SOHO State-of-the-Art Updates and Next Questions: Current Approach to Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) or Immunoglobulin M (IgM) lymphoplasmacytic lymphoma is a heterogeneous clinicopathologic entity with distinguishing features that include circulating monoclonal IgM, lymphoplasmacytic marrow infiltrate, and in > 90% of patients, a recurrent clonal mutation, MYD88^L265. The clinical manifestations are highly variable. Symptomatic patients with indication(s) to start therapy are initially managed with either fixed-duration chemoimmunotherapy (for example, bendamustine-rituximab) or a covalent Bruton tyrosine kinase (BTK) inhibitor (for example, zanubrutinib) given until progression or intolerable toxicity, although these 2 highly different approaches have not been directly compared in randomized trials. MYD88^L265P, CXCR4, and TP53 mutational status may potentially impact treatment decision-making. Options for managing WM are expanding as several recent trials demonstrate the promising efficacy of BCL-2 inhibitors, noncovalent BTK inhibitors and BTK degraders in patients that are previously exposed, or refractory, to a covalent BTK inhibitor and/or chemoimmunotherapy. Preliminary data with novel approaches involving CAR-T cell and bispecific antibodies are continuing to be generated, and the reports, thus far, are encouraging.