What is the initial treatment approach for multiple myeloma?

Initial Treatment Approach for Multiple Myeloma

The optimal initial treatment for multiple myeloma should include a triplet regimen based on a proteasome inhibitor and an immunomodulatory agent, preferably bortezomib, lenalidomide, and dexamethasone (VRd), or daratumumab combined with VRd (D-VRd) for high-risk patients. 1

Patient Stratification for Treatment Selection

Treatment selection depends on several key factors:

1. Transplant eligibility (primarily based on age and comorbidities)
2. Cytogenetic risk stratification
3. Renal function
4. Disease stage (using Durie-Salmon or International Staging System)

For Transplant-Eligible Patients (<65 years)

• Induction therapy: 3-4 cycles of VRd (bortezomib, lenalidomide, dexamethasone) 1
• Consolidation: High-dose melphalan (200 mg/m²) followed by autologous stem cell transplantation (ASCT) 2, 1
• Stem cell source: Peripheral blood progenitor cells rather than bone marrow 2
• Maintenance: Lenalidomide until progression for standard-risk patients; bortezomib plus lenalidomide for high-risk patients 1

For Transplant-Ineligible Patients (>65 years or with significant comorbidities)

• Standard-risk patients: VRd or daratumumab plus lenalidomide and dexamethasone (DRd) 1, 3
• High-risk patients: D-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone) 1
• Elderly/frail patients: Consider dose-adjusted regimens:
  • Reduced-dose dexamethasone (8-20 mg weekly for patients >75 years) 2, 1
  • Adjusted lenalidomide dosing based on renal function 2, 1
  • Subcutaneous bortezomib to reduce neuropathy 1

Evidence Supporting Treatment Recommendations

The MAIA trial demonstrated significant benefits of adding daratumumab to lenalidomide and dexamethasone (DRd) for transplant-ineligible patients, with:

• 44% reduction in risk of disease progression or death compared to Rd alone
• Median PFS of 61.9 months vs 34.4 months
• 32% reduction in risk of death
• Overall response rate of 92.9% vs 81.3% 3

For continuous therapy, the FIRST trial showed that continuous lenalidomide-dexamethasone improved progression-free survival and overall survival compared to fixed-duration therapy, supporting the recommendation for continuous therapy until progression 2.

Treatment Goals and Response Assessment

• Primary goal: Achievement of the best quality and depth of remission 2
• Response assessment: Using International Myeloma Working Group criteria after each cycle during induction and every 3 months once best response is achieved 2, 1
• Monitoring parameters: Serum/urine protein, free light chains, renal function, and calcium 1

Special Considerations

• Renal dysfunction: Bortezomib-based regimens do not require dose adjustment for renal impairment 2, 1
• Elderly patients: Consider bortezomib-cyclophosphamide-dexamethasone as an alternative regimen 1
• Asymptomatic/smoldering myeloma: Immediate treatment is not recommended 2

Pitfalls to Avoid

1. Delaying transplant evaluation in eligible patients
2. Using fixed-duration therapy instead of continuous therapy when using novel agents
3. Overlooking cytogenetic risk stratification which should guide treatment selection
4. Failing to adjust doses for elderly or frail patients, which can lead to unnecessary toxicity and treatment discontinuation
5. Not monitoring for common complications such as renal dysfunction, hypercalcemia, and bone disease

By following these evidence-based recommendations and tailoring treatment based on patient characteristics, the best outcomes in terms of morbidity, mortality, and quality of life can be achieved for patients with multiple myeloma.