Waldenstrom macroglobulinaemia

WM is lymphoplasmacytic lymphoma involving marrow with an IgM paraprotein. Presentation includes fatigue from anaemia, nodes, splenic fullness, infection or B symptoms, but much morbidity is caused by IgM: hyperviscosity, cold agglutinin haemolysis, cryoglobulinaemia, neuropathy, renal disease and occasional amyloid. Examine nodes, spleen, retina, neurological system, perfusion and bleeding. The IgM concentration correlates imperfectly with viscosity and symptoms; compare each patient with their own baseline and act clinically.

Confirm with marrow aspirate and trephine showing small lymphocytes, plasmacytoid lymphocytes and plasma cells with a clonal B-cell and plasma-cell phenotype. MYD88 L265P is present in most WM and supports classification but is not absolutely specific; wild-type disease needs particularly careful review. CXCR4 mutations can associate with higher IgM and slower BTK-inhibitor response. Exclude IgM myeloma with plasma-cell phenotype, lytic disease and t(11;14), and distinguish marginal-zone lymphoma using splenic, nodal and pathological features.

Baseline tests include FBC, film, renal, liver, calcium, LDH, beta-2 microglobulin, quantitative IgM, SPEP, immunofixation, free light chains and immunoglobulins. Test viscosity and examine fundi when symptoms or high IgM raise concern; viscosity measurement must not delay exchange. Use haemolysis, direct antiglobulin, cold agglutinin, cryoglobulin with warm sample handling, neuropathy and anti-MAG tests when indicated. CT stages nodes and spleen; PET is more useful when transformation is suspected.

Observation is first-line for asymptomatic disease regardless of IgM number. Treat symptomatic haemoglobin or platelet compromise, constitutional or bulky disease, hyperviscosity, symptomatic cryoglobulinaemia, cold agglutinin disease, neuropathy, renal disease or amyloid attributable to the clone. Confirm that nonspecific fatigue or neuropathy is actually disease mediated. Use prognostic scores to inform discussion, not as treatment triggers. A slow, low-burden presentation may need a less intensive regimen than rapidly progressive marrow or organ disease.

Symptomatic hyperviscosity needs urgent plasma exchange, generally 1–1.5 calculated plasma volumes with albumin replacement according to the apheresis protocol. One exchange can markedly reduce intravascular IgM, but tissue-to-plasma equilibration and continued production cause rebound. Repeat according to symptoms, fundi, IgM and viscosity while systemic treatment begins. Avoid routine red-cell transfusion until viscosity falls; if severe anaemia threatens oxygen delivery, coordinate small, necessary replacement with exchange and senior assessment.

Systemic selection is individual. Bendamustine–rituximab gives durable disease control but prolonged lymphocyte suppression. Dexamethasone–rituximab–cyclophosphamide is gentler but response may be slower. Zanubrutinib is a continuous BTK inhibitor active across many patients, with response influenced by MYD88 and CXCR4; bleeding, hypertension, atrial arrhythmia, infection and CYP3A interactions matter. Avoid rituximab monotherapy when high IgM creates flare risk. Proteasome-based treatment can act quickly but neuropathy influences choice.

At response, follow symptoms, examination, FBC and IgM trend rather than expecting complete paraprotein disappearance. A biochemical IgM rise alone does not require treatment unless clinical progression follows, but rapid change prompts reassessment. At relapse review remission duration, prior toxicity, mutation context and whether new symptoms are IgM or tumour mediated. Transformation requires biopsy. Support vaccination, infection prevention, neuropathy and cold avoidance and screen for hepatitis B before anti-CD20 therapy.