When should serum protein electrophoresis be considered in adults with suspected plasma cell disorders or abnormal protein levels?

When to Order Serum Protein Electrophoresis

Order serum protein electrophoresis (SPEP) in adults over 50 presenting with unexplained anemia, bone pain, lytic bone lesions, hypercalcemia, renal insufficiency, or recurrent infections—but never order SPEP alone, as it must always be accompanied by serum immunofixation electrophoresis (SIFE) and serum free light chain (FLC) assay to achieve adequate diagnostic sensitivity. 1, 2

Primary Clinical Indications for SPEP

Red Flag Symptoms (CRAB Criteria)

Order SPEP when patients present with any of the following: 1

• Hypercalcemia (elevated serum calcium)
• Renal insufficiency (elevated creatinine or BUN)
• Anemia (unexplained low hemoglobin)
• Bone lesions (lytic lesions on imaging or pathologic fractures)

Additional High-Yield Scenarios

• Unexplained elevation of total serum protein or globulin fraction on routine chemistry panels 1
• Polyneuropathy of unknown etiology, where monoclonal gammopathies have 10% prevalence compared to the general population 2
• Recurrent bacterial infections suggesting immune dysfunction 1
• Unexplained bone pain or pathologic fractures 1

Critical Testing Algorithm: Never Order SPEP Alone

SPEP alone misses 15-20% of plasma cell disorders, particularly light chain-only disease. 1, 3 The mandatory concurrent testing panel includes: 4, 1, 2

Required Simultaneous Tests

• Serum immunofixation electrophoresis (SIFE) to identify the exact immunoglobulin type (IgG, IgA, IgM) and light chain (kappa or lambda)—this is more sensitive than SPEP alone 1, 3
• Serum free light chain (FLC) assay with kappa/lambda ratio, which is essential for detecting light chain myeloma and achieves 100% sensitivity when combined with SPEP 1, 5
• Quantitative immunoglobulin levels (IgG, IgA, IgM) 4, 2
• 24-hour urine collection for total protein, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE) 4, 2

Additional Baseline Studies

When ordering SPEP, simultaneously obtain: 4, 1

• Complete blood count (CBC) with differential to assess for anemia and rouleaux formation
• Comprehensive metabolic panel including calcium, creatinine, BUN, and albumin
• Beta-2 microglobulin and LDH for prognostic stratification
• Skeletal survey or whole-body low-dose CT to evaluate for lytic bone lesions 4

Understanding SPEP Results and Limitations

What SPEP Detects

SPEP separates serum proteins into distinct zones and identifies monoclonal proteins as a homogeneous spike-like peak (M-spike), typically in the gamma-globulin zone. 3, 6 This M-spike indicates clonal plasma cell proliferation producing a single type of immunoglobulin. 3

Critical Pitfalls to Avoid

• Approximately 20% of patients have secretory urinary M-proteins that may not be adequately captured by serum testing alone 4
• 3% of patients have truly non-secretory myeloma with no detectable M-protein on either SPEP or UPEP, requiring bone marrow biopsy and imaging for diagnosis 4, 2
• 15-20% of myeloma cases produce only light chains (not complete antibodies), which may not create a visible spike on standard SPEP and require FLC assay for detection 2, 3
• SPEP has only 71% sensitivity for detecting plasma cell disorders when lytic bone lesions are present 1

When SIFE is More Sensitive

Serum immunofixation electrophoresis identifies 17% of monoclonal gammopathies that SPEP misses, particularly small or non-malignant monoclonal proteins. 2 When clinical suspicion remains high despite negative SPEP, order SIFE. 3

Interpreting Results and Next Steps

If M-Spike is Detected

Any detected monoclonal protein on SPEP requires referral to hematology/oncology. 2, 3 The height and area under the M-spike quantifies disease burden: 2

• MGUS: M-protein <30 g/L, bone marrow plasma cells <10%, no end-organ damage
• Smoldering myeloma: M-protein ≥30 g/L and/or bone marrow plasma cells ≥10%, no end-organ damage
• Symptomatic myeloma: M-protein present, bone marrow plasma cells ≥10%, plus CRAB criteria

Urgent Referral Triggers (Within 1-2 Weeks)

Refer urgently when: 1, 2, 3

• Significant M-protein spike with accompanying symptoms (bone pain, pathologic fractures, lytic lesions)
• CRAB criteria present (anemia, renal dysfunction, hypercalcemia, bone lesions)
• Bone marrow shows ≥10% plasma cells with monoclonal protein detected

If SPEP is Normal but Suspicion Remains High

Order the complete diagnostic panel including SIFE and FLC assay, as these tests are more sensitive and will detect light chain-only disease. 1, 3, 5 The combination of SPEP plus FLC analysis achieves 100% sensitivity for detecting plasma cell disorders. 2, 5

Special Considerations

Renal Impairment

When creatinine >2 mg/dL, the normal kappa/lambda FLC ratio shifts from 0.26-1.65 to 0.34-3.10 due to altered clearance. 3 Adjust interpretation accordingly.

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 per International Myeloma Working Group criteria. 2, 3 Always include SIFE, quantitative immunoglobulins, and FLC assay for complete response assessment. 2

Trace or Faint Bands

For patients without a previous history of gammopathy, trace or faint immunoglobulin bands on IFE do not warrant frequent follow-up investigation, as none progress to symptomatic plasma cell dyscrasia over a mean follow-up of 5 years. 7 However, patients with a prior history of gammopathy require routine follow-up. 7