SOHO State of the Art Updates and Next Questions: Targeted therapies and emerging novel treatment approaches for Waldenstrom Macroglobulinemia

Waldenstrom Macroglobulinemia (WM) is a rare hematologic malignancy characterized by the presence of lymphoplas-macytic lymphoma cells involving the bone marrow and production of a monoclonal IgM paraprotein. Recurrent somatic mutations in MYD88L265P and CXCR4 have been reported in 90% to 95% and 30% to 40% of patients with WM, respectively. Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (eg, bendamus-tine, cyclophosphamide), nucleoside analogs (eg, fludarabine, cladribine), or proteasome inhibitors (eg, bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (eg, tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (eg, pirtobrutinib, ARQ531), BCL-2 antagonists (eg, venetoclax), and CXCR4-targeted agents (eg, mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost. (C) 2022 The Authors. Published by Elsevier Inc.