What is the initial treatment regimen for a patient diagnosed with multiple myeloma?

Initial Treatment Regimen for Multiple Myeloma

For patients newly diagnosed with multiple myeloma, the standard initial treatment regimen should be bortezomib, lenalidomide, and dexamethasone (VRd) for both transplant-eligible and transplant-ineligible patients, with treatment approach modified based on risk stratification. 1

Risk Stratification

Before initiating treatment, proper risk stratification is essential:

• Standard Risk: Absence of high-risk cytogenetic features
• High Risk: Presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, p53 mutation, hypodiploidy, del(13q) by metaphase cytogenetics, or plasma cell labeling index ≥3% 2, 1

Initial Treatment Regimens by Risk Category

Standard-Risk Patients:

• First choice: VRd (Bortezomib, Lenalidomide, Dexamethasone) 2, 1
  • Typically administered for 3-4 cycles before stem cell transplantation in eligible patients
  • For transplant-ineligible patients, continue for 8-12 cycles followed by maintenance 3
  • Response rates: 85-100% overall response rate with 40-74% achieving very good partial response or better 2, 1

High-Risk Patients:

• First choice: D-VRd (Daratumumab, Bortezomib, Lenalidomide, Dexamethasone) 1, 3
  • Bortezomib-containing regimens are strongly recommended for high-risk disease as they may overcome some adverse prognostic effects, especially in t(4;14) translocation 2
  • Alternative triple combinations include:
    • Cyclophosphamide, Bortezomib, Dexamethasone (CyBorD)
    • Bortezomib, Thalidomide, Dexamethasone (VTD)
    • Bortezomib, Doxorubicin, Dexamethasone (PAD) 2

Treatment Approach by Transplant Eligibility

Transplant-Eligible Patients:

1. Induction: 3-4 cycles of VRd (standard risk) or D-VRd (high risk) 1, 3
2. Stem Cell Collection
3. High-Dose Melphalan and Autologous Stem Cell Transplantation (ASCT)
4. Maintenance:
   • Standard risk: Lenalidomide until progression
   • High risk: Bortezomib-based maintenance (often combined with lenalidomide) 1, 3

Transplant-Ineligible Patients:

1. Initial Therapy: VRd for approximately 8-12 cycles or DRd (Daratumumab, Lenalidomide, Dexamethasone) until progression 3
2. Maintenance:
   • Standard risk: Lenalidomide until progression
   • High risk: Bortezomib-based maintenance 1

For elderly or frail patients, a modified "RVd lite" regimen can be considered, which uses reduced dosing (lenalidomide 15mg days 1-21, weekly bortezomib 1.3mg/m² subcutaneously, and dexamethasone 20mg on day of and day after bortezomib) in a 35-day cycle 4.

Evidence Supporting VRd as Standard Regimen

The SWOG S0777 trial demonstrated superior outcomes with VRd compared to Rd (lenalidomide and dexamethasone), with:

• Higher overall response rate (71% vs 64%)
• Improved median progression-free survival (43 months vs 31 months) 2

The ENDURANCE trial compared KRd (carfilzomib, lenalidomide, dexamethasone) to VRd and found similar progression-free survival (34.6 months vs 34.4 months) but higher toxicity with KRd, confirming VRd as the standard of care 5.

Special Considerations

• Renal Impairment: Bortezomib-based regimens are preferred as bortezomib does not require dose adjustment for renal impairment 2, 1
• Elderly/Frail Patients: Consider dose-reduced regimens like "RVd lite" 4
• Peripheral Neuropathy Risk: Subcutaneous administration of bortezomib and weekly dosing can reduce neuropathy risk 4

Common Pitfalls to Avoid

• Failing to perform proper risk stratification before treatment selection
• Not adjusting doses for elderly or frail patients
• Overlooking prophylaxis needs:
  • Antiviral prophylaxis for patients on bortezomib (herpes zoster risk)
  • Thromboprophylaxis for patients on immunomodulatory drugs
  • Bisphosphonates with calcium and vitamin D supplementation 1
• Delaying transplant evaluation in eligible patients

By following this risk-stratified approach to initial therapy for multiple myeloma, clinicians can optimize outcomes while managing toxicity appropriately for each patient population.