What are the treatment strategies for multiple myeloma?

Treatment Strategies for Multiple Myeloma

The treatment of multiple myeloma should follow a risk-adapted approach with combination therapies including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and stem cell transplantation for eligible patients to optimize survival outcomes. 1

Initial Treatment Approach

Transplant-Eligible Patients

Treatment for transplant-eligible patients typically follows a sequential approach:

1. Induction Therapy:

   • First choice: D-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone) is the preferred regimen based on superior progression-free survival (84.3% vs 67.7% at 48 months) compared to VRd alone 2
   • Alternative: VRd (bortezomib, lenalidomide, dexamethasone) if daratumumab is not available 3
   • Typically administered for 3-6 cycles before proceeding to transplant 4

2. Stem Cell Collection: Should be performed early, especially with lenalidomide-based regimens (after 4-6 cycles) 4

3. Autologous Stem Cell Transplantation (ASCT):

   • Significantly improves progression-free survival compared to continued RVD alone (50 months vs 36 months) 5
   • Should be offered to all eligible patients as it remains the standard of care 4

4. Consolidation Therapy:

   • 2 cycles of the induction regimen post-transplant to deepen response 3

5. Maintenance Therapy:

   • Standard approach: Lenalidomide maintenance until disease progression 1
   • For high-risk patients: Consider bortezomib-based maintenance 4

Transplant-Ineligible Patients

1. Preferred Regimen:

   • DRd (daratumumab, lenalidomide, dexamethasone) has demonstrated superior outcomes with 61.9 months median PFS versus 34.4 months with Rd alone 6
   • Treatment continues until disease progression or unacceptable toxicity

2. Alternative Regimens:

   • VRd (bortezomib, lenalidomide, dexamethasone) in a modified dose for frail patients 7
   • Rd (lenalidomide, dexamethasone) for very frail patients 4

Treatment of Relapsed Disease

First Relapse

Treatment selection depends on prior therapy and response duration:

1. For lenalidomide-refractory patients:

   • DVd (daratumumab, bortezomib, dexamethasone) 4
   • KPd (carfilzomib, pomalidomide, dexamethasone) 4

2. For bortezomib-refractory patients:

   • DRd (daratumumab, lenalidomide, dexamethasone) 4
   • KRd (carfilzomib, lenalidomide, dexamethasone) 4

3. For patients with relapse >6 months after stopping therapy:

   • Consider re-treatment with the initial successful regimen 4

Second or Later Relapse

For patients with multiple relapses, treatment should include at least two new drugs that the patient is not refractory to 4:

1. Triple-refractory options:

   • Daratumumab-based combinations (DPd) 4
   • Selinexor-based regimens 4
   • Alkylator-based therapy 4

2. For aggressive relapse/extramedullary disease:

   • VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) followed by ASCT if possible 4

Special Considerations

High-Risk Disease

Patients with high-risk cytogenetics (t(4;14), t(14;16), t(14;20), deletion 17p, gain 1q, or p53 mutation):

• More intensive approach: D-VRd induction followed by ASCT 2
• Consider: Tandem ASCT if not achieving VGPR after first transplant 4
• Maintenance: Bortezomib-based maintenance rather than lenalidomide alone 4

Elderly/Frail Patients

• Dose adjustments: Reduce dexamethasone to 8-20mg weekly for patients >75 years 1
• Avoid: High-dose therapy in patients with significant comorbidities 1
• Consider: Subcutaneous bortezomib to reduce peripheral neuropathy risk 1

Supportive Care

Essential supportive measures include:

• Antithrombotic prophylaxis for patients on immunomodulators 1
• Herpes zoster prophylaxis for patients on proteasome inhibitors 1
• Bisphosphonates with calcium and vitamin D supplementation 4
• Pneumocystis jiroveci prophylaxis for patients on high-dose steroids 4
• Seasonal influenza and pneumococcal vaccinations 4

Monitoring and Response Assessment

• Regular monitoring with serum/urine electrophoresis, free light chain assay, CBC, renal function, and calcium every 3-6 months 1
• MRD assessment in patients achieving complete response to evaluate treatment efficacy 4, 1
• Imaging with CT or PET-CT for bone disease evaluation 4

Common Pitfalls to Avoid

• Delaying transplant evaluation in eligible patients
• Using fixed-duration therapy instead of continuous therapy in most patients
• Overlooking cytogenetic risk stratification which should guide treatment intensity
• Failing to adjust doses for elderly or frail patients
• Not monitoring for second primary malignancies, especially with lenalidomide maintenance (7% incidence) 1
• Neglecting supportive care which is critical for managing complications and improving quality of life

Multiple myeloma treatment continues to evolve rapidly with new effective agents, and combination therapies with non-cross-resistant drugs are leading to deeper, longer responses and improved survival outcomes.