What are the indications for a Protein Electrophoresis (PE) test, particularly in adults over 50 with suspected plasma cell disorders, such as multiple myeloma or lymphoma?

Indications for Protein Electrophoresis Testing

Protein electrophoresis (serum and urine) should be ordered when evaluating for plasma cell disorders, particularly in adults over 50 presenting with unexplained anemia, bone pain, lytic bone lesions, hypercalcemia, renal insufficiency, or recurrent infections. 1

Primary Clinical Indications

Suspected Plasma Cell Disorders

• Order protein electrophoresis when evaluating for multiple myeloma, particularly when patients present with the CRAB criteria: hypercalcemia, renal insufficiency, anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal), or bone lesions. 1, 2
• Use in patients with unexplained lytic bone lesions detected on imaging, though be aware that serum protein electrophoresis (SPEP) alone has only 71% sensitivity in this scenario and misses approximately 15-20% of plasma cell disorders. 3, 4
• Screen patients with unexplained elevation of total serum protein or globulin fraction on routine chemistry panels. 5

Monoclonal Gammopathy Evaluation

• Order when investigating monoclonal gammopathy of undetermined significance (MGUS), defined as serum monoclonal protein <30 g/L with bone marrow plasma cells <10% and no end-organ damage. 1, 6
• Evaluate smoldering (asymptomatic) multiple myeloma, characterized by serum monoclonal protein ≥30 g/L and/or bone marrow plasma cells ≥10% without end-organ damage. 1, 3

Bone Marrow Abnormalities

• When bone marrow biopsy reveals increased plasma cells (≥10%), protein electrophoresis is mandatory to detect and quantify monoclonal protein and assess for light chain restriction. 7
• Use CD138 immunostaining results showing plasma cell infiltration as a trigger for comprehensive protein studies including SPEP, immunofixation, and free light chain assay. 2, 7

Other Hematologic Indications

• Unexplained anemia, particularly normochromic, normocytic anemia with rouleaux formation on peripheral smear. 2
• Suspected Waldenström's macroglobulinemia or other lymphoproliferative disorders with monoclonal protein production. 5, 8
• Evaluation of AL (light chain) amyloidosis when clinical features suggest immunoglobulin deposition disease. 1, 8

Critical Testing Algorithm

Never Order SPEP Alone

SPEP must always be accompanied by a complete diagnostic panel because it misses 15-20% of plasma cell disorders, particularly light chain-only disease. 3 The mandatory concurrent tests include:

• Serum immunofixation electrophoresis (SIFE) to identify the exact immunoglobulin type and light chain, which 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 has prognostic value. 1, 2
• Quantitative immunoglobulin levels (IgG, IgA, IgM) by nephelometry to assess for suppression of uninvolved immunoglobulins. 1, 7
• 24-hour urine collection for total protein, urine protein electrophoresis, and urine immunofixation—never accept a random urine sample. 1, 2

Additional Required Workup When Ordering Protein Studies

When protein electrophoresis is indicated, simultaneously order:

• Complete blood count with differential to assess anemia and look for rouleaux formation. 1, 2
• Comprehensive metabolic panel including serum calcium (corrected for albumin), creatinine, and albumin. 1, 7
• Beta-2 microglobulin and LDH for prognostic stratification. 1
• Skeletal survey (posteroanterior chest, anteroposterior/lateral spine, humeri, femora, skull, pelvis) to detect lytic lesions. 1, 7

Common Pitfalls to Avoid

Interpretation Errors

• A normal SPEP does not exclude plasma cell disorders—the negative predictive value is 94% but sensitivity is only 71%, meaning nearly 30% of myeloma cases may have negative SPEP. 4
• Polyclonal increase on SPEP indicates chronic inflammation, autoimmune disorders, or chronic infections, not plasma cell malignancy. 3, 5
• In renal impairment (creatinine >2 mg/dL), the normal kappa/lambda ratio shifts from 0.26-1.65 to 0.34-3.10, requiring adjusted interpretation. 3

Testing Sequence Mistakes

• Never rely on SPEP alone to rule out myeloma when clinical suspicion is high—proceed with the complete panel including SIFE and FLC assay even if SPEP is negative. 3
• The FLC assay cannot replace 24-hour urine protein electrophoresis for monitoring patients with measurable urinary M-proteins. 1
• Bone marrow examination remains essential even when monoclonal protein is detected, as it confirms diagnosis and quantifies plasma cell burden. 2

Urgent Referral Triggers

Any detected monoclonal protein on SPEP requires hematology/oncology referral. 3 Urgent referral (within 1-2 weeks) is mandatory when:

• Significant M-protein spike is present with accompanying symptoms such as bone pain, pathologic fractures, or lytic lesions. 3
• CRAB criteria are present: anemia, renal dysfunction, hypercalcemia, or bone lesions. 3
• Bone marrow shows ≥10% plasma cells with monoclonal protein detected. 1, 7