What is the appropriate workup for suspected multiple myeloma?

Multiple Myeloma Workup

The diagnostic workup for suspected multiple myeloma requires a comprehensive laboratory, bone marrow, and imaging evaluation to confirm the diagnosis, assess disease burden, and stratify risk. 1, 2

Laboratory Studies

Blood Tests

• Complete blood count (CBC) with differential and peripheral blood smear to assess for anemia (present in 73% at diagnosis), thrombocytopenia, and rouleaux formation 3, 4
• Comprehensive metabolic panel including:
  • Serum creatinine and calculated creatinine clearance (19% present with acute kidney injury) 3, 4
  • Serum calcium (to detect hypercalcemia) 3
  • Serum albumin (for staging and nutritional assessment) 3, 2
  • Liver function tests and electrolytes 3

Protein Studies

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize the monoclonal protein 3, 2
• Quantitative immunoglobulins (IgG, IgA, IgM) measured by nephelometry to track disease burden 3, 2
• Serum free light chain (FLC) assay with kappa/lambda ratio for diagnosis, prognosis, and monitoring 3, 2
  • This test is essential even when SPEP shows a monoclonal protein, as it provides additional prognostic information 1
  • Note that renal impairment can cause false elevations of both kappa and lambda free light chains 2

Prognostic Markers

• Serum beta-2 microglobulin (reflects tumor burden and forms the basis for International Staging System) 3
• Lactate dehydrogenase (LDH) (has independent prognostic significance) 3, 2

Urine Studies

• 24-hour urine collection for total protein, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE) 3, 2
• Critical pitfall: A 24-hour urine collection cannot be replaced by a random morning urine sample or spot urine corrected for creatinine—this method has not been validated for myeloma diagnosis 3, 1
• Immunofixation should be performed even if there is no measurable protein or peak on urine electrophoresis 3
• The serum FLC assay cannot replace 24-hour UPEP for monitoring patients with measurable urinary M-protein 3, 2

Bone Marrow Evaluation

• Unilateral bone marrow aspirate and/or biopsy to confirm ≥10% clonal plasma cells (required for diagnosis) 3, 2
• CD138 immunoperoxidase staining should be used to accurately determine the percentage of plasma cells 3, 1
• Clonality confirmation by immunoperoxidase staining or immunofluorescence to identify monoclonal immunoglobulin in plasma cell cytoplasm 3
• When both aspirate and biopsy are performed, record the highest plasma cell percentage from either procedure 3

Cytogenetic Studies

• Standard metaphase cytogenetics to separate hyperdiploid from nonhyperdiploid patients and capture uncommon abnormalities (despite only 20% yield) 3
• Fluorescence in situ hybridization (FISH) after plasma cell sorting with probes for high-risk features 3, 1:
  • del(17p)
  • t(4;14)
  • t(14;16)
  • t(14;20)
  • gain 1q
  • del 1p
  • p53 mutation
• These cytogenetic abnormalities define high-risk myeloma and guide treatment decisions 5, 6

Imaging Studies

Skeletal Survey

• Complete skeletal bone survey including posteroanterior chest, anteroposterior and lateral views of cervical/thoracic/lumbar spine, skull (AP and lateral), humeri, femora, and pelvis to detect osteolytic bone disease (present in 79% at diagnosis) 3, 1, 4

Advanced Imaging

• MRI of spine and pelvis is mandatory in certain circumstances 3:
  • Patients with pre-existing conditions like cervical spondylosis to differentiate myelomatous lesions from degenerative changes 1
  • To detect cord compression and assess bone marrow involvement 1
  • When skeletal survey is negative but clinical suspicion remains high
• PET/CT or whole-body CT may be performed as clinically indicated to distinguish active myeloma from smoldering disease and detect extramedullary disease 3, 1

Common Pitfalls and Caveats

• Do not attribute all bone abnormalities to pre-existing conditions (e.g., spondylosis) without MRI confirmation, as new lytic lesions or pathologic fractures may be myelomatous 1
• Do not rely solely on skeletal survey in patients with known degenerative spine disease, as it has limited sensitivity for early marrow involvement 1
• Do not skip serum FLC testing even if SPEP shows a monoclonal protein, as the FLC ratio provides additional prognostic information 1
• Approximately 3% of patients have nonsecretory myeloma with neither serum nor urine proteins, making bone marrow evaluation and imaging critical 2
• Urine-free light chain assay should not be performed—only serum FLC assay is validated 3, 2
• Erythrocyte sedimentation rate does not provide additional information and is not required 3

Diagnostic Confirmation

The diagnosis of multiple myeloma requires all three criteria 3, 5:

1. ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma
2. Monoclonal protein detected in serum or urine (except in nonsecretory myeloma)
3. Evidence of end-organ damage (CRAB criteria: hypercalcemia, renal insufficiency, anemia, bone lesions) OR myeloma-defining events (≥60% bone marrow plasma cells, serum involved/uninvolved FLC ratio ≥100 with involved FLC ≥100 mg/L, or >1 focal lesion on MRI)