What is the appropriate management for a patient with elevated Serum Protein Electrophoresis (SPEP)/Urine Protein Electrophoresis (UPEP)?

Management of Elevated SPEP/UPEP

Do not rely on SPEP/UPEP alone to exclude monoclonal protein—immediately order serum immunofixation electrophoresis (SIFE), urine immunofixation electrophoresis (UIFE), and serum free light chain (sFLC) assay to complete the diagnostic workup. 1

Initial Diagnostic Workup

When SPEP/UPEP shows elevation, the following tests must be ordered immediately to characterize the monoclonal protein:

• Serum immunofixation electrophoresis (SIFE) to identify the specific type of monoclonal protein (IgG, IgA, IgM, or light chain only) 1
• Urine immunofixation electrophoresis (UIFE) on 24-hour urine collection to detect Bence Jones proteins 1
• Serum free light chain (sFLC) assay with kappa/lambda ratio—this combination with SPEP and SIFE provides the highest sensitivity for detecting plasma cell disorders 1
• Quantitative immunoglobulins (IgG, IgA, IgM) to assess for immunoparesis 1

Critical pitfall: SPEP/UPEP have lower sensitivity than immunofixation, particularly in AL amyloidosis where monoclonal protein levels are typically low. SPEP/UPEP should never be used alone to exclude a monoclonal protein. 1

Additional Laboratory Studies

Complete the following to assess for end-organ damage and disease burden:

• Complete blood count (CBC) with differential to evaluate for anemia 1
• Comprehensive metabolic panel including creatinine, calcium, and albumin to assess for renal dysfunction and hypercalcemia 1
• Beta-2 microglobulin and LDH as markers of tumor burden and prognosis 1
• Bone marrow aspirate and biopsy with immunohistochemical staining for kappa and lambda light chains, plus Congo red staining if amyloidosis is suspected 1

Imaging Studies

• Skeletal survey (full skeleton radiographs) to evaluate for lytic bone lesions 1
• Consider PET/CT or MRI if skeletal survey is negative but clinical suspicion remains high, as these modalities are more sensitive for detecting bone marrow involvement 1

Special Considerations for Serum Free Light Chains

Important nuances regarding sFLC interpretation:

• Renal impairment can cause false-positive elevated kappa/lambda ratios up to 3.1 due to decreased clearance—interpret sFLC results in context of serum creatinine 2
• Polyclonal hypergammaglobulinemia can also mildly elevate the kappa/lambda ratio 2
• Lambda chain lesions are relatively under-detected by sFLC assay compared to kappa chain lesions—approximately 25% of lambda chain monoclonal gammopathies may have normal kappa/lambda ratios despite detectable free lambda chains in urine 3

Tissue Diagnosis for Suspected Amyloidosis

If amyloidosis is suspected based on clinical presentation (cardiac involvement, nephrotic syndrome, neuropathy):

• Abdominal fat pad aspiration as initial less-invasive biopsy (84% sensitivity for AL cardiac amyloidosis) 1
• If fat pad is negative, proceed to biopsy of the affected organ to definitively exclude AL amyloidosis 1
• Mass spectrometry (LC-MS/MS) is the gold standard for identifying the amyloid precursor protein type (sensitivity 88%, specificity 96%) 1
• Never rely on Congo red staining alone—tissue typing by mass spectrometry or immunohistochemistry is essential, especially when MGUS coexists with suspected ATTR amyloidosis 1

Risk Stratification After Diagnosis

Once monoclonal protein is confirmed, obtain:

• Cytogenetics and FISH on bone marrow plasma cells to identify high-risk chromosomal abnormalities including del(17p), t(4;14), t(14;16), and del(13) 1
• Multiparameter flow cytometry on bone marrow to quantify abnormal plasma cells (>95% abnormal plasma cells predicts higher risk of progression) 1

Management Based on Disease Classification

For Monoclonal Gammopathy of Undetermined Significance (MGUS):

• Observation with repeat testing every 3-6 months 1
• Monitor CBC, comprehensive metabolic panel, quantitative immunoglobulins, SPEP, SIFE, and sFLC 1

For Smoldering (Asymptomatic) Myeloma:

• Observation at 3-6 month intervals (Category 1 recommendation) 1
• Annual bone survey or as clinically indicated 1
• Consider enrollment in clinical trials 1

For Symptomatic Multiple Myeloma:

• Immediate hematology/oncology referral for systemic chemotherapy 1
• Treatment selection based on transplant eligibility, cytogenetic risk, and performance status 1

For AL Amyloidosis:

• Urgent hematology referral for plasma cell-directed therapy 1
• Cardiology consultation for cardiac monitoring during treatment 1
• Consider palliative care consultation to discuss goals of care 1

For Solitary Plasmacytoma:

• Radiation therapy (≥40-50 Gy) to involved field with 2 cm margin 1
• Monitor for progression with same tests every 4 weeks initially, then every 3-6 months if paraprotein disappears 1