What are the diagnostic criteria for multiple myeloma?

Diagnostic Criteria for Multiple Myeloma

The diagnosis of multiple myeloma requires ≥10% clonal plasma cells in bone marrow or a biopsy-proven plasmacytoma, plus evidence of end-organ damage (CRAB criteria) or one of the newer myeloma defining events. 1, 2

Core Diagnostic Requirements

Essential Criteria

Multiple myeloma diagnosis is based on two fundamental requirements:

1. Clonal Plasma Cell Evidence:

   • ≥10% clonal plasma cells in bone marrow examination OR
   • Biopsy-proven plasmacytoma 1, 2

2. PLUS at least one of the following:

   • CRAB features (end-organ damage attributable to plasma cell disorder):
     • C: Hypercalcemia (serum calcium >11.5 mg/dl)
     • R: Renal insufficiency (serum creatinine >2 mg/dl or creatinine clearance <40 ml/min)
     • A: Anemia (hemoglobin <10 g/dl or ≥2 g/dl below lower limit of normal)
     • B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 3, 1

   OR one of the newer myeloma defining events:

   • Bone marrow clonal plasmacytosis ≥60% (regardless of CRAB features)
   • Serum involved/uninvolved free light chain ratio ≥100 (provided involved FLC is ≥100 mg/L)

   • 1 focal lesion on magnetic resonance imaging 2

Comprehensive Diagnostic Workup

Laboratory Tests

• Complete blood count with differential
• Comprehensive metabolic panel (including calcium, creatinine)
• Serum protein electrophoresis with immunofixation
• Quantitative immunoglobulins (IgG, IgA, IgM)
• Serum free light chain assay
• 24-hour urine collection for:
  • Total protein
  • Urine protein electrophoresis
  • Urine immunofixation 1

Imaging Studies

• Skeletal survey (radiographs of spine, pelvis, skull, humeri, femurs)
• Advanced imaging when indicated:
  • MRI (especially for suspected spinal cord compression)
  • CT scan
  • PET-CT (not routinely recommended but may be useful in certain cases) 3, 1

Bone Marrow Assessment

• Bone marrow aspiration and biopsy to:
  • Quantify plasma cell percentage
  • Assess morphology
  • Perform cytogenetic/FISH studies for risk stratification
  • Conduct immunophenotypic analysis 3, 1

Differential Diagnosis

The diagnostic criteria help differentiate between three plasma cell disorders:

Disorder	Diagnostic Criteria
MGUS	• Serum monoclonal protein <3 g/dl • Clonal bone marrow plasma cells <10% • Absence of CRAB features
Smoldering MM	• Serum monoclonal protein (IgG or IgA) ≥3 g/dl and/or clonal bone marrow plasma cells ≥10% • Absence of CRAB features
Multiple Myeloma	• ≥10% clonal plasma cells or plasmacytoma • PLUS CRAB features or other myeloma defining events [3]

Risk Stratification

Once diagnosed, risk stratification is essential for treatment planning:

• High-risk features: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation
• Double-hit myeloma: Presence of any two high-risk factors
• Triple-hit myeloma: Three or more high-risk factors 2

Common Pitfalls and Caveats

• Mimicking conditions: In elderly patients, comorbidities like mild renal insufficiency, anemia, diffuse osteoporosis, and hypercalcemia can mimic myeloma manifestations 1
• Incomplete evaluation: Failure to perform comprehensive bone marrow assessment including cytogenetics/FISH can lead to inadequate risk stratification
• Overlooking newer criteria: The updated diagnostic criteria include myeloma defining events beyond traditional CRAB features 2
• Misattribution of symptoms: CRAB features must be attributable to the plasma cell disorder, not to other medical conditions 3, 1

Staging

The International Staging System (ISS) combines:

• Beta-2 microglobulin
• Albumin
• LDH levels

Stage	Beta-2 microglobulin	Albumin
I	<3.5 mg/L	≥3.5 g/dL
II	3.5-5.5 mg/L or <3.5 mg/L	<3.5 g/dL
III	≥5.5 mg/L	any [1]

The most recent diagnostic criteria from 2024 provide the most comprehensive approach to multiple myeloma diagnosis, incorporating both traditional CRAB features and newer myeloma defining events that warrant treatment even in the absence of end-organ damage.