Which laboratory tests should be ordered to diagnose multiple myeloma?

Laboratory Tests for Diagnosing Multiple Myeloma

To diagnose multiple myeloma, you must order a comprehensive panel including: complete blood count with differential, complete metabolic panel (including calcium, creatinine, albumin), serum protein electrophoresis with immunofixation, quantitative immunoglobulins by nephelometry, 24-hour urine collection for protein electrophoresis and immunofixation, serum free light chains with ratio, beta-2 microglobulin, LDH, and bone marrow aspirate/biopsy with cytogenetics. 1, 2

Essential Blood Tests

Complete Blood Count and Chemistry

• CBC with differential and peripheral blood smear to identify rouleaux formation (red cells appearing as stacks of coins), circulating plasma cells, and anemia 1, 2
• Complete metabolic panel including:
  • Serum calcium (≥11.5 mg/dL indicates hypercalcemia, a diagnostic criterion) 1
  • Serum creatinine and calculated creatinine clearance (≥2 mg/dL indicates renal insufficiency, a diagnostic criterion) 1, 2
  • Serum albumin (for International Staging System prognostication) 1, 2
  • Liver function tests and electrolytes 1, 2

Monoclonal Protein Detection (Critical for Diagnosis)

• Serum protein electrophoresis (SPEP) using agarose gel or capillary zone electrophoresis to screen for monoclonal protein 1, 3
• Serum immunofixation electrophoresis (SIFE) to confirm presence and identify the specific type of heavy and light chain 1, 3
• Nephelometric quantitation of immunoglobulins (IgG, IgA, IgM) - this is complementary to electrophoresis and particularly useful for detecting low levels of uninvolved immunoglobulins 1

Important caveat: Both densitometer tracing from electrophoresis AND nephelometric quantitation should be performed, as they are complementary tests. Nephelometry may overestimate monoclonal protein when values are high. 1

Serum Free Light Chain Assay

• Serum free light chain (FLC) measurement with kappa/lambda ratio is essential for:
  • High sensitivity screening (detects monoclonal protein in 99% of myeloma cases when combined with SPEP/SIFE) 2, 4
  • Monitoring light chain myeloma and non-secretory myeloma 2
  • Documenting stringent complete response per IMWG criteria 2
  • Prognostication 2

Critical distinction: Serum FLC assay CANNOT replace 24-hour urine collection for monitoring measurable urinary M-protein and is affected by renal function. 2

Prognostic Markers

• Beta-2 microglobulin - reflects tumor burden and is part of the International Staging System 1, 2
• Lactate dehydrogenase (LDH) - reflects tumor cell characteristics and proliferation 2

Essential Urine Tests

24-Hour Urine Collection (Mandatory)

• 24-hour urine collection for total protein quantification 1
• Urine protein electrophoresis (UPEP) on concentrated 24-hour specimen to identify and quantify monoclonal protein 1, 2
• Urine immunofixation electrophoresis (UIFE) to confirm presence and type of light chains (Bence Jones protein) 1, 2

Critical pitfall: Immunofixation should be performed even if there is no measurable protein peak on urine electrophoresis, as light chains may still be present. A 24-hour collection cannot be replaced by random urine samples with creatinine correction. 1

• Routine urinalysis as initial screening 2

Do NOT order: Urine free light chain assay - this test should not be performed. 1

Bone Marrow Evaluation

• Unilateral bone marrow aspirate and/or biopsy to demonstrate ≥10% clonal plasma cells (major diagnostic criterion) 1, 2
• CD138 immunoperoxidase or immunofluorescence staining to accurately determine plasma cell percentage and establish clonality 1
• Cytogenetics including metaphase karyotype and FISH for prognostic stratification 1

Practical consideration: Trephine biopsy should be performed alongside aspirate because it provides more reliable assessment of plasma cell infiltration and avoids need for repeat procedure if aspirate is inadequate. 1

Diagnostic Criteria Context

The diagnosis requires all three of the following 1:

1. Clonal bone marrow plasma cells ≥10%
2. Presence of serum and/or urinary monoclonal protein (except in non-secretory myeloma)
3. Evidence of end-organ damage (CRAB criteria: hypercalcemia, renal insufficiency, anemia with hemoglobin ≥2 g/dL below normal or <10 g/dL, bone lesions)

Key principle: Use the same quantitative test (either densitometry or nephelometry) for serial monitoring to ensure accurate comparison over time. 2