What is the appropriate diagnostic workup for a patient with a monoclonal IgM paraprotein?

Diagnostic Workup for IgM Monoclonal Gammopathy

The initial workup for an IgM monoclonal paraprotein requires serum protein electrophoresis with immunofixation, serum free light chain assay, 24-hour urine protein electrophoresis with immunofixation, complete blood count, comprehensive metabolic panel, and bone marrow biopsy with immunophenotyping to distinguish between IgM MGUS, Waldenström's macroglobulinemia, and other lymphoproliferative disorders. 1

Initial Laboratory Testing

The diagnostic approach differs from IgG/IgA paraproteins because IgM is specifically associated with lymphoplasmacytic disorders rather than multiple myeloma:

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize the monoclonal IgM protein 1, 2
• Serum free light chain (FLC) assay with κ/λ ratio to assess clonality and detect light chain disease 2, 3
• Nephelometric quantification of IgG, IgA, and IgM to measure total IgM levels, as values >60 g/L indicate imminent hyperviscosity risk 1, 3
• 24-hour urine collection with protein electrophoresis and immunofixation to detect urinary monoclonal proteins 2, 3

Essential Blood Work

• Complete blood count with differential to assess for anemia, which is a common treatment indication 1, 3
• Serum calcium and creatinine to evaluate for end-organ damage 3
• Beta-2 microglobulin and albumin for prognostic stratification 1
• Lactate dehydrogenase (LDH) for prognostic information 1

Specialized Testing for IgM-Specific Complications

IgM paraproteins cause unique clinical problems due to their large pentameric structure:

• Serum viscosity measurement if IgM >30 g/L or symptoms of hyperviscosity (headache, blurred vision, bleeding) are present 1
• Fundoscopic examination to detect retinal vein "sausaging," which is the most reliable clinical indicator of hyperviscosity 1
• Coombs test and cold agglutinin testing to assess for IgM-associated hemolysis 1
• Cryoglobulin testing as cryoglobulins can affect IgM measurement accuracy 1
• Coagulation parameters to evaluate for IgM-associated coagulopathy 1

Neuropathy Evaluation (If Present)

• Anti-myelin-associated glycoprotein (anti-MAG) antibodies 1
• Anti-ganglioside M1 and anti-sulfatide IgM antibodies to support diagnosis of IgM-related neuropathy 1

Bone Marrow Examination

Bone marrow aspirate and trephine biopsy are mandatory for all IgM paraproteins to establish the diagnosis and distinguish between entities 1:

• Morphologic assessment for lymphoplasmacytic cell infiltration pattern 1
• Immunophenotyping by flow cytometry and/or immunohistochemistry showing CD19, CD20, CD22, and CD79a expression to confirm lymphoplasmacytic lymphoma 1
• Immunofluorescence microscopy to detect dispersed monotypic B-lineage populations that may not be apparent on routine morphology 4
• MYD88 L265P mutation testing is strongly recommended as this mutation is present in >90% of Waldenström's macroglobulinemia cases and helps distinguish it from IgM myeloma, marginal zone lymphoma, and MALT lymphoma 1, 5

A critical pitfall: 13 of 16 patients with IgM paraproteins and morphologically "normal" bone marrow biopsies were found to have monoclonal B-lineage populations when immunophenotyping was performed, emphasizing that immunophenotypic studies are not optional 4.

Imaging Studies

• CT or MRI of chest, abdomen, and pelvis to document organomegaly and lymphadenopathy 1
• PET scanning is not routinely indicated unless transformation to aggressive lymphoma is suspected, in which case biopsy of the most FDG-avid lesion should be performed 1
• Skeletal survey is not indicated for IgM paraproteins as lytic bone lesions are characteristic of myeloma, not lymphoplasmacytic disorders 1

Renal-Specific Workup (If Renal Dysfunction Present)

When creatinine is elevated or proteinuria is present:

• Urinalysis with albumin:creatinine ratio and protein:creatinine ratio 1
• Serum bicarbonate, chloride, phosphate, and uric acid to assess for Fanconi syndrome 1
• Kidney biopsy with immunofixation studies for light chains (κ and λ), heavy chains (IgG, IgM, IgA), and complement (C1q, C3) if albumin:creatinine ratio >30 mg/mmol or eGFR <60 mL/min/1.73m² 1
• Congo red staining of bone marrow and fat aspirate to evaluate for AL or AA amyloidosis 1
• Cardiac biomarkers (NT-proBNP, troponins) and echocardiography if amyloidosis is suspected 1

Diagnostic Classification

The bone marrow findings determine the diagnosis:

• IgM MGUS: IgM monoclonal protein (any level per European criteria, or <30 g/L per Mayo criteria), <10% bone marrow lymphoplasmacytic cells, no symptoms 1
• Waldenström's macroglobulinemia: IgM monoclonal protein + bone marrow infiltration by lymphoplasmacytic lymphoma (≥10% lymphoplasmacytic cells with CD19+/CD20+ immunophenotype) 1
• IgM myeloma: Rare entity with lytic bone lesions and >10% clonal plasma cells (not lymphoplasmacytic cells); MYD88 L265P typically negative 5

Critical Methodologic Considerations

• Sequential IgM measurements must use the same methodology (densitometry vs. nephelometry) in the same laboratory, as nephelometry systematically gives higher values than densitometry 1
• Immunofixation is more sensitive than SPEP alone for detecting small monoclonal proteins 2, 6
• Serum free light chain testing alone is insufficient for IgM paraproteins and should not replace comprehensive evaluation 1