When to Order Serum Protein Electrophoresis (SPEP)
SPEP should be ordered when patients present with unexplained anemia, renal insufficiency, hypercalcemia, bone lesions, elevated total protein or globulin levels, or proteinuria, as these are hallmark presentations of plasma cell disorders. 1
Primary Clinical Indications
SPEP is a core diagnostic test for suspected plasma cell disorders and should be ordered in the following clinical scenarios:
Red Flag Symptoms and Laboratory Findings
- Unexplained anemia (normochromic, normocytic with hemoglobin ≥2 g/dL below normal or <10 g/dL) 2, 1
- Renal insufficiency (serum creatinine ≥2 mg/dL without clear etiology) 2, 1
- Hypercalcemia (serum calcium ≥11.5 mg/dL) 2, 1
- Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 2, 1
- Elevated total protein or globulin fraction on routine chemistry panels 1, 3
- Proteinuria detected on routine urinalysis 2, 1
Additional High-Risk Scenarios
- Hypogammaglobulinemia with elevated alpha2-globulin/alpha1-globulin ratio, low hemoglobin, or elevated creatinine—these parameters increase the odds of detecting a monoclonal protein even when the initial SPEP appears normal 4
- Suspected AL amyloidosis (unexplained nephrotic syndrome, cardiomyopathy, peripheral neuropathy, or hepatomegaly) 5
- Suspected Waldenström's macroglobulinemia (lymphadenopathy, hepatosplenomegaly, hyperviscosity symptoms) 2, 3
Essential Testing Algorithm
When SPEP is ordered, it must be part of a comprehensive workup, not performed in isolation:
Initial Diagnostic Panel
- SPEP with immunofixation to confirm and type any detected monoclonal protein 2, 1
- 24-hour urine collection for protein electrophoresis and immunofixation—critical because 20% of patients with plasma cell disorders secrete monoclonal proteins only in urine 1
- Serum free light chain (FLC) assay with kappa/lambda ratio (normal 0.26-1.65) 6, 5
- Complete blood count with differential 2
- Comprehensive metabolic panel including calcium and creatinine 2
- Nephelometric quantitation of immunoglobulins (IgG, IgA, IgM) 2, 1
Critical pitfall: Never rely on SPEP alone without urine studies, as this misses one-fifth of secretory plasma cell disorders 1. Random urine samples cannot replace 24-hour collections for accurate quantification 2.
Follow-Up and Monitoring Scenarios
After Initial Detection of Monoclonal Protein
- Repeat SPEP at 3-6 months after initial recognition to exclude evolving multiple myeloma or Waldenström's macroglobulinemia 2, 6
Risk-Stratified Monitoring for MGUS
Low-risk MGUS (M-protein <15 g/L, IgG type, normal FLC ratio):
Intermediate or high-risk MGUS (M-protein ≥15 g/L, IgA or IgM type, or abnormal FLC ratio):
- SPEP at 6 months, then annually for life 2, 6
- Bone marrow biopsy required at baseline to exclude underlying malignancy 2, 6
Smoldering Multiple Myeloma
- SPEP at 2-3 months after initial recognition 2
- If stable, every 4-6 months for the first year, then every 6-12 months 2
When NOT to Order SPEP as Initial Test
SPEP should not be ordered as a screening test in asymptomatic patients without risk factors, as the prevalence of MGUS is only 3.2% in the general population over age 50, and most cases never progress to malignancy 2. The detection of trace monoclonal bands in asymptomatic patients may represent transient phenomena in infectious or autoimmune conditions, leading to unnecessary patient anxiety and healthcare costs 7.
Technical Considerations
- Use the same testing method for serial monitoring to ensure accurate comparison of M-protein levels over time 1
- Nephelometric quantitation may overestimate monoclonal protein concentration at high values, which can impact treatment decisions 2, 1
- Immunofixation must always follow any detected M-protein to confirm heavy and light chain type 2, 1