What are the diagnostic criteria for multiple myeloma?

Diagnostic Criteria for Multiple Myeloma

Multiple myeloma is diagnosed when there are ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma, plus evidence of one or more multiple myeloma defining events (MDE) including CRAB criteria or other specific biomarkers. 1, 2

Core Diagnostic Requirements

• Clonal plasma cell evidence: Either ≥10% clonal bone marrow plasma cells OR a biopsy-proven plasmacytoma 2, 1

• PLUS at least one of the following multiple myeloma defining events (MDE):

  • CRAB criteria (evidence of end-organ damage):

    • C: Hypercalcemia (serum calcium >11.5 mg/dL) 2
    • R: Renal insufficiency (serum creatinine >2 mg/dL or creatinine clearance <40 mL/min) 2
    • A: Anemia (hemoglobin <10 g/dL or 2 g/dL below lower limit of normal) 2
    • B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 2

  • OR any of these biomarkers of malignancy (even without CRAB features):

    • Bone marrow clonal plasmacytosis ≥60% 3, 1
    • Serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L) 1

    • 1 focal lesion on magnetic resonance imaging (MRI) 1

Diagnostic Workup

Initial Laboratory Testing

• Serum and urine protein electrophoresis with immunofixation 2
• 24-hour urine collection for protein electrophoresis (not random sample) 2
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 2
• Serum free light chain (FLC) assay with kappa/lambda ratio 2
• Complete blood count (CBC) 4
• Serum calcium and creatinine 4
• β2-microglobulin 4

Bone Marrow Examination

• Bone marrow aspiration and biopsy 2
• CD138 staining to accurately determine plasma cell percentage 2
• Cytogenetic/FISH studies for risk stratification 2

Imaging

• Skeletal survey 4
• MRI of thoracic-lumbar spine and pelvis (especially if conventional imaging is negative) 4, 1

Distinguishing Multiple Myeloma from Related Conditions

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Serum monoclonal protein <3 g/dL 2
• Clonal bone marrow plasma cells <10% 2
• Absence of end-organ damage (CRAB criteria) 2
• No immediate treatment required, but lifelong follow-up recommended 2

Smoldering Multiple Myeloma (SMM)

• Intermediate stage between MGUS and MM 2
• Higher risk of progression (10% per year for first 5 years) 2
• Requires closer monitoring than MGUS 2
• No immediate treatment currently recommended 2

Risk Stratification

• High-risk multiple myeloma features include:
  • del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 1
  • Double-hit myeloma: presence of any two high-risk factors 1
  • Triple-hit myeloma: presence of three or more high-risk factors 1

Common Pitfalls to Avoid

• Failing to distinguish between smoldering multiple myeloma and symptomatic multiple myeloma, which require different management approaches 5
• Performing unnecessary bone marrow biopsies and imaging in low-risk MGUS patients 2
• Delaying treatment in patients with clear CRAB criteria, which can lead to increased morbidity and mortality 5
• Not recognizing the evolving versus non-evolving patterns of disease, which have different progression timelines (evolving: ~1.5 years; non-evolving: ~4 years) 4

Follow-up Recommendations

• For confirmed SMM patients: follow-up at 3-month intervals for the first year to establish the pattern of evolution 4
• For high-risk SMM patients (M-protein >3 g/dL and >10% BMPC, >95% phenotypically abnormal BMPC, immunoparesis, or evolving type): closer monitoring 4
• For lower-risk patients: less frequent follow-up may be sufficient 4