In an 83‑year‑old woman with acute back pain, severe anemia and markedly elevated erythrocyte sedimentation rate, should the initial diagnostic test be serum protein electrophoresis (SPEP) with immunofixation rather than beta‑2 microglobulin (β2‑M)?

SPEP with Immunofixation Should Be the Initial Diagnostic Test

In an 83-year-old woman presenting with acute back pain, severe anemia, and markedly elevated ESR—a clinical picture highly suspicious for multiple myeloma—serum protein electrophoresis (SPEP) with immunofixation should be ordered immediately as the primary diagnostic test, not beta-2 microglobulin alone. 1, 2

Rationale for SPEP as the Initial Test

Diagnostic Priority in Suspected Myeloma

• SPEP with immunofixation is the cornerstone diagnostic test for detecting and characterizing monoclonal proteins (M-proteins), which are the hallmark of plasma cell disorders including multiple myeloma 1, 2

• The International Myeloma Workshop Consensus Panel explicitly recommends SPEP with immunofixation as part of the standard investigative workup for suspected multiple myeloma 1

• SPEP identifies the presence, type, and quantity of M-proteins, providing both diagnostic confirmation and a baseline for disease monitoring 2

Why Not Beta-2 Microglobulin First?

• Beta-2 microglobulin (β2-M) is a prognostic marker, not a diagnostic test for multiple myeloma 1

• β2-M reflects tumor burden and forms the basis for the International Staging System, but it cannot diagnose myeloma or detect monoclonal proteins 1

• β2-M is recommended only after the diagnosis is established, as it provides prognostic information but does not confirm the presence of a plasma cell disorder 1

The Complete Initial Diagnostic Panel

Essential Tests to Order Simultaneously

When ordering SPEP, the following tests should be obtained concurrently to maximize diagnostic sensitivity:

• Serum immunofixation electrophoresis (SIFE) to identify the exact immunoglobulin type (IgG, IgA, IgM) and light chain (kappa or lambda) 2, 3

• Serum free light chain (FLC) assay with kappa/lambda ratio, as the combination of SPEP plus FLC achieves 100% sensitivity for detecting plasma cell disorders 2, 4

• 24-hour urine collection for urine protein electrophoresis (UPEP) and urine immunofixation, since approximately 20% of patients have secretory urinary M-proteins not adequately captured by serum testing alone 2, 5

• Complete blood count (CBC) to quantify the anemia 2

• Comprehensive metabolic panel including calcium and creatinine to assess for hypercalcemia and renal dysfunction 1, 2

Why SPEP Alone Is Insufficient

• SPEP has only 71% sensitivity when lytic bone lesions are present, emphasizing the need for concurrent immunofixation and FLC testing 2, 4

• Immunofixation electrophoresis is more sensitive than SPEP alone, detecting 100% of monoclonal gammopathies compared to SPEP's 96.19% detection rate 6, 7

• Approximately 15-20% of myeloma cases produce only light chains, which may not create a visible spike on standard SPEP and require FLC assays for detection 2

• IFE identified 17% of monoclonal gammopathies that SPEP missed in screening studies 2

Critical Pitfalls to Avoid

Common Diagnostic Errors

• Do not order β2-M as the initial diagnostic test—it will not confirm or exclude myeloma and delays appropriate diagnosis 1

• Do not rely on SPEP alone without immunofixation—this misses a significant proportion of cases, particularly light chain disease 2, 6, 7

• Do not skip urine testing—approximately 20% of patients have urinary M-proteins that may be missed by serum testing alone 2, 5

• Do not substitute serum FLC for 24-hour urine collection in patients with measurable urinary M-proteins during monitoring 5

When to Add Beta-2 Microglobulin

• Order β2-M after diagnosis is confirmed by SPEP/immunofixation to establish prognostic staging using the International Staging System 1

• β2-M should be obtained alongside lactate dehydrogenase (LDH) for complete prognostic assessment 1

Additional Baseline Studies After Initial Diagnosis

Once monoclonal protein is detected, the following tests complete the diagnostic workup:

• Bone marrow aspirate and/or biopsy to confirm >10% clonal plasma cells 1

• Skeletal survey (plain radiographs) including spine, pelvis, skull, humeri, and femurs to detect lytic lesions 1, 2

• Cytogenetics (metaphase karyotype and FISH) for prognostic stratification 1

• Quantitative immunoglobulin levels (IgG, IgA, IgM) to assess for immune paresis 2, 3

Clinical Context Matters

In this 83-year-old woman with the classic triad of back pain (suggesting vertebral involvement), severe anemia, and markedly elevated ESR, the pretest probability of multiple myeloma is extremely high. This clinical presentation demands immediate comprehensive diagnostic testing with SPEP/immunofixation, not prognostic markers like β2-M 1, 2. Any detected monoclonal protein should prompt urgent referral to a hematologist/oncologist within 1-2 weeks given the accompanying symptoms and anemia 2.