How do I interpret Serum Protein Electrophoresis (SPEP) results in a patient with a history of plasma cell disorders, such as multiple myeloma?

How to Interpret Serum Protein Electrophoresis (SPEP) in Plasma Cell Disorders

Understanding the SPEP Pattern

SPEP is a fundamental screening test that separates serum proteins into distinct zones (albumin, alpha-1, alpha-2, beta, and gamma regions) and identifies monoclonal proteins as a homogeneous spike-like peak, typically in the gamma-globulin zone. 1

Normal vs. Abnormal Patterns

• Monoclonal spike (M-spike): A sharp, narrow peak indicates clonal plasma cell proliferation producing a single type of immunoglobulin, suggesting multiple myeloma, Waldenström's macroglobulinemia, or MGUS 1
• Polyclonal increase: A broad-based elevation in the gamma region represents increased production of multiple immunoglobulin types from many different plasma cell clones, commonly seen in chronic inflammation, autoimmune disorders, or chronic infections 2
• Hypogammaglobulinemia: Decreased gamma region may indicate immunodeficiency or immune suppression 3

Critical Limitations of SPEP Alone

SPEP misses approximately 15-20% of plasma cell disorders, particularly light chain-only disease, making it insufficient as a standalone diagnostic test. 1

Specific Pitfalls to Avoid

• Light chain-only myeloma: Produces only free light chains (not complete antibodies), creating no visible spike on standard SPEP 1
• Non-secretory myeloma: Approximately 3% of cases produce no detectable M-protein on SPEP or urine studies 1, 4
• Small M-proteins: SPEP may miss small monoclonal proteins that immunofixation can detect—IFE identifies 17% of monoclonal gammopathies that SPEP misses 1
• Biclonal gammopathy: Rarely, two M-bands may appear, requiring immunofixation to distinguish true biclonality from a single clone producing protein in different regions 5

Mandatory Follow-Up Testing Algorithm

When SPEP shows an M-spike or clinical suspicion remains high despite negative SPEP, you must order a complete diagnostic panel—never rely on SPEP alone. 3, 1

Essential Complementary Tests

1. Serum immunofixation electrophoresis (SIFE): Identifies the exact immunoglobulin type (IgG, IgA, IgM) and light chain (kappa or lambda); more sensitive than SPEP and mandatory even when SPEP is negative if clinical suspicion exists 3, 1, 4

2. Serum free light chain (FLC) assay with kappa/lambda ratio:

   • Normal ratio: 0.26-1.65 (rises to 0.34-3.10 in severe renal impairment) 4
   • High ratio indicates kappa clone; low ratio indicates lambda clone 4
   • Critical: SPEP plus FLC achieves 100% sensitivity for detecting plasma cell disorders 1
   • Can eliminate need for 24-hour urine collection in initial screening 1

3. Quantitative immunoglobulin levels (IgG, IgA, IgM): Assess specific monoclonal immunoglobulin and check for immune paresis 3, 1

4. 24-hour urine collection: For urine protein electrophoresis (UPEP) and urine immunofixation (UIFE) to detect Bence Jones proteinuria 3, 4

5. Bone marrow biopsy: Required when ≥10% clonal plasma cells confirm multiple myeloma diagnosis 3, 4

Quantifying Disease Burden

Measure M-protein concentration by densitometer tracing of the M-spike on SPEP—this value tracks disease progression and treatment response. 3

Diagnostic Thresholds

• MGUS: M-protein <30 g/L (or <3 g/dL), bone marrow plasma cells <10%, no end-organ damage 3, 1
• Smoldering myeloma: M-protein ≥30 g/L (or ≥3 g/dL) and/or bone marrow plasma cells ≥10%, no end-organ damage 3
• Symptomatic myeloma: M-protein present (any level), bone marrow plasma cells ≥10%, plus CRAB criteria (hypercalcemia >11.5 mg/dL, renal insufficiency creatinine >2 mg/dL, anemia Hb <10 g/dL, bone lesions) 3

Monitoring Treatment Response

Track M-protein concentration changes over time using SPEP as the primary method for determining treatment efficacy, but never use SPEP alone to categorize response depth. 1

Response Assessment Protocol

• Perform after each cycle initially, then every other cycle once response trend observed, less frequently in plateau phase 1
• Significant M-protein reduction indicates partial response (PR) or very good partial response (VGPR) 1
• Must include: SIFE, quantitative immunoglobulins, and FLC assay to properly classify response depth per International Myeloma Working Group criteria 1

Watch for Light Chain Escape

• 15-20% of cases develop "light chain escape" where disease evolves to produce only light chains 1
• Standard SPEP may not adequately capture this phenomenon 1
• Always monitor serum FLC levels alongside SPEP to detect this evolution 1

Special Considerations for Renal Impairment

• Renal dysfunction affects FLC concentration and interpretation 4
• Normal kappa/lambda ratio shifts from 0.26-1.65 to 0.34-3.10 in severe renal impairment 4
• Adjust interpretation accordingly when creatinine >2 mg/dL 4

When to Refer Urgently

Any detected monoclonal protein on SPEP requires hematology/oncology referral, with urgent referral (within 1-2 weeks) for patients with significant M-protein spike, accompanying symptoms, anemia, renal dysfunction, or hypercalcemia. 1

Red Flags Requiring Immediate Action

• M-protein with bone pain, pathologic fractures, or lytic lesions 3
• M-protein with unexplained anemia (Hb <10 g/dL) 3
• M-protein with renal insufficiency (creatinine >2 mg/dL) 3
• M-protein with hypercalcemia (>11.5 mg/dL) 3

Assay Consistency in Monitoring

Use the same FLC assay throughout patient monitoring—different assays (N Latex vs. FreeLite) are not mathematically convertible. 4