What are the diagnostic and treatment approaches for multiple myeloma?

Multiple Myeloma Diagnosis and Treatment

Multiple myeloma diagnosis requires a comprehensive panel of tests including serum protein electrophoresis with immunofixation, 24-hour urine protein electrophoresis, serum free light chain assay, bone marrow biopsy showing ≥10% clonal plasma cells, and advanced skeletal imaging, with treatment decisions based on transplant eligibility, risk stratification, and presence of myeloma-defining events. 1

Diagnostic Approach

Initial Laboratory Evaluation

• Serum studies:

  • Complete blood count (anemia is present in 73% of patients) 2
  • Serum calcium, creatinine, BUN, and electrolytes
  • Serum protein electrophoresis (SPEP) with immunofixation (SIFE)
  • Quantification of immunoglobulins (IgG, IgA, IgM)
  • Serum free light chain assay and ratio calculation
  • Beta-2 microglobulin, albumin, and LDH for staging and prognosis 1

• Urine studies:

  • 24-hour urine protein electrophoresis (UPEP) with immunofixation (UIFE) 1
  • Pitfall: Using random urine samples instead of 24-hour collections can lead to missed diagnosis 1

Bone Marrow Assessment

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

Skeletal Imaging

• Full skeletal survey (X-rays) including spine, pelvis, skull, humeri, and femurs 3, 1
• Advanced imaging recommended:
  • MRI provides greater detail and is essential if spinal cord compression is suspected 3
  • CT scan and PET/CT scan may help distinguish between MGUS, smoldering, and overt myeloma 1

Diagnostic Criteria and Staging

Diagnostic Criteria

Multiple myeloma diagnosis requires:

• ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma, AND
• 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

  • 1 focal lesion on MRI 1

Staging Systems

• International Staging System (ISS):

  • Stage I: Beta-2 microglobulin <3.5 mg/L and albumin ≥3.5 g/dL
  • Stage II: Neither stage I nor III
  • Stage III: Beta-2 microglobulin ≥5.5 mg/L 1

• Revised ISS (R-ISS) incorporates cytogenetic abnormalities and LDH for more precise prognostication 1, 2

Treatment Approach

Treatment Decision Algorithm

1. Determine transplant eligibility (age <70, good performance status, absence of significant comorbidities)
2. Assess risk status based on cytogenetics and R-ISS staging
3. Determine if immediate treatment is needed (symptomatic vs. smoldering myeloma)

Transplant-Eligible Patients

• Induction therapy: Bortezomib, lenalidomide, dexamethasone (VRd) for 3-4 cycles 1
• Followed by stem cell harvest and autologous stem cell transplantation
• Maintenance therapy:
  • Standard-risk patients: Lenalidomide
  • High-risk patients: Bortezomib plus lenalidomide 1

Transplant-Ineligible Patients

• Oral melphalan (9 mg/m²/day for 4 days) and prednisone (30 mg/m²/day for 4 days), repeated every 4-6 weeks until stable response 3
• Alternative: Daratumumab with lenalidomide and dexamethasone (DRd) has shown significant improvement in progression-free survival and overall survival compared to lenalidomide and dexamethasone alone 4
  • DRd reduced risk of disease progression or death by 44% 4
  • DRd showed 32% reduction in risk of death 4

Supportive Care

• Bisphosphonates to reduce skeletal-related events 1
• Radiation therapy for painful bone lesions or impending fractures
• Thromboprophylaxis during treatment
• Infection prophylaxis 2

Common Pitfalls to Avoid

• Failing to perform immunofixation when protein electrophoresis is negative 1
• Using random urine samples instead of 24-hour urine collection for protein electrophoresis 1
• Inadequate imaging assessment and incomplete cytogenetic evaluation 1
• Failing to distinguish between MGUS, smoldering myeloma, and symptomatic myeloma 1
• Initiating treatment in patients with indolent (smoldering) myeloma without myeloma-defining events 3

Treatment Response Assessment

• Regular monitoring of serum and urine M-protein levels
• Assessment of minimal residual disease (MRD) in patients achieving complete response
• Periodic imaging to evaluate bone disease response
• Regular evaluation for treatment-related toxicities

By following this structured approach to diagnosis and treatment, patients with multiple myeloma can benefit from improved survival outcomes and quality of life that have been achieved with modern therapeutic advances.