What are the diagnostic criteria and tests for Multiple Myeloma?

How to Diagnose Multiple Myeloma

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

Essential Laboratory Tests

Monoclonal Protein Detection

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

Blood and Chemistry Tests

• Complete blood count with differential to assess for anemia 4, 1
• Serum creatinine and creatinine clearance (calculated using MDRD or CKD-EPI equations) to evaluate renal function 4, 1
• Serum calcium to detect hypercalcemia 4, 1
• Serum β2-microglobulin, albumin, and lactate dehydrogenase for International Staging System (ISS) risk stratification 1, 5

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy are mandatory to quantify clonal plasma cell percentage 4, 1, 2
• CD138 staining should be performed to accurately determine plasma cell percentage 4, 1
• Cytogenetic/FISH studies are essential for risk stratification, specifically testing for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, and p53 mutation 4, 1, 3

Important caveat: Bone marrow examination is not routinely needed for IgG MGUS if serum M-protein is ≤15 g/L without end-organ damage, but should be performed for all IgA and IgM M-proteins. 1

Imaging Requirements

• Full skeletal X-ray survey (spine, pelvis, skull, humeri, femurs) remains the standard for detecting lytic bone lesions 4, 2
• MRI of spine and pelvis provides superior detail and is mandatory when spinal cord compression is suspected or when skeletal survey is negative but symptoms suggest bone lesions 4, 2
• CT scan may be needed to evaluate symptomatic bony sites if skeletal survey is negative 4
• PET-CT is under evaluation but should not be used systematically 4

CRAB Criteria for End-Organ Damage

The presence of any one CRAB criterion attributable to the plasma cell disorder confirms symptomatic myeloma requiring treatment: 1, 2

• 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 imaging 1, 2

Additional Myeloma-Defining Events (Without CRAB)

Even without CRAB criteria, multiple myeloma is diagnosed if: 1, 2, 3

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

Risk Stratification

International Staging System (ISS)

• Stage I: β2-microglobulin <3.5 mg/L AND albumin ≥3.5 g/dL 1, 2
• Stage II: Neither Stage I nor III 1, 2
• Stage III: β2-microglobulin ≥5.5 mg/L (worst prognosis) 1, 2

High-Risk Cytogenetics

High-risk features include del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation. 1, 2, 3 The presence of two high-risk factors defines double-hit myeloma; three or more defines triple-hit myeloma. 3 These cytogenetic findings fundamentally alter treatment approach and prognosis, so testing must not be overlooked. 2

Differential Diagnosis

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
• Progresses to myeloma at 1% per year 4

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
• Progresses at 10% per year for first 5 years, then 3% per year for next 5 years, then 1.5% per year thereafter 4

Critical Pitfalls to Avoid

• Never use random urine samples for protein electrophoresis—only 24-hour concentrated collections are acceptable 1, 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 2
• Ensure CD138 staining is performed to avoid underestimating plasma cell percentage 4, 1