What is the appropriate workup for a typical adult patient, likely over 60 years old, presenting with symptoms such as anemia, bone pain, or recurrent infections, suspected of having multiple myeloma?

Multiple Myeloma Workup

The workup for suspected multiple myeloma requires serum protein electrophoresis with immunofixation, 24-hour urine collection for protein electrophoresis and immunofixation, complete blood count, comprehensive metabolic panel including calcium and creatinine, serum-free light chains, bone marrow aspirate and biopsy with cytogenetics (metaphase karyotype and FISH), skeletal survey, serum β2-microglobulin, and LDH. 1

Laboratory Evaluation

Serum Studies

• Complete blood count with differential to assess for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal), which is a CRAB criterion for symptomatic myeloma 1, 2, 3
• Chemistry panel including serum calcium (≥11.5 mg/dL indicates hypercalcemia, a CRAB criterion) and creatinine (≥2 mg/dL indicates renal insufficiency, a CRAB criterion) 1, 2
• Serum protein electrophoresis with immunofixation to identify and characterize the monoclonal protein (M-protein) 1
• Nephelometric quantification of serum immunoglobulins to measure the exact concentration of the monoclonal protein and assess for suppression of uninvolved immunoglobulins 1
• Serum-free light chain assay to measure involved and uninvolved free light chains; an involved/uninvolved ratio ≥100 (with involved FLC ≥100 mg/L) is a myeloma-defining event 1, 2, 3

Urine Studies

• 24-hour urine collection for protein electrophoresis and immunofixation to detect and quantify urinary monoclonal protein (Bence Jones protein); this cannot be replaced by random urine samples 1
• Routine urinalysis as initial screening 1

Prognostic Markers

• Serum β2-microglobulin which reflects tumor burden and is essential for International Staging System classification 1
• Serum lactate dehydrogenase (LDH) which has independent prognostic significance 1
• Serum albumin for staging purposes 1

Bone Marrow Evaluation

• Unilateral bone marrow aspirate and/or biopsy is mandatory; ≥10% clonal plasma cells confirms the diagnosis when combined with myeloma-defining events 1, 2, 3
• CD138 immunostaining on trephine biopsy should be performed to accurately quantify plasma cells 1
• Clonality assessment by immunoperoxidase staining or immunofluorescence to identify monoclonal immunoglobulin in plasma cell cytoplasm 1
• When both aspirate and biopsy are performed, use the highest plasma cell percentage from either procedure for diagnostic purposes 1

Cytogenetic Analysis

• Standard metaphase cytogenetics to identify hyperdiploid versus nonhyperdiploid disease and detect uncommon translocations, despite only 20% yield 1
• Fluorescent in situ hybridization (FISH) after plasma cell sorting with probes for high-risk abnormalities including:
  • del(17p)
  • t(4;14)
  • t(14;16)
  • t(14;20) 1, 2, 3, 4

These cytogenetic abnormalities define high-risk disease and fundamentally alter prognosis and treatment decisions 2, 3, 4.

Imaging Studies

Skeletal Survey (Standard)

• Plain radiographs remain the standard initial imaging modality and should include:
  • Posteroanterior chest view
  • Anteroposterior and lateral views of cervical, thoracic, and lumbar spine
  • Anteroposterior and lateral views of skull
  • Anteroposterior view of pelvis
  • Anteroposterior views of humeri and femora 1

MRI (Selective Indications)

• MRI of spine and pelvis is mandatory in patients with suspected solitary plasmacytoma to exclude additional lesions 1
• MRI should be considered in smoldering (asymptomatic) myeloma as it detects occult lesions and predicts more rapid progression to symptomatic disease 1
• More than one focal lesion on MRI constitutes a myeloma-defining event even without CRAB features 2, 3, 4

Critical Diagnostic Thresholds

The diagnosis of symptomatic multiple myeloma requires all three criteria 1:

1. Clonal bone marrow plasma cells ≥10%
2. Presence of serum and/or urinary monoclonal protein (except in nonsecretory myeloma)
3. Evidence of end-organ damage (CRAB features) OR myeloma-defining events (≥60% plasma cells, involved/uninvolved FLC ratio ≥100, or >1 focal MRI lesion)

Common Pitfalls

• Do not rely on random urine samples for protein quantification; 24-hour collection is mandatory 1
• Perform immunofixation even when no peak is visible on electrophoresis, as small monoclonal proteins can be missed 1
• Do not skip FISH testing even if metaphase cytogenetics are normal, as FISH detects high-risk translocations that metaphase analysis misses 1
• Obtain both bone marrow aspirate and biopsy when possible, as aspirate alone may be inadequate or hemodiluted 1
• Measure serum-free light chains in all patients, as this identifies light chain-only disease and provides prognostic information 1