What are the initial steps in the workup and treatment of a patient suspected of having multiple myeloma?

Initial Workup and Treatment of Multiple Myeloma

The initial diagnostic workup for multiple myeloma requires comprehensive laboratory testing, bone marrow evaluation, and skeletal imaging to detect clonal plasma cells and evidence of end-organ damage, followed by risk stratification to guide treatment decisions. 1

Diagnostic Workup

Essential Laboratory Tests

• Complete Blood Count (CBC)

  • Hemoglobin measurement to assess for anemia (present in ~73% of patients at diagnosis) 2
  • White blood cell count with differential 1

• Blood Chemistry

  • Serum calcium (to detect hypercalcemia) 3, 1
  • Blood urea nitrogen (BUN) and serum creatinine (to assess renal function) 3
  • Serum electrolytes 3
  • Albumin (for staging and prognosis) 3, 1
  • Lactate dehydrogenase (LDH) (for prognosis and tumor burden assessment) 3
  • Beta-2 microglobulin (important prognostic marker) 3, 1

• Monoclonal Protein Assessment

  • Serum protein electrophoresis (SPEP) with immunofixation (SIFE) 3, 1
  • Urine protein electrophoresis (UPEP) on 24-hour collection with immunofixation (UIFE) 3
  • Quantification of immunoglobulins (IgG, IgA, IgM) 3
  • Serum free light chain assay and ratio calculation 3, 1

Bone Marrow Evaluation

• Bone marrow aspirate and biopsy to:
  • Quantify plasma cell infiltration (diagnosis requires ≥10% clonal plasma cells) 3, 4
  • Assess plasma cell morphology 1
  • Perform immunohistochemistry or immunofluorescence to establish clonality 3
  • Conduct cytogenetic/FISH analysis for prognostic markers: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, p53 mutation 3, 1, 4

Skeletal Imaging

• Full skeletal survey (X-rays) including spine, pelvis, skull, humeri, and femurs 3
• Advanced imaging recommended:
  • MRI for suspected spinal cord compression and to detect bone lesions not visible on X-rays 3
  • CT scan (avoid contrast if renal impairment) 3
  • PET/CT scan as clinically indicated 3

Diagnosis Criteria

Multiple myeloma diagnosis requires:

1. ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma, AND
2. One or more myeloma defining events:
   • CRAB features (hypercalcemia, renal failure, anemia, bone lesions)
   • Bone marrow clonal plasmacytosis ≥60%
   • Serum involved/uninvolved free light chain ratio ≥100 (provided involved FLC is ≥100 mg/L)

   • 1 focal lesion on MRI 4

Risk Stratification

The International Staging System (ISS) combines:

• Beta-2 microglobulin
• Albumin
• LDH
• Cytogenetic abnormalities by FISH 1, 2

High-risk features include:

• del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation
• Double-hit myeloma: presence of any two high-risk factors
• Triple-hit myeloma: three or more high-risk factors 4

Initial Treatment Approach

For Transplant-Eligible Patients

1. Induction therapy with bortezomib, lenalidomide, dexamethasone (VRd) for 3-4 cycles
2. Stem cell harvest (adequate for 2 transplants)
3. Autologous stem cell transplantation
4. Maintenance therapy with lenalidomide for standard-risk patients or bortezomib plus lenalidomide for high-risk patients 4

For high-risk patients, consider daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) as an alternative to VRd 4

For Transplant-Ineligible Patients

• VRd for 8-12 cycles followed by maintenance, OR
• Daratumumab, lenalidomide, dexamethasone (DRd) until progression 4
• Oral melphalan (9 mg/m²/day for 4 days) and prednisone (30 mg/m²/day for 4 days) remains a standard treatment option, repeated every 4-6 weeks until stable response 3

Supportive Care

• Bisphosphonates to reduce skeletal-related events 3
• Radiation therapy for painful bone lesions or impending fractures 3
• Surgical intervention for pathological fractures or spinal cord compression 5

Common Pitfalls to Avoid

1. Failing to distinguish between MGUS, smoldering myeloma, and symptomatic myeloma, which have different management approaches 1
2. Inadequate imaging assessment - relying only on X-rays when more advanced imaging can detect additional lesions 1
3. Incomplete cytogenetic evaluation, which significantly impacts prognosis and treatment decisions 1
4. Overlooking non-secretory or light-chain-only myeloma by not performing serum free light chain assays 1
5. Not performing immunofixation when protein electrophoresis is negative 3
6. Using random urine samples instead of 24-hour urine collection for protein electrophoresis 3

The diagnostic workup for multiple myeloma has evolved significantly with the introduction of new diagnostic criteria and treatment options. A systematic approach to diagnosis and risk stratification is essential to guide appropriate therapy and improve patient outcomes.