When should serum protein electrophoresis (SPEP) be ordered?

When to Order Serum Protein Electrophoresis (SPEP)

Order SPEP when patients present with unexplained anemia (hemoglobin ≥2 g/dL below normal or <10 g/dL), renal insufficiency (creatinine ≥2 mg/dL), hypercalcemia (calcium ≥11.5 mg/dL), lytic bone lesions, or proteinuria, as these are cardinal presentations of plasma cell disorders that require immediate screening. 1

Primary Clinical Indications

SPEP is indicated for the following specific clinical scenarios:

Hematologic Abnormalities

• Unexplained normochromic, normocytic anemia with hemoglobin ≥2 g/dL below reference range or <10 g/dL warrants SPEP to evaluate for plasma cell disorders 1
• This threshold is critical because anemia is one of the CRAB criteria (calcium elevation, renal insufficiency, anemia, bone lesions) that defines symptomatic multiple myeloma 2

Renal Dysfunction

• Serum creatinine ≥2 mg/dL without obvious cause requires SPEP 1
• Approximately 20% of plasma cell disorders secrete monoclonal proteins only in urine, making combined serum and urine testing essential 3, 1

Metabolic Abnormalities

• Hypercalcemia (serum calcium ≥11.5 mg/dL) should prompt SPEP, particularly when PTH is suppressed and malignancy is suspected 1, 4
• Multiple myeloma causes hypercalcemia in 10-25% of cases through lytic bone destruction 4

Skeletal Findings

• Radiologic evidence of lytic bone lesions, severe osteopenia, or pathologic fractures is a trigger for SPEP 1
• These findings suggest malignant bone turnover from plasma cell infiltration 1

Urinary Abnormalities

• Proteinuria identified on routine urinalysis is a recognized indication for SPEP to screen for monoclonal gammopathies 1
• Must be followed by 24-hour urine protein electrophoresis with immunofixation, as spot urine specimens are insufficient 1

Suspected Lymphoproliferative Disorders

• Clinical features suggesting Waldenström's macroglobulinemia (lymphadenopathy, hepatosplenomegaly, hyperviscosity symptoms) require SPEP as part of diagnostic work-up 1

Complete Diagnostic Panel When Ordering SPEP

When SPEP is indicated, order the following tests simultaneously to ensure comprehensive evaluation 1:

• Serum protein electrophoresis with immunofixation to confirm monoclonal protein and determine heavy- and light-chain type 1
• Complete blood count with differential to detect cytopenias accompanying plasma cell disorders 1
• Comprehensive metabolic panel including calcium and creatinine to assess organ dysfunction 1
• Serum immunoglobulin quantitation (IgG, IgA, IgM) by nephelometry for baseline levels 1
• 24-hour urine protein electrophoresis with immunofixation because relying on serum testing alone misses 20% of cases 3, 1
• Serum free light chain assay with kappa/lambda ratio (normal 0.26-1.65), as 15-20% of myeloma cases produce only light chains without visible M-spike 4

When NOT to Order SPEP

Routine screening of asymptomatic individuals without risk factors is discouraged 1. The prevalence of MGUS in persons >50 years is only ~3.2%, and most cases never progress to malignancy 1. SPEP should be reserved for patients with specific clinical indicators listed above.

Follow-Up Monitoring After Initial Detection

Initial Repeat Testing

• Repeat SPEP in 3-6 months after initial detection of monoclonal protein to determine stability versus evolution toward multiple myeloma or Waldenström's macroglobulinemia 1, 2

MGUS Risk-Stratified Monitoring

Low-risk MGUS (M-protein <15 g/L, IgG type, normal free-light-chain ratio):

• SPEP at 6 months, then every 2-3 years if stable 1

Intermediate/High-risk MGUS (M-protein ≥15 g/L, IgA or IgM type, or abnormal free-light-chain ratio):

• SPEP at 6 months, then annually for life 1
• Baseline bone marrow biopsy to exclude overt malignancy 1
• Twenty-year progression risk: 58% with 3 risk factors, 37% with 2 factors, 21% with 1 factor, 5% with 0 factors 2

Smoldering Multiple Myeloma

• Initial SPEP repeat at 2-3 months after diagnosis 1
• If stable, every 4-6 months during first year, then every 6-12 months thereafter 1

Solitary Plasmacytoma

• Mandatory monitoring with serum electrophoresis and immunofixation after radiation therapy completion 3
• Persistence of serum monoclonal protein 1 year after treatment predicts higher risk of progression to multiple myeloma 3

Critical Technical Considerations

• Use the same analytical method for serial SPEP measurements to ensure accurate comparison of M-protein levels over time 1
• Immunofixation must follow any detected M-protein to definitively identify heavy- and light-chain composition 3, 1
• Nephelometric quantitation may overestimate monoclonal protein when values are high, potentially influencing treatment decisions 1
• Incomplete 24-hour urine collection leads to falsely negative results, emphasizing proper collection technique 1