.6%) achieved very good partial remission. The overall, major, and deep remission rates were 100%, 95.8%, and 45.8%, respectively. The median time to response was 2 months (range, 1-5). Five of the 22 patients had a CXCR4 mutation, with no disparity in deep remission between the patients with and without a CXCR4 mutation (40% vs. 50%; P = 0.594). The median abnormal lymphocyte (7.6% vs. 1.6%; P = 0.0019) and plasma cells (0.28%-0.02%; P = 0.0306) in bone marrow were significantly reduced after treatment. The median follow-up was 30.9 months (range, 15-42). The estimated median progression-free survival and overall survival were 40 months (95% confidence interval, 35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4 mutations. The most common adverse event was hematologic toxicity. CONCLUSIONS: The ZID regimen might offer deep remission and provide a time-limited Bruton's tyrosine kinase inhibitor therapy in patients with WM.