What is the initial workup for suspected multiple myeloma?

Initial Workup for Multiple Myeloma

The workup for suspected multiple myeloma requires a comprehensive laboratory, bone marrow, imaging, and cytogenetic evaluation to establish diagnosis, assess disease burden, and determine prognosis. 1, 2

Blood Tests

Essential Hematologic and Chemistry Studies

• Complete blood count (CBC) with differential and peripheral blood smear to assess for anemia (present in ~73% at diagnosis), rouleaux formation, and circulating plasma cells 1, 2, 3
• Comprehensive metabolic panel including BUN, serum creatinine, and electrolytes to evaluate renal function (acute kidney injury occurs in ~19% at presentation) 1, 2, 3
• Serum calcium to detect hypercalcemia, a key CRAB criterion 1, 2
• Serum albumin for nutritional status and International Staging System (ISS) prognostication 1, 2

Prognostic Biomarkers

• Beta-2 microglobulin is mandatory as it reflects tumor burden and forms the basis of the ISS staging system 1, 2
• Lactate dehydrogenase (LDH) has independent prognostic significance and is part of the Revised ISS (R-ISS) staging 1, 2, 3

Protein Studies (Critical for Diagnosis)

• Serum protein electrophoresis (SPEP) to screen for and quantify monoclonal protein spikes 1, 4, 2
• Serum immunofixation electrophoresis (SIFE) to confirm and type the monoclonal protein—this is more sensitive than SPEP alone and must be performed even if SPEP is negative 1, 4, 2
• Quantitative immunoglobulins (IgG, IgA, IgM) by nephelometry to complement electrophoretic measurements and track disease 1, 4, 2
• Serum free light chain (FLC) assay with kappa/lambda ratio is essential for detecting light chain-only disease and is a myeloma-defining event when the involved/uninvolved ratio is ≥100 (with involved FLC ≥100 mg/L) 1, 4, 2, 5, 6, 7

Urine Studies

• 24-hour urine collection for total protein quantification is mandatory and cannot be replaced by random or morning urine samples 1, 2
• Urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE) on the 24-hour collection to identify urinary monoclonal proteins (Bence Jones proteins) 1, 4, 2
• Routine urinalysis for initial screening 1

Critical caveat: Urine-free light chain assay should NOT be performed—only electrophoresis and immunofixation on properly collected 24-hour specimens 1, 2

Bone Marrow Evaluation

• Unilateral bone marrow aspirate and/or biopsy is required for diagnosis, with ≥10% clonal plasma cells confirming myeloma 1, 2, 5, 6, 7
• CD138 immunohistochemistry staining should be used whenever possible to accurately determine plasma cell percentage 1
• Clonality confirmation via immunoperoxidase or immunofluorescence staining for monoclonal immunoglobulin in plasma cell cytoplasm 1
• Both aspirate and biopsy should be performed during the same procedure when possible, as the biopsy provides more reliable assessment of infiltration and avoids repeat procedures if aspirate is inadequate 1

Cytogenetic Studies (Essential for Risk Stratification)

• Standard metaphase cytogenetics should be included despite low yield (~20%), as it separates hyperdiploid from nonhyperdiploid patients and captures uncommon abnormalities 1
• Fluorescence in situ hybridization (FISH) is mandatory, preferably after plasma cell sorting, with probes for: 1, 2
  • del(17p) (high-risk)
  • t(4;14) (high-risk)
  • t(14;16) (high-risk)
  • t(14;20) (high-risk)
  • t(11;14) (standard-risk)
  • del(13) (prognostic significance)
  • gain 1q (high-risk)
  • del(1p) (high-risk)

The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation defines high-risk myeloma 5, 6, 7

Imaging Studies

Standard Skeletal Survey

• Plain radiographs remain the standard initial imaging and should include: 1, 2
  • Posteroanterior chest view
  • Anteroposterior and lateral views of cervical, thoracic, and lumbar spine
  • Anteroposterior and lateral skull views
  • Anteroposterior pelvis view
  • Anteroposterior views of humeri and femora

This detects lytic bone lesions (present in ~79% at diagnosis) and identifies long bones at risk of pathologic fracture 1, 3

Advanced Imaging (When Indicated)

• MRI of spine and pelvis is mandatory in certain circumstances, particularly when skeletal survey is negative but clinical suspicion remains high, as it detects focal lesions that predict progression and provides detailed bone marrow involvement patterns 1, 2
• CT scan (avoid contrast due to renal concerns) or PET/CT may be useful for detecting extramedullary disease and assessing treatment response 1, 2, 3

Note: More than one focal lesion on MRI is a myeloma-defining event even without CRAB features 5, 6, 7

Common Pitfalls to Avoid

• Do not rely on SPEP alone—it has only 71% sensitivity for plasma cell neoplasms in lytic bone lesions; always perform SIFE and serum FLC assay 8
• Do not substitute random urine samples for 24-hour collection—this is not validated and will miss significant urinary monoclonal proteins 1, 2
• Do not skip immunofixation even if SPEP shows no peak—approximately 3% of patients have nonsecretory myeloma 2
• Do not use serum FLC to replace 24-hour UPEP for monitoring patients with measurable urinary M-proteins—both are needed 2, 9
• Remember renal impairment can elevate both kappa and lambda FLC, potentially causing false interpretation; always assess the kappa/lambda ratio 2, 9
• Use the same assay for serial FLC measurements to ensure accurate relative quantification 2, 9

Risk Stratification Framework

Once diagnosis is established, integrate findings to determine risk category:

• Revised International Staging System (R-ISS) combines beta-2 microglobulin, albumin, LDH, and high-risk cytogenetics (del(17p), t(4;14), t(14;16)) 3, 5, 6, 7
• Double-hit myeloma = any two high-risk cytogenetic factors 5, 6, 7
• Triple-hit myeloma = three or more high-risk factors 5, 6, 7

This comprehensive workup establishes diagnosis, quantifies disease burden, identifies end-organ damage (CRAB features), and stratifies risk to guide treatment intensity.