Macroglobulinemia

Waldenström macroglobulinemia is the most common form of macroglobulinemia and represents a type of non-Hodgkin lymphoma. It is characterized by clonal lymphoplasmacytic cells accumulating in the bone marrow and the production of a monoclonal IgM protein, often accompanied by various systemic manifestations. The disease is usually slow-growing and most often diagnosed in middle-aged to older adults.

Pathophysiology commonly involves an IgM-secreting B-cell clone. A significant proportion of patients carry the MYD88 L265P mutation, with additional CXCR4 mutations in a subset. The IgM protein can cause hyperviscosity of the blood, contributing to many symptoms, while marrow infiltration can lead to anemia and cytopenias. Extramedullary involvement and cryoglobulinemia or cold agglutinin disease may occur.

Clinical features vary widely. Hyperviscosity can cause headaches, blurred vision, dizziness, mucosal bleeding, and neurologic disturbances. Patients may also experience fatigue, weight loss, fever, enlarged spleen or lymph nodes, and neuropathy. Autoimmune phenomena and cryoglobulinemia are possible. Symptom-driven treatment decisions are common.

Diagnosis relies on a combination of laboratory and tissue findings. Serum protein electrophoresis and immunofixation reveal IgM monoclonal protein, with elevated IgM levels on quantitative testing. Bone marrow examination shows lymphoplasmacytic infiltration. Flow cytometry and molecular testing for MYD88 and CXCR4 mutations support the diagnosis and help guide therapy. It is important to distinguish WM from other IgM-related disorders and other lymphomas.

Treatment is indicated for symptoms or complications such as hyperviscosity. Plasmapheresis can rapidly reduce IgM levels in hyperviscosity. Systemic therapy typically includes rituximab-based regimens (for example, bendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide), proteasome inhibitors, and Bruton’s tyrosine kinase inhibitors (such as ibrutinib or zanubrutinib). Autologous stem cell transplant may be considered in select cases. The disease is monitored with clinical assessment, IgM levels, blood counts, and imaging as needed. Prognosis varies with disease features and response to therapy, and advances in targeted therapies have improved outcomes.