Is protein electrophoresis (SPEP - Serum Protein Electrophoresis and UPEP - Urine Protein Electrophoresis) sufficient for the diagnosis and management of multiple myeloma?

Is Protein Electrophoresis Enough for Myeloma?

No, protein electrophoresis alone is not sufficient for the diagnosis and management of multiple myeloma—you must also obtain immunofixation, serum free light chains, bone marrow examination, and imaging studies to properly diagnose and manage this disease. 1, 2, 3

Why SPEP/UPEP Alone Is Inadequate

Missing Critical Diagnostic Components

Protein electrophoresis detects only 96% of M-proteins, missing approximately 4% of cases, particularly light chain and some IgA subtypes. 4 When immunofixation is added, detection increases to 100% of cases. 4

• Bone marrow confirmation is mandatory: You cannot diagnose multiple myeloma without demonstrating ≥10% clonal plasma cells in the bone marrow, regardless of what the protein studies show. 1, 3

• End-organ damage assessment requires additional testing: The CRAB criteria (hypercalcemia >11.5 mg/dL, renal failure with creatinine >2 mg/dL, anemia <10 g/dL, bone lesions) cannot be evaluated with protein studies alone. 3

• Skeletal survey or advanced imaging is essential: Full skeletal X-ray survey remains the standard for detecting lytic bone lesions, with MRI providing superior detail when spinal cord compression is suspected. 1, 2, 3

Required Laboratory Tests Beyond Electrophoresis

You must obtain these additional tests for proper diagnosis: 1, 2, 3

• Serum immunofixation electrophoresis: Confirms the presence and characterizes the heavy and light chain type, even when SPEP shows no measurable protein. 1, 5

• Serum free light chain assay with kappa/lambda ratio: Particularly critical when standard SPEP is negative or shows minimal abnormality, and detects response/progression 3+ months earlier than SPEP. 2, 6

• 24-hour urine collection for protein electrophoresis and immunofixation: Random urine samples are insufficient and cannot replace the 24-hour collection. 1, 5 Immunofixation must be performed even if there is no visible peak on urine electrophoresis. 1, 5

• Nephelometric quantification of IgG, IgA, and IgM: Provides absolute quantification of immunoglobulins. 1, 2

• Complete blood count, serum calcium, creatinine, albumin, beta-2 microglobulin, and LDH: Required for staging (International Staging System) and assessing end-organ damage. 1, 2, 3

Algorithmic Approach to Myeloma Workup

Step 1: Initial Protein Studies

• Obtain both serum protein electrophoresis with immunofixation and 24-hour urine protein electrophoresis with immunofixation. 1, 2
• Add serum free light chain assay with kappa/lambda ratio. 2, 3

Step 2: Bone Marrow Assessment

• Perform bone marrow aspiration and biopsy with immunohistochemistry or flow cytometry to confirm ≥10% clonal plasma cells. 1, 3
• Obtain cytogenetics (metaphase karyotype and FISH) for risk stratification—high-risk features like del(17p), t(4;14), t(14;16) fundamentally alter prognosis and treatment. 1, 3

Step 3: End-Organ Damage Evaluation

• Complete blood count for anemia assessment. 2, 3
• Serum calcium and creatinine for hypercalcemia and renal failure. 2, 3
• Full skeletal X-ray survey (spine, pelvis, skull, humeri, femurs) for lytic lesions. 1, 2
• MRI of spine/pelvis if spinal cord compression suspected or to distinguish MGUS from smoldering/overt myeloma. 1, 2, 3

Step 4: Staging and Risk Assessment

• Calculate International Staging System using beta-2 microglobulin and albumin levels. 2, 3
• Review cytogenetics for high-risk features. 3

Critical Pitfalls to Avoid

Failing to perform immunofixation when SPEP appears normal: Immunofixation must be done even when there is no measurable protein or visible peak, as it detects cases missed by electrophoresis alone. 1, 5, 4

Using random urine samples instead of 24-hour collection: This leads to false-negative results and cannot be corrected by adjusting for creatinine concentration. 1, 5

Relying solely on SPEP for monitoring: Serum free light chains detect response and progression approximately 3 months earlier than SPEP, providing earlier clinical decision-making opportunities. 6

Missing light chain-only myeloma: Approximately 3% of cases are light chain type that may show minimal or no abnormality on standard SPEP but are detected by urine studies and serum free light chains. 4

Overlooking the need for bone marrow examination: Even with a clear M-protein, you cannot diagnose multiple myeloma without confirming clonal plasma cell infiltration in the bone marrow. 1, 3