Waldenström macroglobulinemia

Definition

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow infiltration and production of a monoclonal IgM paraprotein. Clinically, the disease resembles an indolent lymphoma more than multiple myeloma; osteolytic lesions are usually absent. After myeloma, it is the second most common malignant disorder associated with a monoclonal gammopathy.

Occurrence & epidemiology

The disease is uncommon. The median age at diagnosis is about 70 years; men are affected more often than women.

Aetiopathogenesis

The cause is unknown. The hallmark mutation is MYD88 L265P in more than 90 % of lymphoplasmacytic lymphomas; CXCR4 mutations are found in up to about 40 %. IgM MGUS frequently precedes the disease. The large IgM pentamer increases plasma viscosity; some IgM paraproteins act as rheumatoid factors or cold agglutinins, and about 10 % are cryoglobulins. Amyloidosis occurs in about 5 %.

Clinical features

• Many patients are asymptomatic; diagnosis is often an incidental finding of IgM gammopathy.
• Anemia with fatigue and weakness.
• Hyperviscosity syndrome: fatigue, skin and mucosal bleeding, visual disturbances, headache, peripheral neuropathy, and changing neurologic deficits; increased plasma volume may precipitate heart failure.
• Fundus: sausage-like engorged, segmentally narrowed retinal veins; later retinal hemorrhages, exudates, microaneurysms, and papilledema.
• Lymphadenopathy, hepatosplenomegaly, purpura.
• Cold sensitivity, Raynaud syndrome, recurrent bacterial infections.

Diagnosis

• Protein studies: serum electrophoresis showing an M-protein, immunofixation (IgM; in urine often monoclonal light chains, mostly kappa), quantitative immunoglobulins (normal immunoglobulins reduced in half of patients), free light chains.
• Blood count: moderate normocytic, normochromic anemia, marked rouleaux formation, very high ESR; occasionally leukopenia, relative lymphocytosis, thrombocytopenia.
• Cryoglobulins, rheumatoid factor, cold agglutinins, direct Coombs test, coagulation studies; cold agglutinins and cryoglobulins may distort routine values.
• Plasma viscosity: with hyperviscosity usually > 4.0 mPa·s (normal 1.4–1.8); additionally retinal fluorescein angiography.
• Bone marrow examination: increase in plasma cells, lymphocytes, plasmacytoid lymphocytes, and mast cells; detection of MYD88 and CXCR4 mutations. Lymph node biopsy if the bone marrow is unremarkable.

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Further reading (open access)

1. MSD Manual Professional: Macroglobulinemia
2. Alaggio et al., Leukemia 2022: WHO-Klassifikation (5. Aufl.), lymphatische Neoplasien (PMC-Volltext)
3. Clin Exp Med 2026: Monoclonal gammopathies, MGUS, SMM and multiple myeloma (PMC-Volltext)

Cross-references