What is the appropriate management for a patient with Waldenström's macroglobulinemia (WM) and a high Immunoglobulin G (IgG) result in Serum Protein Electrophoresis (SPEP)?

Management of High IgG in Waldenström's Macroglobulinemia

A high IgG result on SPEP in a patient with Waldenström's macroglobulinemia requires verification that the diagnosis is correct, as WM is defined by monoclonal IgM—not IgG—and the finding of elevated IgG suggests either a diagnostic error or a concurrent condition. 1

Diagnostic Verification

WM diagnosis requires both:

• Bone marrow infiltration by monoclonal lymphoplasmacytic cells 1
• Serum monoclonal IgM of any amount confirmed by immunofixation 1

If SPEP shows high IgG instead of IgM, consider:

• Misdiagnosis: The patient may have IgG multiple myeloma or another lymphoproliferative disorder rather than WM 1
• Concurrent IgG paraprotein: Rare cases may have both IgM (from WM) and a separate IgG monoclonal protein 1
• Polyclonal IgG elevation: This can occur as a reactive process and is not the disease-defining paraprotein 1

Essential Workup

Immediately obtain:

• Serum protein electrophoresis with immunofixation to identify the specific immunoglobulin type and confirm monoclonality 1
• Quantification of IgM, IgG, and IgA levels by nephelometry 1
• Review bone marrow biopsy for lymphoplasmacytic infiltration with CD19, CD20, CD22, and CD79a positivity 1
• MYD88 L265P mutation testing (present in ~90% of WM cases; its absence raises diagnostic doubt) 1, 2, 3

Management Algorithm Based on Findings

If IgM is Actually Elevated (IgG is Incidental)

Asymptomatic patients should not be treated but followed every 3-6 months 1

Treatment indications include: 1

• B symptoms (fever, night sweats, weight loss)
• Severe cytopenias
• Hyperviscosity syndrome
• Moderate or severe neuropathy
• Symptomatic organomegaly
• Amyloidosis
• Symptomatic cryoglobulinemia or cold agglutinin disease

First-line therapy options for symptomatic WM: 1, 2, 3

• Bendamustine/rituximab (BR) for bulky disease requiring expeditious control 1
• Bortezomib/dexamethasone/rituximab (BDR) or bortezomib/rituximab (VR) for very high IgM levels or hyperviscosity 1
• Zanubrutinib or ibrutinib as preferred BTK inhibitor options 4, 5, 2, 3
• Dexamethasone/rituximab/cyclophosphamide (DRC) when disease burden is low 1

Plasmapheresis should be used concomitantly with systemic therapy for hyperviscosity or pre-emptively in patients with very high IgM levels at risk for IgM-related complications 1

If IgG is the Predominant Paraprotein (Not IgM)

This is NOT Waldenström's macroglobulinemia 1

Reconsider diagnosis:

• IgG multiple myeloma if plasma cell infiltration with lytic lesions, hypercalcemia, or renal dysfunction 1
• Other lymphoproliferative disorders (marginal zone lymphoma, CLL) if lymphocytic infiltration without IgM 1
• Refer to appropriate disease-specific guidelines for management

Critical Pitfalls to Avoid

Do not treat based on IgM level alone without symptoms or disease-related complications 1

Avoid rituximab monotherapy in patients with hyperviscosity or very high serum IgM without pre-emptive plasmapheresis, as it can cause IgM flare 1

Do not use rituximab maintenance therapy outside clinical trials 1

Ensure fundoscopic examination for venous engorgement ("sausaging") in patients with suspected hyperviscosity, as serum viscosity measurements correlate poorly with clinical severity 1

Evaluate for neuropathy with anti-MAG antibodies (present in 50% of WM patients with neuropathy) and consider neurology consultation, as neuropathy may not always be WM-related 1