What is Waldenström macroglobulinemia?

Waldenström Macroglobulinemia: Definition and Key Features

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative disorder defined by bone marrow infiltration with lymphoplasmacytic cells producing monoclonal IgM protein. 1

Epidemiology and Demographics

• WM accounts for 1-2% of all hematological malignancies, with an age-adjusted incidence of 3.4 per million males and 1.7 per million females in the United States 1
• The disease predominantly affects elderly patients, with median age at diagnosis of 63-75 years and male predominance 1
• Strong familial clustering exists, with first-degree relatives having up to 20-fold increased risk for developing WM 1
• WM is more common in Caucasians than African-Americans (incidence rate ratio: 1.75) 1

Diagnostic Criteria: Two Essential Components Required

Both criteria must be present for WM diagnosis:

1. Histopathological Confirmation

• Bone marrow biopsy demonstrating infiltration by lymphoplasmacytic cells/lymphoplasmacytic lymphoma (LPL) 1, 2
• Immunophenotyping showing CD19+, CD20+, CD22+, and CD79a+ expression 1, 2
• At least 10% clonal lymphoplasmacytic cells in bone marrow 2

2. Monoclonal IgM Protein Detection

• Any amount of monoclonal IgM protein confirmed by immunofixation 1, 2
• IgM distinguishes WM from multiple myeloma, which typically presents with IgG or IgA paraproteins 2

Critical Diagnostic Pitfall

Monoclonal IgM alone without bone marrow LPL does NOT constitute WM diagnosis 1. This scenario could represent:

• IgM monoclonal gammopathy of undetermined significance (MGUS)
• Nodal LPL without bone marrow involvement
• Other lymphoproliferative disorders

Conversely, LPL without monoclonal IgM does not fulfill WM criteria 1.

Molecular Signature

• Approximately 90% of WM patients harbor the MYD88 L265P mutation, which serves as a critical diagnostic tool to differentiate WM from multiple myeloma (where this mutation is rare) 1, 2
• The MYD88 L265P mutation alone is NOT diagnostic of WM, as it also occurs in 50-80% of IgM MGUS cases and other lymphomas such as marginal zone lymphoma 1
• 5-10% of WM patients lack the MYD88 L265P mutation and may have other MYD88 variants or wild-type MYD88 1

Clinical Manifestations

Symptoms arise from two mechanisms:

Tumor Burden Effects

• Constitutional symptoms (fever, night sweats, weight loss, fatigue) 1
• Lymphadenopathy (symptomatic or bulky ≥5 cm) 1
• Hepatosplenomegaly 1
• Cytopenias from bone marrow infiltration 3

IgM-Related Complications

• Hyperviscosity syndrome (most characteristic complication) 3, 4
• Peripheral neuropathy 1, 3
• Cold agglutinin disease (up to 10% of patients) 2
• Cryoglobulinemia (up to 20% of patients) 2
• Coagulopathy 1

Asymptomatic Disease

• At least 25% of patients are asymptomatic at presentation 5
• 50% of asymptomatic patients will not require therapy for almost 3 years, and 10% remain treatment-free for 10 years 5
• Asymptomatic patients should NOT be treated based solely on laboratory abnormalities 5

Prognosis

• Median disease-specific survival is 10-11 years 5
• 5-year survival rates by International Prognostic Scoring System for WM (IPSSWM):
  • Low risk (0-1 adverse factors): 87% 5
  • Intermediate risk (2 factors): 68% 5
  • High risk (≥3 factors): 36% 5

Adverse prognostic factors include: age >65 years, hemoglobin <11.5 g/dL, platelets <100×10⁹/L, β2-microglobulin >3 mg/L, and serum monoclonal protein >70 g/L 5.

Treatment Indications

Therapy should be initiated ONLY when symptomatic disease develops 1:

• Recurrent constitutional symptoms
• Hyperviscosity syndrome
• Symptomatic or bulky lymphadenopathy (≥5 cm)
• Symptomatic hepatosplenomegaly
• Symptomatic organomegaly or tissue infiltration
• Peripheral neuropathy due to WM
• Disease-related cytopenias

The IgM level alone should NOT determine treatment urgency, as it does not correlate with tumor burden or survival 5.