Systematic Diagnostic Workup for Multiple Myeloma
Initial Laboratory Screening
When multiple myeloma is suspected, immediately order a comprehensive laboratory panel including complete blood count, comprehensive metabolic panel (with calcium and creatinine), serum protein electrophoresis with immunofixation, serum free light chain assay with kappa/lambda ratio, and quantitative immunoglobulins (IgG, IgA, IgM). 1, 2
Essential Blood Tests
- Serum protein electrophoresis with immunofixation to detect and characterize monoclonal protein (M-protein) 2, 3
- Serum free light chain assay with kappa/lambda ratio to identify light chain disease and assess the involved/uninvolved ratio 2, 3
- Nephelometric quantification of IgG, IgA, and IgM to measure total immunoglobulin levels 2, 3
- Complete blood count to assess for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal) 2, 4
- Serum calcium to detect hypercalcemia (>11.5 mg/dL) 2, 3
- Serum creatinine and creatinine clearance to evaluate renal function (renal insufficiency defined as creatinine >2 mg/dL or clearance <40 mL/min) 2, 3
- β2-microglobulin, albumin, and lactate dehydrogenase for staging and prognostication 3, 4
Urine Studies
- 24-hour urine protein electrophoresis with immunofixation (not random urine samples) to detect Bence Jones protein 2, 3
Bone Marrow Examination
If laboratory screening reveals M-protein or abnormal free light chain ratio, proceed immediately to bone marrow aspiration and biopsy. 1, 2
Bone Marrow Requirements
- ≥10% clonal plasma cells on bone marrow examination is required for diagnosis 2, 5, 6
- CD138 staining should be performed to accurately quantify plasma cell percentage 1, 2
- Cytogenetic/FISH studies are mandatory for risk stratification, specifically evaluating for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, and p53 mutation 2, 3, 6
Skeletal Imaging
Whole-body low-dose CT or FDG-PET/CT is now preferred over conventional skeletal survey, detecting 25.5% more lesions than plain radiographs. 1
Imaging Protocol
- Whole-body low-dose CT or FDG-PET/CT as first-line imaging for suspected myeloma 1
- MRI of spine and pelvis if conventional imaging is negative but clinical suspicion remains high, or if spinal cord compression is suspected 3, 4
- Look for focal lytic "punched-out" lesions particularly in skull, spine, ribs, and pelvis 1
Diagnostic Confirmation Criteria
Multiple myeloma requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event. 3, 5, 6
CRAB Criteria (End-Organ Damage)
- Hypercalcemia: serum calcium >11.5 mg/dL 2, 3
- Renal insufficiency: creatinine >2 mg/dL or clearance <40 mL/min 2, 3
- Anemia: hemoglobin <10 g/dL or ≥2 g/dL below normal 2, 3
- Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures 2, 3
Alternative Myeloma-Defining Biomarkers
- ≥60% bone marrow plasma cells 3, 5, 6
- Serum involved/uninvolved free light chain ratio ≥100 (provided involved FLC ≥100 mg/L) 3, 5, 6
- >1 focal lesion ≥5mm on MRI 3
Critical Diagnostic Pitfalls to Avoid
- Do not use random urine samples for protein electrophoresis; always collect 24-hour urine 2, 3
- Do not confuse severe osteoporosis with myeloma; always check for M-protein before assuming osteoporosis in patients with multiple vertebral fractures 1
- Do not order unnecessary bone marrow biopsies in low-risk MGUS patients (IgG M-protein ≤15 g/L without end-organ damage) 2
- Do not miss spinal cord compression; obtain urgent MRI when clinically indicated 3
- Do not overlook cytogenetic testing, as high-risk features fundamentally alter treatment approach and prognosis 3
Distinguishing from MGUS and Smoldering Myeloma
- MGUS: M-protein <3 g/dL, bone marrow plasma cells <10%, no CRAB criteria 2, 7
- Smoldering myeloma: M-protein ≥3 g/dL and/or bone marrow plasma cells ≥10%, but no CRAB criteria or myeloma-defining biomarkers 2, 7
- Active myeloma: Requires CRAB criteria or myeloma-defining biomarkers in addition to clonal plasma cells 2, 3