Novel agents and evolving strategies in Waldenström macroglobulinemia: clinical trial updates from ASH 2025

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoplasmacytic lymphoma characterized by bone marrow infiltration of IgM-secreting lymphoplasmacytic cells and associated with the MYD88(L265P) mutation in over 90% of cases. This mutation drives constitutive NF-κB signaling through aberrant MYD88 oligomerization, rendering WM dependent on BCR-proximal kinases including BTK for survival. Despite significant therapeutic advances over the past decade, including the established efficacy of BTK inhibitors, proteasome inhibitors, and anti-CD20 monoclonal antibodies in both frontline and relapsed settings, unmet needs persist-particularly regarding treatment durability, acquired resistance to covalent BTK inhibitors via C481S mutations, and the need for chemotherapy-free alternatives. The 2025 American Society of Hematology (ASH) Annual Meeting featured several pivotal clinical trials addressing these challenges, spanning optimized immunochemotherapy combinations in treatment-naive disease, next-generation BTK-targeted agents for relapsed/refractory cases including non-covalent inhibitors that bypass C481S-mediated resistance and protein degraders that eliminate both BTK kinase activity and scaffolding function, and emerging modalities including BCL2 inhibitors that exploit the apoptotic dependence of WM cells on BCL2 family proteins, MALT1 inhibitors that target downstream NF-κB signaling, and CD19-targeted antibody-drug conjugates and cellular therapies.