What is the initial treatment approach for newly diagnosed multiple myeloma?

Multiple Myeloma Treatment Algorithm

For newly diagnosed multiple myeloma, the initial treatment approach should be a triple or quadruple combination regimen based on risk stratification, with bortezomib-lenalidomide-dexamethasone (VRd) as the standard regimen for transplant-eligible patients and daratumumab-lenalidomide-dexamethasone (DRd) for transplant-ineligible patients. 1, 2

Risk Stratification

Before initiating treatment, all patients should undergo:

1. International Staging System (ISS) classification (Level of evidence: 1A) 1
2. Cytogenetic risk assessment by FISH (Level of evidence: 2B) 1

Risk Categories:

• Standard risk: Hyperdiploidy, t(11;14), t(6;14), ISS I+II
• High risk: t(4;14), t(14;16), t(14;20), del17p, 1q gain/del1p, high LDH, ISS III, high plasma cell proliferation rate, extramedullary disease 1, 2

Treatment Algorithm for Newly Diagnosed Multiple Myeloma

Transplant-Eligible Patients:

1. Induction Therapy (3-4 cycles):

   • Standard risk: VRd (bortezomib, lenalidomide, dexamethasone) 1, 3
   • High risk: D-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone) 1, 2, 4

   Recent data shows D-VRd significantly improves progression-free survival (84.3% vs 67.7% at 48 months) compared to VRd alone 4

2. Stem Cell Collection (after 3-4 cycles)

   • Avoid prolonged induction (>4-6 cycles) to ease stem cell harvest 1
   • Consider plerixafor for mobilization, especially with prolonged lenalidomide exposure 1

3. Autologous Stem Cell Transplantation (ASCT)

   • Remains standard of care for eligible patients 2
   • Significantly improves progression-free survival compared to continued RVD alone (50 months vs 36 months) 5

4. Consolidation (2 cycles post-ASCT)

   • Same regimen as induction 1

5. Maintenance:

   • Standard risk: Lenalidomide until progression 1, 2
   • High risk: Bortezomib-based maintenance 1

Transplant-Ineligible Patients:

1. Initial Therapy:

   • Standard risk:

     • DRd (daratumumab, lenalidomide, dexamethasone) until progression 1, 6
     • Alternative: Rd (lenalidomide, low-dose dexamethasone) continuously 1

   • High risk:

     • VRd for 8-12 cycles 1
     • Alternative: VMP (bortezomib, melphalan, prednisone) 1

2. Maintenance:

   • Standard risk: Lenalidomide until progression 2
   • High risk: Bortezomib-based maintenance 1

Special Considerations

Renal Failure

• Start induction immediately with bortezomib and dexamethasone-based regimens 1
• VCd (bortezomib, cyclophosphamide, dexamethasone) is preferred for acute renal failure 1
• Avoid nephrotoxic drugs and maintain euvolemia 1

Elderly/Frail Patients

• Reduce dexamethasone dose to 8-20 mg weekly for patients >75 years 2
• Adjust lenalidomide dose based on creatinine clearance 2
• Bortezomib does not require dose adjustment for renal impairment 2

Supportive Care

• Administer subcutaneous bortezomib (preferred over IV) to reduce peripheral neuropathy 1
• Weekly bortezomib schedule preferred over twice-weekly to reduce neuropathy 1
• Bisphosphonates for bone disease with calcium and vitamin D supplementation 2
• Antithrombotic prophylaxis for patients on immunomodulators 2
• Herpes zoster prophylaxis for patients on proteasome inhibitors 2

Response Assessment

• Complete response (CR): Negative serum/urine immunofixation, <5% plasma cells in bone marrow 2
• Very good partial response (VGPR): ≥90% reduction of serum M-component 2
• Partial response (PR): ≥50% reduction of M-gradient in serum 2
• Monitor every 3-6 months with blood counts, serum and urine electrophoresis, free light chains, creatinine, calcium, and β2-microglobulin 2

Common Pitfalls to Avoid

1. Delaying transplant evaluation in eligible patients
2. Using fixed-duration therapy instead of continuous therapy in standard risk patients
3. Overlooking cytogenetic risk stratification
4. Failing to adjust doses for elderly or frail patients
5. Not providing adequate supportive care 2

The treatment landscape for multiple myeloma continues to evolve, with recent evidence strongly supporting the addition of daratumumab to standard regimens, particularly for high-risk patients. The choice between triplet and quadruplet regimens should be based on risk stratification, with the goal of improving progression-free survival and overall survival.