Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinaemia (WM) is a lymphoplasmacytic lymphoma with bone marrow infiltration and monoclonal IgM.

• Rare (3 per million), median age 70, male predominance.

• MYD88 L265P in 90% and CXCR4 mutations in 30 to 40%.

• IgM related complications: hyperviscosity, cryoglobulinaemia, cold agglutinin disease, peripheral neuropathy (anti-MAG), amyloidosis, Bing-Neel syndrome (CNS infiltration).

• Smouldering WM: asymptomatic with IgM over 3 g/dL.

• Fatigue, anaemia, weight loss, bleeding (nose, gums), visual disturbance, headache, dizziness (hyperviscosity).

• Lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, Raynaud, renal involvement.

• Retinal haemorrhages and sausage vein dilation.

• Serum protein electrophoresis with IgM monoclonal protein, immunofixation, serum viscosity.

• Marrow biopsy: lymphoplasmacytic infiltrate (CD19, CD20, CD79a positive, CD138 variable), MYD88 and CXCR4 testing.

• Blood count, LDH, beta-2 microglobulin, cryoglobulins, cold agglutinin, anti-MAG, CT for nodes and spleen.

• Exclude IgM MGUS, CLL, marginal zone lymphoma, myeloma.

• Observation for asymptomatic disease.

• Hyperviscosity syndrome: urgent plasmapheresis (1 to 1.5 plasma volumes daily until symptoms resolve), avoid transfusion before plasmapheresis and rituximab (IgM flare).

• Treatment indications: cytopenias, symptomatic hyperviscosity, bulky disease, neuropathy, amyloid.

• First line options: BTK inhibitors (zanubrutinib 160 mg twice daily, ibrutinib 420 mg daily) continuous; bendamustine 90 mg/m2 on days 1 and 2 with rituximab 375 mg/m2 for 6 cycles; DRC (dexamethasone, rituximab, cyclophosphamide); bortezomib-rituximab (neuropathy caution).

• Delay rituximab until IgM below 4000 mg/dL or cover with plasmapheresis (IgM flare).

• Relapse: BTK inhibitor, venetoclax, proteasome inhibitor, autologous transplant, CAR-T trials.

• Bing-Neel syndrome: BTK inhibitor with CNS penetration, high dose methotrexate.

• Supportive: IVIG, vaccination, antiviral prophylaxis, plasmapheresis for cryoglobulinaemia.