What is the role of immunofixation in diagnosing and monitoring plasma cell dyscrasias, such as multiple myeloma?

Immunofixation in Plasma Cell Dyscrasias

Immunofixation electrophoresis (IFE) is essential for both diagnosing and monitoring plasma cell dyscrasias, as it identifies and characterizes monoclonal proteins with superior sensitivity compared to serum protein electrophoresis alone, detecting M-proteins in 100% of multiple myeloma cases versus 96% with electrophoresis alone. 1

Role in Initial Diagnosis

Superior Detection Capability

• Immunofixation must be performed alongside serum protein electrophoresis (SPEP) because SPEP alone misses up to 50% of monoclonal proteins, particularly in light chain disease and low-concentration M-proteins. 2
• IFE detects M-proteins in 100% of multiple myeloma cases, while SPEP detects only 96.19%, with IFE identifying the 3.81% of cases missed by SPEP alone (particularly IgA and light chain types). 1
• The combination of SPEP with serum immunofixation electrophoresis (SIFE) is mandatory for initial diagnostic workup according to NCCN guidelines. 3

Specific Diagnostic Applications

• Both serum and urine immunofixation are required because some patients have negative serum but positive urine findings—24-hour urine immunofixation electrophoresis (UIFE) is critical and cannot be replaced by random urine samples. 3, 2
• Immunofixation characterizes the specific type of monoclonal protein (IgG, IgA, IgM, IgD, IgE, or free light chains kappa/lambda), which is essential for classification and prognostication. 4, 5
• For patients with atypical presentations or suspected non-secretory myeloma, immunofixation is particularly valuable as a screening tool. 1

Role in Disease Monitoring

Response Assessment

• Negative immunofixation on both serum and urine is required to document complete response (CR) in multiple myeloma, along with <5% plasma cells in bone marrow and disappearance of soft tissue plasmacytomas. 2
• Stringent complete response (sCR) requires negative immunofixation plus a normal serum free light chain ratio according to International Myeloma Working Group criteria. 3
• Serial immunofixation testing tracks disease response and detects early relapse by identifying reappearance of the monoclonal protein. 6

Monitoring Frequency Considerations

• For patients with established plasma cell dyscrasias requiring routine follow-up, serial immunofixation contributes to overall survival given multiple treatment options now available. 7
• However, for patients without previous history of gammopathy who have only trace, faint, or scarcely visible bands on immunofixation, frequent follow-up is not warranted—none of these patients progressed to symptomatic disease over 5 years of observation. 7

Diagnostic Algorithm Integration

Initial Workup Panel

The recommended diagnostic screening panel includes: 6

• Serum protein electrophoresis (SPEP)
• Serum immunofixation electrophoresis (SIFE)
• Serum free light chain (FLC) assay with kappa/lambda ratio
• 24-hour urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE)

Distinguishing Disease Entities

• MGUS: Serum M-protein <3 g/dL, clonal bone marrow plasma cells <10%, no end-organ damage, confirmed by immunofixation. 5
• Smoldering myeloma: Serum M-protein ≥3 g/dL and/or clonal plasma cells ≥10%, no end-organ damage, with positive immunofixation. 5
• Multiple myeloma: ≥10% clonal plasma cells plus CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions), with monoclonal protein confirmed by immunofixation. 4, 5

Critical Pitfalls to Avoid

Technical Considerations

• Always use the same laboratory and testing method for serial studies to ensure accurate quantification and comparison—switching between laboratories can lead to false interpretations of disease progression or response. 3
• Immunofixation cannot replace 24-hour urine protein electrophoresis for monitoring patients with measurable urinary M-proteins, as quantification requires electrophoresis. 3

Clinical Interpretation

• Trace bands on immunofixation in patients without prior gammopathy history do not require aggressive follow-up, as progression risk is extremely low. 7
• For rare plasma cell dyscrasias (Waldenström's macroglobulinemia, AL-amyloidosis, POEMS syndrome), immunofixation combined with immunophenotyping is essential for accurate diagnosis and classification. 3
• In non-secretory myeloma (3% of cases), immunofixation will be negative, requiring reliance on bone marrow plasma cell percentage (≥10%) and serum free light chain assay for diagnosis and monitoring. 3