What are the diagnostic criteria for multiple myeloma?

Diagnostic Criteria for Multiple Myeloma

Multiple myeloma requires ≥10% clonal plasma cells in bone marrow (or biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event: either CRAB criteria (hypercalcemia, renal failure, anemia, bone lesions) attributable to the plasma cell disorder, OR specific biomarkers of malignancy (≥60% bone marrow plasma cells, serum involved/uninvolved free light chain ratio ≥100, or >1 focal lesion ≥5mm on MRI). 1, 2, 3

Core Diagnostic Requirements

Plasma Cell Threshold

• ≥10% clonal plasma cells must be documented on bone marrow aspiration and biopsy, with CD138 immunostaining performed to accurately quantify the plasma cell percentage 4, 2
• Alternatively, a biopsy-proven plasmacytoma satisfies this requirement 4, 3

Myeloma-Defining Events: CRAB Criteria

The presence of any one CRAB criterion attributable to the plasma cell disorder confirms symptomatic myeloma requiring treatment 2:

• C (Hypercalcemia): Serum calcium >11.5 mg/dL 4, 1
• R (Renal insufficiency): Serum creatinine >2 mg/dL OR creatinine clearance <40 mL/min 4, 1
• A (Anemia): Hemoglobin <10 g/dL OR ≥2 g/dL below the lower limit of normal (normochromic, normocytic) 4, 1
• B (Bone lesions): Lytic lesions, severe osteopenia, or pathologic fractures on skeletal imaging 4, 1

Biomarkers of Malignancy (Without CRAB)

Even in the absence of CRAB criteria, multiple myeloma is diagnosed if any of these biomarkers are present 1, 2, 3:

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

Essential Laboratory Workup

Protein Studies

• Serum protein electrophoresis with immunofixation to identify and characterize the monoclonal protein 1, 2
• 24-hour urine protein electrophoresis with immunofixation using a concentrated 24-hour collection—never use random urine samples 1, 2
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 4, 2
• Serum free light chain (FLC) assay with kappa/lambda ratio measurement 4, 2

Hematology and Chemistry

• Complete blood count with differential to assess for anemia 4
• Serum creatinine and creatinine clearance (using validated equations like MDRD or CKD-EPI) 4, 5
• Serum calcium to detect hypercalcemia 4
• β2-microglobulin, albumin, and LDH for prognostic stratification 1

Bone Marrow Evaluation

• Bone marrow aspiration and trephine biopsy are mandatory to confirm ≥10% clonal plasma cells 4, 2
• CD138 immunostaining must be performed to accurately quantify plasma cell infiltration—failure to do this can lead to underestimation of plasma cell percentage 1, 2
• Cytogenetic/FISH studies are required for risk stratification, specifically testing for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, and p53 mutation 1, 2, 3

Skeletal Imaging

• Whole-body low-dose CT or FDG-PET/CT is now the preferred imaging modality for detecting osteolytic disease 1
• If advanced imaging is unavailable, a conventional skeletal survey should include spine, pelvis, skull, humeri, and femora 1, 2
• MRI of thoracolumbar spine and pelvis is mandatory when skeletal survey is negative but clinical suspicion persists, or when spinal cord compression is suspected 4, 2

Critical Differential Diagnoses

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Serum monoclonal protein <3 g/dL 4, 2
• Clonal bone marrow plasma cells <10% 4, 2
• No CRAB criteria or myeloma-defining biomarkers 4, 2
• Progresses to myeloma at approximately 1% per year 1

Smoldering Multiple Myeloma (SMM)

• Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10% 4, 2
• No CRAB criteria or myeloma-defining biomarkers 4, 2
• Progresses to symptomatic myeloma at approximately 10% per year during the first five years 1
• Immediate treatment is not recommended—observation with close monitoring is the standard 4, 1

Risk Stratification

International Staging System (ISS)

• Stage I: β2-microglobulin <3.5 mg/L AND albumin ≥3.5 g/dL 2, 5
• Stage II: Neither Stage I nor III 2, 5
• Stage III: β2-microglobulin ≥5.5 mg/L (worst prognosis) 2, 5

High-Risk Cytogenetics

• Del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 2, 3
• Presence of any two high-risk factors is considered double-hit myeloma 3, 6
• Three or more high-risk factors is triple-hit myeloma 3, 6

Common Pitfalls to Avoid

• Never use random urine samples for protein electrophoresis—only 24-hour concentrated collections are acceptable 2
• Do not perform unnecessary bone marrow biopsies in low-risk MGUS patients 1, 2
• Do not miss spinal cord compression—obtain urgent MRI when clinically indicated 2
• Do not overlook cytogenetic testing—high-risk features fundamentally change treatment decisions and prognosis 2
• Ensure CD138 staining is performed to avoid underestimating plasma cell percentage 1, 2