What lab tests are necessary to diagnose multiple myeloma?

Laboratory Testing Necessary to Diagnose Multiple Myeloma

To diagnose multiple myeloma, you must obtain serum and urine protein electrophoresis with immunofixation, serum free light chains, complete blood count, serum calcium, serum creatinine, bone marrow aspiration/biopsy with cytogenetics, and skeletal imaging—these tests together establish both the presence of clonal plasma cells and end-organ damage required for diagnosis. 1

Essential Laboratory Tests for Monoclonal Protein Detection

The detection and characterization of the monoclonal (M-) protein is fundamental to diagnosis:

• Serum protein electrophoresis with immunofixation to identify and characterize the monoclonal protein 1
• 24-hour urine collection (not random sample) for urine protein electrophoresis with immunofixation—this is critical as random samples are insufficient 2, 3
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins to measure total immunoglobulin levels 1
• Serum free light chain (FLC) assay with kappa/lambda ratio—especially important for detecting light chain myeloma and monitoring non-secretory disease 1

Bone Marrow Evaluation

Bone marrow assessment is mandatory to establish clonality and quantify plasma cell infiltration:

• Bone marrow aspiration and/or biopsy to evaluate plasma cell percentage—diagnosis requires ≥10% clonal plasma cells 1
• CD138 staining should be performed to accurately determine the plasma cell percentage 2, 3
• Cytogenetic/FISH studies for risk stratification, specifically looking for del(17p), t(4;14), t(14;16), and del(13q) which are associated with poorer outcomes 1
• Immunohistochemistry or immunofluorescence to establish clonality of plasma cells 3

Laboratory Tests for End-Organ Damage (CRAB Criteria)

These tests determine whether the patient has symptomatic myeloma requiring treatment:

• Complete blood count (CBC) to assess for anemia—defined as hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 1
• Serum calcium to detect hypercalcemia—defined as >11.5 mg/dL 1
• Serum creatinine and creatinine clearance to assess renal function—renal insufficiency defined as creatinine >2 mg/dL or clearance <40 mL/min 1
• Serum β2-microglobulin and albumin for prognostic staging using the International Staging System 1, 2

Imaging Studies (Not Laboratory but Essential)

While not laboratory tests, imaging is required to complete the diagnostic workup:

• Full skeletal survey (X-rays of spine, pelvis, skull, humeri, and femurs) to detect lytic bone lesions 1
• MRI of spine and pelvis if skeletal survey is negative but symptoms suggest bone lesions, or if spinal cord compression is suspected 1

Critical Diagnostic Distinctions

The laboratory workup allows differentiation between three entities:

• MGUS: Serum M-protein <3 g/dL, clonal bone marrow plasma cells <10%, and no CRAB criteria 1, 2
• Smoldering myeloma: Serum M-protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%, but no CRAB criteria 1, 2
• Multiple myeloma: ≥10% clonal plasma cells PLUS evidence of end-organ damage (CRAB criteria) or myeloma-defining biomarkers 1

Common Pitfalls to Avoid

Do not use random urine samples—always collect 24-hour urine for protein electrophoresis, as random samples are inadequate for diagnosis 2, 3. The guidelines consistently emphasize this point across multiple sources.

Do not skip serum free light chains—this test is essential for detecting light chain myeloma and monitoring non-secretory disease, which would otherwise be missed 1.

Do not omit cytogenetics—FISH analysis is critical for risk stratification and treatment planning, as high-risk cytogenetic abnormalities fundamentally alter prognosis and management 1.