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 (MDE), which includes either CRAB criteria or specific biomarkers indicating imminent organ damage. 1, 2

Core Diagnostic Requirements

Bone Marrow Component

• ≥10% clonal plasma cells on bone marrow aspiration and biopsy is the fundamental requirement 1, 3
• CD138 staining must be performed to accurately quantify the plasma cell percentage 1
• Flow cytometry should be utilized to confirm monoclonality of plasma cells, particularly in atypical presentations 4
• A biopsy-proven plasmacytoma can substitute for the bone marrow requirement 1, 2

Myeloma-Defining Events (MDE)

CRAB Criteria (End-Organ Damage):

• Hypercalcemia: Serum calcium >11.5 mg/dL 1, 3
• Renal insufficiency: Serum creatinine >2 mg/dL or creatinine clearance <40 mL/min 1
• Anemia: Hemoglobin <10 g/dL or ≥2 g/dL below the lower limit of normal 1
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures on skeletal survey 1

Biomarkers of Imminent Organ Damage (SLiM Criteria):

• Bone marrow clonal plasmacytosis ≥60% 5, 6, 2
• Serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L and urine monoclonal protein is ≥200 mg/24 h) 2
• >1 focal lesion on MRI (≥5 mm in size) 5, 6, 2

Required Laboratory Workup

Protein Studies

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

Additional Essential Tests

• Complete blood count, serum calcium, creatinine, and β2-microglobulin 1
• Bone marrow aspiration and biopsy with cytogenetic/FISH studies for risk stratification 1
• Skeletal survey and MRI of thoracic-lumbar spine and pelvis 1

Critical Distinctions to Prevent Misdiagnosis

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Serum monoclonal protein <3 g/dL 1
• Clonal bone marrow plasma cells <10% 1
• No CRAB criteria or myeloma-defining biomarkers 1
• No treatment required, but lifelong monitoring needed 1

Smoldering Multiple Myeloma (SMM)

• Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10% 1
• No CRAB criteria or myeloma-defining biomarkers 1
• Higher progression risk (10% per year for first 5 years) but no immediate treatment indicated 1
• Requires closer monitoring than MGUS 1

Common Pitfalls and How to Avoid Them

• Do not rely solely on fixed bone marrow plasma cell percentage thresholds without considering monoclonal plasma cell proliferation evidence, as this leads to misdiagnosis of early or atypical cases 4
• Always use CD138 staining and flow cytometry to accurately quantify and confirm clonality of plasma cells, particularly when morphology is ambiguous 1, 4
• Ensure CRAB criteria are attributable to the plasma cell disorder and not other comorbidities before diagnosing symptomatic myeloma 5, 6, 2
• Use advanced imaging (MRI) when skeletal survey is negative but clinical suspicion remains high, as focal lesions on MRI constitute a myeloma-defining event 1, 2
• Avoid unnecessary bone marrow biopsies in low-risk IgG MGUS (serum M-protein ≤15 g/L without end-organ damage), but perform them for all IgA and IgM M-proteins 1