How do I interpret Serum Protein Electrophoresis (SPEP), Serum Immunofixation Electrophoresis (SIFE), quantitative Immunoglobulin G (IgG), Immunoglobulin A (IgA), Immunoglobulin M (IgM), and Free Light Chain (FLC) lab results to diagnose a potential plasma cell dyscrasia or immunoglobulin-related disorder?

Interpreting SPEP, SIFE, Quantitative Immunoglobulins, and FLC for Plasma Cell Dyscrasia Diagnosis

Use a systematic algorithmic approach combining all five tests together—SPEP, SIFE, quantitative IgG/IgA/IgM, and serum free light chains with kappa/lambda ratio—because SPEP alone misses 15-20% of plasma cell disorders, particularly light chain-only disease. 1, 2

Step 1: Start with SPEP Pattern Recognition

• Look for an M-spike (monoclonal spike): A sharp, homogeneous peak typically in the gamma-globulin zone indicates clonal plasma cell proliferation producing a single immunoglobulin type 2
• Quantify the M-spike by densitometer tracing: Measure the concentration in g/dL to establish disease burden and track response 3, 2
• Recognize SPEP limitations immediately: If clinical suspicion remains high despite negative SPEP, proceed with full workup anyway because SPEP has only 71% sensitivity for detecting plasma cell disorders 1, 2
• Note beta-region migration: Some IgA monoclonal proteins (50% of cases) and occasional IgG proteins (10% of cases) migrate in the beta region rather than gamma, making them harder to identify 4

Step 2: Confirm and Type with SIFE

• Use SIFE to identify the exact immunoglobulin heavy chain type (IgG, IgA, IgM, IgD, or IgE) and light chain type (kappa or lambda): SIFE is more sensitive than SPEP alone and definitively characterizes the monoclonal protein 3, 1, 2
• SIFE detects monoclonal proteins that SPEP misses: Particularly important when M-spike is small or absent 5
• Look for immunoparesis: Suppression of uninvolved immunoglobulin classes on SIFE suggests more aggressive disease 3

Step 3: Measure Quantitative Immunoglobulins by Nephelometry

• Order total IgG, IgA, and IgM levels: These complement electrophoretic measurements and are particularly useful for IgA and IgD myeloma where nephelometric quantitation may be necessary 3
• Compare nephelometric values with SPEP M-spike quantification: Both methods are complementary, though nephelometry may overestimate monoclonal protein when values are high 3, 6
• Assess for immunoparesis: Low levels of uninvolved immunoglobulins (the other two classes) indicate immune suppression and suggest more advanced disease 3

Step 4: Analyze Serum Free Light Chains (FLC)

• Calculate the kappa/lambda ratio: Normal range is 0.26-1.65 in patients with normal renal function 2, 5
• Abnormal ratios indicate clonal light chain production: Ratio >1.65 suggests kappa-producing clone; ratio <0.26 suggests lambda-producing clone 5, 7
• FLC is essential for light chain-only myeloma: When SPEP shows no M-spike but clinical suspicion is high, FLC may be the only marker of disease 3, 5, 7
• Adjust interpretation for renal impairment: In severe renal dysfunction (creatinine >2 mg/dL), the normal kappa/lambda ratio shifts to 0.34-3.10 2
• FLC is more sensitive than SPEP for monitoring: The kappa/lambda ratio can detect residual disease when SPEP and SIFE are negative 7

Step 5: Integrate Results into Diagnostic Categories

Multiple Myeloma (Symptomatic)

• ≥10% clonal bone marrow plasma cells (requires bone marrow biopsy) 3, 6
• Presence of serum and/or urinary monoclonal protein (detected by SPEP/SIFE or FLC) 3, 6
• Evidence of CRAB criteria: Hypercalcemia (calcium ≥11.5 mg/dL), Renal insufficiency (creatinine ≥2 mg/dL), Anemia (hemoglobin ≥2 g/dL below normal or <10 g/dL), Bone lesions (lytic lesions on imaging) 3, 6

Smoldering Multiple Myeloma (Asymptomatic)

• Serum monoclonal protein ≥3 g/dL and/or ≥10% clonal bone marrow plasma cells 3, 6, 2
• Absence of CRAB criteria or other myeloma-defining events 3, 6

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Serum monoclonal protein <3 g/dL 3, 6, 2
• <10% clonal bone marrow plasma cells 3, 6
• Absence of CRAB criteria 3, 6

Light Chain Myeloma

• No M-spike on SPEP, negative or minimal findings on SIFE 7
• Abnormal FLC kappa/lambda ratio with elevated involved light chain 5, 7
• ≥10% bone marrow plasma cells and/or CRAB criteria present 3, 7

Waldenström's Macroglobulinemia

• IgM monoclonal protein on SPEP/SIFE 3
• Lymphoplasmacytoid cells in bone marrow 3
• Often presents with hyperviscosity symptoms 3

Step 6: Recognize Special Patterns and Pitfalls

• Oligosecretory or nonsecretory myeloma: When bone marrow shows ≥10% plasma cells with CRAB criteria but minimal or no M-protein, rely on FLC for diagnosis and monitoring 3
• Beta-migrating monoclonal proteins: Particularly common with IgA, may be missed if you only look in gamma region 4
• Biclonal gammopathies: Rare but possible; SIFE will show two distinct monoclonal bands 5
• Polyclonal hypergammaglobulinemia: Broad-based elevation in gamma region without sharp peak; seen in chronic inflammation, autoimmune disease, or chronic infection—not a plasma cell dyscrasia 2

Step 7: Mandatory Concurrent Testing

• Complete blood count with differential: Look for anemia, rouleaux formation on peripheral smear, circulating plasma cells 3, 1, 6
• Comprehensive metabolic panel: Assess calcium, creatinine, albumin, and liver function 3, 1
• Beta-2 microglobulin and LDH: For prognostic stratification 3, 1
• 24-hour urine collection with UPEP and urine immunofixation: Essential for detecting Bence Jones proteinuria in light chain disease 3

Step 8: Determine Urgency of Referral

• Urgent hematology/oncology referral (within 1-2 weeks): Any M-protein with CRAB criteria, significant M-spike (≥3 g/dL), bone pain, pathologic fractures, lytic lesions, or symptomatic hyperviscosity 1, 2
• Routine referral (within 4 weeks): MGUS or smoldering myeloma for risk stratification and surveillance planning 1

Critical Monitoring Principle

• Use the same method consistently for each patient during follow-up: If you start with SPEP M-spike quantification, continue with SPEP; if you start with nephelometry, continue with nephelometry; if you start with FLC, continue with FLC 3
• Never use SPEP alone to determine treatment response depth: Always include SIFE and FLC to properly classify complete response versus very good partial response per International Myeloma Working Group criteria 2