What tests are used to diagnose multiple myeloma?

Diagnostic Testing for Multiple Myeloma

To diagnose multiple myeloma, you must obtain serum and urine protein studies, bone marrow examination with cytogenetics, complete skeletal imaging, and basic labs to assess for end-organ damage (CRAB criteria). 1

Initial Laboratory Testing

Protein Studies (Essential for M-protein Detection)

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize the monoclonal protein 1, 2
• 24-hour urine collection for protein electrophoresis and immunofixation—a random urine sample is insufficient 2
• Nephelometric quantification of immunoglobulins (IgG, IgA, IgM) 1, 2
• Serum free light chain (FLC) assay with kappa/lambda ratio—this is particularly critical for detecting light chain myeloma 2

Assessment for End-Organ Damage (CRAB Criteria)

• Complete blood count to evaluate for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal) 1, 3
• Serum calcium to detect hypercalcemia (>11.5 mg/dL) 1, 3
• Serum creatinine to assess renal function (>2 mg/dL or creatinine clearance <40 mL/min) 1, 3

Bone Marrow Evaluation

Bone marrow aspiration and biopsy are mandatory to quantify plasma cell infiltration—diagnosis requires ≥10% clonal plasma cells 1, 2

Additional Bone Marrow Studies

• CD138 staining to accurately determine plasma cell percentage 2
• Immunohistochemistry or immunofluorescence to establish clonality of plasma cells 2
• Cytogenetics and FISH studies to detect high-risk features including del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 1, 2, 4

Imaging Studies for Bone Lesions

Primary Imaging

• Full skeletal survey (X-rays) including spine, pelvis, skull, humeri, and femurs to detect lytic bone lesions 1, 2

Advanced Imaging When Indicated

• MRI of spine and pelvis if symptoms suggest bone lesions despite negative skeletal survey, or if spinal cord compression is suspected 1, 2
• CT scan to evaluate symptomatic bony sites 1, 2
• PET scan may help distinguish between MGUS, smoldering myeloma, and overt myeloma, though not routinely recommended 1, 2

Diagnostic Criteria

Multiple myeloma diagnosis requires BOTH:

1. ≥10% clonal plasma cells on bone marrow examination OR biopsy-proven plasmacytoma 1, 5
2. Evidence of end-organ damage (CRAB criteria) attributable to the plasma cell disorder 1, 3

CRAB Criteria Specifics

• Hypercalcemia: serum calcium >11.5 mg/dL 1, 3
• Renal insufficiency: creatinine >2 mg/dL or creatinine clearance <40 mL/min 1, 3
• Anemia: hemoglobin <10 g/dL or ≥2 g/dL below normal 1, 3
• Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures 1, 3

Differential Diagnosis

This workup allows you to distinguish between three entities 1, 2:

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Serum M-protein <3 g/dL
• Clonal bone marrow plasma cells <10%
• No CRAB criteria 1, 6

Smoldering Multiple Myeloma

• Serum M-protein ≥3 g/dL AND/OR clonal bone marrow plasma cells ≥10%
• No CRAB criteria 1

Symptomatic Multiple Myeloma

• Clonal bone marrow plasma cells ≥10% OR plasmacytoma
• CRAB criteria present 1

Common Pitfalls to Avoid

• Do not rely on random urine samples—always obtain a 24-hour urine collection for accurate protein quantification 2
• Do not skip immunofixation—SPEP alone may miss or mischaracterize monoclonal proteins 2, 7
• Do not omit serum free light chains—essential for light chain myeloma detection 2
• Do not forget FISH studies on bone marrow—critical for risk stratification and prognosis 1, 4
• Always perform bone marrow examination if any CRAB criteria are present to avoid missing the diagnosis or misclassifying as MGUS 6