PURPOSE: Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. BTK inhibitor have shown promising outcomes, yet achieving deep remission (VGPR or CR) remains challenging and time-limited therapy with proteasome-inhibition has not been reported. We conducted a phase 2 clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib and dexamethasone (ZID) in newly diagnosed WM patients.

PATIENTS AND METHODS: 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-days' cycles, followed by consolidation therapy up to total 24 cycles. The primary endpoint was the deep remission rate.

RESULTS: Overall, 24 of 27 enrolled patients completed induction treatment. One patient (4.2%) achieved CR. 10 patients (41.6%) achieved VGPR. 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 22 patients had CXCR4 mutation, with no disparity in the deep remission between the patients with/without 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% to 0.02%, P =0.0306) in bone marrow were significantly reduced after treatment. With a median follow-up of 30.9 months (range, 15-42). The estimated median PFS and OS were 40 months (95% CI:35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4mutations. The most common AE was hematological toxicity.

CONCLUSION: ZID regimen might offer deep remission and provided a time-limited BTKi therarpy in WM patients<SPAN style="font-weight: 400;">. </SPAN>.