What is the diagnostic workup for multiple myeloma?

Diagnostic Workup for Multiple Myeloma

The diagnostic workup for multiple myeloma requires serum and urine protein electrophoresis, immunoglobulin quantification, bone marrow evaluation, and skeletal imaging to detect clonal plasma cells and evidence of end-organ damage. 1

Core Diagnostic Tests

Laboratory Evaluation

• Monoclonal Protein Assessment:

  • Serum protein electrophoresis and immunofixation 1
  • Urine protein electrophoresis (24-hour collection) 1
  • Quantification of IgG, IgA, and IgM immunoglobulins 1
  • Serum free light chain (FLC) measurement and ratio calculation 1, 2

• Complete Blood Count:

  • Hemoglobin (to assess for anemia) 1
  • White blood cell count with differential 1
  • Platelet count

• Blood Chemistry:

  • Serum calcium (to detect hypercalcemia) 1
  • Serum creatinine (to assess renal function) 1
  • Lactate dehydrogenase (LDH) 1
  • Beta-2 microglobulin (important prognostic marker) 1
  • Albumin (for staging) 1

Bone Marrow Assessment

• Bone marrow aspiration and biopsy to:
  • Quantify plasma cell infiltration (≥10% clonal plasma cells required for diagnosis) 1
  • Assess morphology of plasma cells 1
  • Perform cytogenetic/FISH analysis for prognostic markers 1
    • Key abnormalities: del(17p), t(4;14), t(14;16), del(13q), gain 1q, del 1p 2

Imaging Studies

• Skeletal Survey:
  • Full skeleton X-ray survey (traditional approach) 1
  • More advanced imaging recommended in current practice:
    • Whole-body low-dose CT scan 3
    • MRI (especially for suspected spinal cord compression) 1
    • PET-CT (helpful for detecting active lesions) 3

Diagnostic Criteria

The diagnosis of symptomatic multiple myeloma requires:

1. ≥10% clonal plasma cells in bone marrow or biopsy-proven plasmacytoma 1, 2
2. Evidence of end-organ damage attributable to plasma cell disorder (CRAB features) 1, 2:
   • C: Hypercalcemia (serum calcium >11.5 mg/dl)
   • R: Renal insufficiency (creatinine >2 mg/dl or clearance <40 ml/min)
   • A: Anemia (hemoglobin <10 g/dl or 2 g/dl below normal)
   • B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures)

OR one of the following myeloma-defining events 2:

• Bone marrow clonal plasmacytosis ≥60%
• Serum involved/uninvolved free light chain ratio ≥100 (if involved FLC ≥100 mg/L)

• 1 focal lesion on MRI

Risk Stratification

After diagnosis, risk stratification should be performed using:

• International Staging System (ISS) combining beta-2 microglobulin and albumin 1
• Revised ISS (R-ISS) which also incorporates cytogenetic abnormalities and LDH 3
• Cytogenetic risk classification 2:
  • High-risk: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation
  • Double-hit: presence of any two high-risk factors
  • Triple-hit: three or more high-risk factors

Common Pitfalls to Avoid

• Failing to distinguish between MGUS, smoldering myeloma, and symptomatic myeloma 1

  • MGUS: <3 g/dl M-protein, <10% clonal plasma cells, no CRAB features
  • Smoldering myeloma: ≥3 g/dl M-protein or ≥10% clonal plasma cells, no CRAB features
  • Symptomatic myeloma: requires CRAB features or myeloma-defining events

• Inadequate imaging assessment 1, 3

  • Traditional skeletal surveys may miss lesions that more advanced imaging can detect
  • MRI is essential when spinal cord compression is suspected

• Incomplete cytogenetic evaluation 1, 2

  • Cytogenetic abnormalities significantly impact prognosis and treatment decisions
  • Both conventional karyotyping and FISH analysis may be needed for comprehensive assessment

• Overlooking non-secretory or light-chain-only myeloma 1

  • Approximately 3% of patients have non-secretory disease
  • Serum free light chain assay is essential for detecting and monitoring these variants

By following this comprehensive diagnostic approach, clinicians can accurately diagnose multiple myeloma, differentiate it from related plasma cell disorders, and appropriately risk-stratify patients to guide treatment decisions.