What lab tests are used to diagnose and monitor multiple myeloma?

Laboratory Tests for Multiple Myeloma

The diagnostic workup for multiple myeloma requires serum and urine protein electrophoresis with immunofixation, serum free light chain assay, bone marrow aspiration/biopsy, and assessment of end-organ damage through complete blood count, serum calcium, creatinine, and skeletal imaging. 1

Core Laboratory Tests for Diagnosis

Monoclonal Protein Detection

• Serum protein electrophoresis (SPEP) with immunofixation is essential to detect and characterize the monoclonal (M-) protein, identifying the specific heavy chain (IgG, IgA, or IgM) and light chain (kappa or lambda) type 2, 1
• Nephelometric quantification of immunoglobulins (IgG, IgA, IgM) provides quantitative measurement of total immunoglobulin levels 2, 1
• 24-hour urine collection for protein electrophoresis and immunofixation is mandatory—random urine samples are insufficient even when corrected for creatinine 1, 3
• Serum free light chain (FLC) assay with kappa/lambda ratio is critical for detecting light chain myeloma and monitoring non-secretory or oligo-secretory disease 2, 1

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy must demonstrate ≥10% clonal plasma cells for diagnosis 2, 1
• CD138 staining should be performed to accurately quantify plasma cell percentage 1, 4
• Immunohistochemistry or immunofluorescence establishes clonality of plasma cells 1
• Cytogenetic/FISH analysis is essential for risk stratification, specifically evaluating for del(13q), t(4;14), t(14;16), and del(17p), which predict poorer outcomes 2, 4

Assessment of End-Organ Damage (CRAB Criteria)

Required Blood Tests

• Complete blood count (CBC) to detect anemia (hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal) 1, 4
• Serum calcium to identify hypercalcemia (>11.5 mg/dL) 2, 4
• Serum creatinine and creatinine clearance to assess renal insufficiency (creatinine >2 mg/dL or clearance <40 mL/min) 2, 4

Prognostic Markers

• Beta-2 microglobulin (β2M) is the most commonly used prognostic marker and forms the basis of the International Staging System when combined with serum albumin 2, 5
• Serum albumin combined with β2M provides staging information 2, 5
• Lactate dehydrogenase (LDH) is incorporated into the Revised International Staging System for prognostic assessment 2, 5

Imaging Studies

• Full skeletal survey (X-rays of spine, pelvis, skull, humeri, and femurs) is recommended to detect lytic bone lesions 2, 1
• MRI of spine and pelvis is necessary when spinal cord compression is suspected or if symptoms suggest bone lesions despite negative X-rays 2, 1
• CT or PET-CT may provide additional detail for evaluating symptomatic bony sites and distinguishing between MGUS, smoldering myeloma, and active myeloma 1, 5

Monitoring Disease Response

Serial Measurements

• Serial M-protein quantification (both serum and urine) tracks treatment response and disease progression 3
• Complete response requires negative immunofixation of both serum and urine, plus normal FLC ratio 3
• Partial response is defined as ≥50% reduction in serum M-protein and ≥90% reduction in 24-hour urinary light chain excretion (or to <200 mg/24h) 3

Critical Pitfalls to Avoid

• Never substitute random urine samples for 24-hour collections—this leads to false-negative results and inadequate monitoring 1, 3
• Always perform immunofixation even when no visible M-spike is present on electrophoresis, as some patients have low-level or light chain-only disease 3
• Use the same testing method for serial studies to ensure accurate comparison of M-protein levels over time 3
• Do not skip bone marrow examination in IgA or IgM monoclonal proteins, even if levels appear low 4
• Ensure adequate urine concentration when performing urine protein electrophoresis to avoid false negatives 3

Differential Diagnosis Framework

This comprehensive workup distinguishes between three entities 2, 1:

• MGUS: M-protein <3 g/dL, bone marrow plasma cells <10%, no CRAB criteria 4
• Smoldering myeloma: M-protein ≥3 g/dL and/or bone marrow plasma cells ≥10%, but no CRAB criteria 4
• Active multiple myeloma: ≥10% clonal plasma cells PLUS CRAB criteria or myeloma-defining biomarkers 1, 4