Waldenström Macroglobulinemia: 2025 Update on Diagnosis, Risk Stratification, and Management

DISEASE OVERVIEW: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: The presence of IgM monoclonal protein associated with ≥ 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis. RISK STRATIFICATION: microglobulin, Lactate dehydrogenase (LDH), and monoclonal IgM concentrations are characteristics that are predictive of outcomes. RISK-ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to combination regimens. Recommended first-line therapy can be chemoimmunotherapy or a covalent Bruton tyrosine kinase inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, pirtobrutinib, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection. Most patients succumb to causes unrelated to macroglobulinemia.