When should serum protein electrophoresis (SPE) be considered in adults over 40 with symptoms such as anemia, bone pain, or recurrent infections?

Serum Protein Electrophoresis: When to Order in Adults Over 40

Serum protein electrophoresis (SPE) should be ordered in adults over 40 presenting with unexplained anemia, bone pain (especially with lytic lesions), recurrent infections, renal insufficiency, hypercalcemia, or unexplained proteinuria, as these are cardinal manifestations of plasma cell disorders including multiple myeloma. 1

Primary Clinical Indications for SPE

Mandatory Testing Scenarios

SPE must be performed when any of the following "CRAB" criteria or related findings are present:

• Unexplained anemia (hemoglobin <10 g/dL without other identifiable cause) 1
• Bone pain with lytic lesions on skeletal survey or pathologic fractures 1
• Recurrent bacterial infections attributable to immunodeficiency 1
• Renal insufficiency (creatinine ≥177 μmol/L or 2 mg/dL) without clear alternative etiology 1
• Hypercalcemia (>3.0 mmol/L) after excluding hyperparathyroidism 1
• Unexplained proteinuria detected on urinalysis 1

Additional High-Yield Scenarios

• Elevated total protein on routine chemistry panel with normal albumin (suggesting hyperglobulinemia) 2, 3
• Markedly elevated ESR without obvious inflammatory cause 2
• Peripheral neuropathy of unclear etiology (may indicate AL amyloidosis or POEMS syndrome) 4
• Unexplained osteoporosis with sudden onset or compression fractures 1

Critical Testing Algorithm

Initial Workup Must Include Three Components

When SPE is ordered, it must be accompanied by the following to achieve adequate diagnostic sensitivity:

1. Serum immunofixation electrophoresis (SIFE) - identifies and types the monoclonal protein even when SPE shows no visible spike 5, 6
2. 24-hour urine protein electrophoresis with immunofixation (UPEP/UIFE) - detects Bence Jones proteins that may be absent from serum 5, 6
3. Serum free light chain (FLC) assay with kappa/lambda ratio - most sensitive for light chain-only disease and prognostic stratification 1, 4

Critical pitfall: SPE alone misses up to 50% of plasma cell disorders, particularly light chain-only myeloma where no intact immunoglobulin is produced 6, 7. Random urine samples are inadequate and cannot replace 24-hour collection 5.

Interpretation and Follow-Up Based on Results

If M-Protein Detected: Risk Stratification Required

Low-risk profile (likely MGUS):

• M-protein <15 g/L (1.5 g/dL)
• IgG type
• Normal FLC ratio
• No concerning symptoms
• Action: Repeat SPE in 3-6 months to exclude rapidly progressive disease, then every 2-3 years if stable 1, 4

Intermediate/High-risk profile (requires bone marrow biopsy):

• M-protein ≥15 g/L 1, 4
• IgA or IgM type (20.5% risk of ≥10% plasma cells even at low levels) 4
• Abnormal FLC ratio 1, 4
• Any CRAB criteria present 1

Smoldering multiple myeloma criteria:

• M-protein ≥30 g/L OR bone marrow plasma cells ≥10%
• No end-organ damage
• Progression risk: 10% per year for first 5 years (versus 1% per year for MGUS) 1, 4

If M-Protein ≥30 g/L or Bone Marrow Plasma Cells ≥10%

Mandatory baseline studies include:

• Bone marrow aspiration and biopsy with cytogenetics/FISH 1
• Complete skeletal survey 1
• MRI of spine and pelvis (detects occult lesions predicting rapid progression) 1
• Complete blood count, calcium, creatinine 1
• Repeat testing in 2-3 months, then every 4-6 months for first year 1

Common Pitfalls to Avoid

1. Ordering SPE alone without immunofixation and urine studies - This misses light chain-only disease and reduces sensitivity by 50% 5, 6, 7

2. Accepting random urine samples instead of 24-hour collection - Random samples cannot adequately assess Bence Jones proteinuria even when corrected for creatinine 5

3. Attributing laboratory abnormalities to age or comorbidities without excluding myeloma - Elderly patients often have diabetes, hypertension, or osteoporosis that can mimic myeloma findings; however, sudden onset favors malignancy 1

4. Relying on negative SPE to rule out plasma cell disorders - SPE has only 71% sensitivity for myeloma in patients with lytic bone lesions, but 94% negative predictive value when combined with complete testing 7

5. Using different laboratory methods for serial monitoring - This prevents accurate comparison of M-protein levels over time 5

Diagnostic Sensitivity Considerations

SPE combined with immunofixation and FLC assay achieves the highest sensitivity for plasma cell disorders 5, 6. When evaluating lytic bone lesions specifically, SPE alone has:

• Sensitivity: 71%
• Specificity: 83%
• Negative predictive value: 94%
• Positive predictive value: only 47% 7

This underscores why bone marrow biopsy remains mandatory when clinical suspicion is high despite negative or equivocal SPE results 1, 7.