What are the diagnostic criteria for multiple myeloma in terms of clonal bone marrow plasma cells as detected by histopathology and biomarkers of malignancy?

Understanding the Diagnostic Criteria for Multiple Myeloma: Clonal Bone Marrow Plasma Cells

The ≥10% threshold is the minimum requirement for diagnosis when combined with CRAB criteria or other myeloma-defining events, while ≥60% clonal bone marrow plasma cells alone is sufficient to diagnose multiple myeloma even without end-organ damage—this is a biomarker of malignancy that independently defines the disease. 1, 2

The Two-Pathway Diagnostic Framework

Multiple myeloma can be diagnosed through either of two distinct pathways, both requiring ≥10% clonal bone marrow plasma cells as the baseline threshold:

Pathway 1: Traditional CRAB Criteria

• Requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS evidence of end-organ damage 1, 3
• The CRAB criteria include:
  • Hypercalcemia: Serum calcium >11.5 mg/dL 1, 2
  • Renal insufficiency: 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 1, 2

Pathway 2: Biomarkers of Malignancy (Without CRAB)

• When clonal bone marrow plasma cells reach ≥60%, this alone constitutes a myeloma-defining event 2, 4, 5
• This threshold indicates such high tumor burden that treatment is warranted even without symptomatic end-organ damage 4, 6
• Two additional biomarkers can also define myeloma independently:
  • Involved/uninvolved serum free light chain ratio ≥100 (provided involved FLC ≥100 mg/L) 2, 4, 5

  • 1 focal lesion on MRI (each lesion ≥5 mm) 2, 4, 5

Why This Distinction Matters Clinically

The ≥60% threshold represents a paradigm shift from waiting for organ damage to occur before treating. 4, 6 Studies demonstrated that patients with ≥60% clonal plasma cells progress to symptomatic myeloma so rapidly (typically within 2 years) that immediate treatment improves outcomes compared to observation. 7, 8

Critical Diagnostic Steps

• CD138 staining should be performed on bone marrow specimens to accurately quantify plasma cell percentage 1, 2
• This is essential because visual estimation can underestimate the true clonal burden
• All patients require serum free light chain assay with kappa/lambda ratio to assess for the FLC ratio biomarker 1, 2
• MRI of spine and pelvis is recommended to identify focal lesions that may not be visible on skeletal survey 2

Common Pitfalls to Avoid

Do not confuse smoldering multiple myeloma (SMM) with active myeloma requiring treatment. 1, 3 SMM has ≥10% clonal plasma cells but <60%, with no CRAB criteria and no other myeloma-defining biomarkers—these patients are observed, not treated immediately. 1

The 10% threshold is not sufficient alone for diagnosis—it must be accompanied by either CRAB criteria OR one of the three biomarkers of malignancy (≥60% plasma cells, FLC ratio ≥100, or >1 MRI focal lesion). 1, 2, 4

Patients with exactly 60% plasma cells meet diagnostic criteria and should be treated, not observed, as this represents the biomarker threshold for inevitable progression. 2, 4, 5