What is the recommended workup for multiple myeloma?

Workup for Multiple Myeloma

Initial Blood Tests

The diagnostic workup for suspected multiple myeloma requires a comprehensive panel of blood tests to establish the diagnosis, assess end-organ damage, and determine prognosis. 1

Essential Hematologic and Chemistry Studies

• Obtain a complete blood count (CBC) with differential and peripheral blood smear to evaluate for anemia (hemoglobin <10 g/dL or >2 g/dL below normal), rouleaux formation, and circulating plasma cells 2, 1
• Measure serum creatinine and blood urea nitrogen (BUN) to assess for renal insufficiency (creatinine ≥2 mg/dL is a CRAB criterion) 2, 1
• Check serum calcium levels to detect hypercalcemia (≥11.5 mg/dL is a CRAB criterion) 2, 1
• Measure serum albumin to evaluate nutritional status and for International Staging System calculation 2, 1

Critical Prognostic Markers

• Measure serum beta-2 microglobulin, which reflects tumor burden and forms the basis for the International Staging System 2, 1
• Obtain serum lactate dehydrogenase (LDH), which has independent prognostic significance 2, 1

Protein Studies (Most Critical for Diagnosis)

Serum Protein Analysis

• Perform serum protein electrophoresis (SPEP) using agarose gel or capillary zone electrophoresis to screen for monoclonal protein 2, 1
• Conduct serum immunofixation electrophoresis (SIFE) to confirm the type of heavy chain and light chain present 2, 1
• Measure quantitative immunoglobulins (IgG, IgA, IgM) by nephelometry, as this is complementary to SPEP and particularly useful for low levels of uninvolved immunoglobulins 2, 1
• Perform serum free light chain (FLC) assay to screen for disease and monitor response, especially important for light chain and oligosecretory myeloma 2, 1

A critical pitfall: Nephelometric quantitation may overestimate monoclonal protein concentration when values are high, so use both densitometer tracing and nephelometry together. 2

Urine Protein Analysis

• Collect a 24-hour urine specimen for total protein quantification, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE) 2, 1
• Perform immunofixation on the urine even if there is no measurable protein peak on electrophoresis, as approximately 20% of patients have secretory urinary proteins only 2, 3

Critical caveat: A 24-hour urine collection cannot be replaced by a morning urine sample or random urine samples corrected for creatinine. 2, 1 Do not perform urine-free light chain assay, as it is not validated. 2, 1

Bone Marrow Evaluation

Aspirate and Biopsy

• Perform unilateral bone marrow aspirate and/or biopsy to confirm ≥10% clonal plasma cells, which is required for diagnosis 2, 4, 5
• Use CD138 immunoperoxidase staining to accurately determine the percentage of plasma cells in bone marrow biopsies 2
• Establish clonality by identifying monoclonal immunoglobulin in plasma cell cytoplasm using immunoperoxidase staining or immunofluorescence 2
• Record the highest plasma cell percentage obtained from either aspirate or biopsy for diagnostic purposes 2

A trephine biopsy should be performed alongside aspirate because it provides more reliable assessment of plasma cell infiltration and avoids the need for repeat procedures if aspirate is inadequate. 2

Cytogenetic Studies (Essential for Risk Stratification)

• Perform standard metaphase cytogenetics to separate hyperdiploid from nonhyperdiploid patients and capture uncommon chromosomal abnormalities (despite only 20% yield) 2
• Conduct fluorescence in situ hybridization (FISH), preferably after CD138 sorting of plasma cells, with probes for high-risk features including: 2, 4, 5
  • del(17p)
  • t(4;14)
  • t(14;16)
  • t(14;20)
  • gain 1q
  • p53 mutation

The presence of any two high-risk factors constitutes "double-hit" myeloma, and three or more constitutes "triple-hit" myeloma, which significantly impacts treatment decisions. 4, 5

Imaging Studies

Skeletal Survey (Standard Initial Imaging)

• Obtain plain radiographs including: 2, 1
  • Posteroanterior chest view
  • Anteroposterior and lateral views of cervical, thoracic, and lumbar spine
  • Anteroposterior and lateral skull views
  • Anteroposterior views of humeri and femora
  • Anteroposterior pelvis view

The skeletal survey remains the standard screening method at diagnosis because it is readily available, cost-effective, allows assessment of large skeletal areas, and detects long bone lesions at risk of pathologic fracture. 2

Advanced Imaging (When Indicated)

• Perform MRI of spine and pelvis when: 2, 6
  • Suspected vertebral compression is present
  • Skeletal survey is negative but clinical suspicion remains high
  • Assessment of soft tissue disease arising from bone lesions is needed
  • Evaluating for >1 focal lesion (which is a myeloma-defining event)
• Consider whole-body CT, PET/CT, or MRI for detecting extramedullary disease and evaluating extent of bone involvement 1, 6

Diagnostic Criteria Summary

Multiple myeloma is diagnosed when ≥10% clonal bone marrow plasma cells are present PLUS one or more myeloma-defining events (MDE): 4, 5

CRAB Features (attributable to plasma cell disorder)

• Calcium elevation: serum calcium ≥11.5 mg/dL 2
• Renal insufficiency: serum creatinine ≥2 mg/dL 2
• Anemia: hemoglobin <10 g/dL or >2 g/dL below normal 2
• Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures 2

Biomarker Criteria (even without CRAB)

• Bone marrow clonal plasmacytosis ≥60% 4, 5
• Serum involved/uninvolved FLC ratio ≥100 (provided involved FLC ≥100 mg/L) 4, 5

• 1 focal lesion on MRI (≥5 mm) 4, 5

Common Pitfalls to Avoid

• Do not rely on serum studies alone—approximately 20% of patients have measurable urinary M-proteins only, and 3% have nonsecretory myeloma 1, 3
• Renal impairment causes decreased clearance of both kappa and lambda free light chains, potentially leading to false elevations of the FLC ratio 1
• Incomplete or inadequate concentration of 24-hour urine specimens leads to falsely negative results 3
• Do not use erythrocyte sedimentation rate for myeloma assessment, as it provides no additional diagnostic or prognostic information 2
• Always follow the same test method for serial studies to ensure accurate monitoring of disease response 3