What are the diagnostic criteria for multiple myeloma?

Diagnostic Criteria for Multiple Myeloma

Multiple myeloma requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event, which includes either CRAB criteria (end-organ damage) or specific high-risk biomarkers. 1, 2

Core Diagnostic Requirements

Bone Marrow Component

• ≥10% clonal plasma cells on bone marrow aspiration and biopsy is the fundamental requirement 1, 2
• CD138 staining should be performed to accurately quantify the plasma cell percentage 1, 2
• Cytogenetic/FISH studies must be obtained for risk stratification, looking specifically for t(4;14), deletion(17p), t(14;16), and chromosome 1 abnormalities 1, 2

Myeloma-Defining Events (Must Have At Least One)

CRAB Criteria (End-Organ Damage):

• Hypercalcemia: Serum calcium >11.5 mg/dL 1, 2
• Renal insufficiency: Serum creatinine >2 mg/dL or creatinine clearance <40 mL/min 1, 2
• Anemia: Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 1, 2
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures on skeletal survey 1, 2

Biomarkers of Malignancy (Even Without CRAB):

• ≥60% clonal plasma cells in bone marrow 2, 3
• Involved/uninvolved serum free light chain ratio ≥100 (provided involved FLC is ≥100 mg/L) 2, 3
• >1 focal lesion on MRI (each lesion must be ≥5 mm in size) 2, 3

Required Laboratory Workup

Protein Studies

• Serum protein electrophoresis with immunofixation to identify monoclonal protein 1
• 24-hour urine collection for protein electrophoresis with immunofixation (not random sample) 1, 2
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 1, 2
• Serum free light chain assay with kappa/lambda ratio 1, 2

Additional Essential Tests

• Complete blood count with differential 2
• Serum calcium 1, 2
• Serum creatinine and creatinine clearance (using MDRD or CKD-EPI equations) 2
• Serum β2-microglobulin for International Staging System classification 2
• Serum albumin for staging 2

Imaging Requirements

• Skeletal survey to identify lytic lesions 1
• MRI of thoracic-lumbar spine and pelvis, especially if conventional imaging is negative 1

Critical Distinctions to Avoid Misdiagnosis

MGUS (Does NOT Require Treatment)

• Serum monoclonal protein <3 g/dL 1
• Clonal bone marrow plasma cells <10% 1
• Absence of CRAB criteria and myeloma-defining biomarkers 1

Smoldering Multiple Myeloma (Does NOT Require Immediate Treatment)

• Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10% 1
• No CRAB criteria or myeloma-defining biomarkers present 1
• Requires closer monitoring than MGUS (3-month intervals first year) but immediate treatment is not recommended 1

Common Pitfalls

The most frequent diagnostic error is using fixed bone marrow plasma cell percentage thresholds without considering monoclonal plasma cell proliferation evidence. 4 Flow cytometry should be utilized to confirm clonality in atypical cases where plasma cell percentage is borderline. 4

Do not delay treatment once CRAB criteria are confirmed, as this leads to increased morbidity and mortality. 5 However, equally important is avoiding unnecessary treatment in smoldering myeloma patients who lack myeloma-defining events. 5

Advanced imaging with MRI is essential when skeletal survey is negative but clinical suspicion remains high, as focal lesions >5 mm on MRI constitute a myeloma-defining event even without CRAB criteria. 2, 3