What is the initial treatment approach for multiple myeloma?

Initial Treatment Approach for Multiple Myeloma

The initial treatment for multiple myeloma should include a triplet regimen consisting of bortezomib, lenalidomide, and dexamethasone (VRd) for both transplant-eligible and transplant-ineligible patients. 1

Risk Stratification and Initial Assessment

• All newly diagnosed multiple myeloma patients should undergo risk stratification to guide treatment decisions, including assessment of cytogenetic abnormalities (del 17p, t(4;14), t(14;16), t(14;20)) 1, 2
• Patient-specific considerations include age, comorbidities, functional status, and frailty assessment to determine transplant eligibility 3
• Baseline evaluation should include complete blood count, serum creatinine, calcium, and whole-body low-dose CT for bone assessment 1, 2

Treatment Algorithm for Newly Diagnosed Multiple Myeloma

Transplant-Eligible Patients

• Induction therapy with VRd for 3-6 cycles 1, 4
• Followed by high-dose melphalan (200 mg/m²) with autologous stem cell transplantation 1, 4
• Post-transplant consolidation with 2 additional cycles of VRd 4, 5
• Maintenance therapy with lenalidomide continued until disease progression 1, 2

Transplant-Ineligible Patients

• Two preferred regimens with strong evidence:
  • VRd (bortezomib, lenalidomide, dexamethasone) 3, 2
  • DRd (daratumumab, lenalidomide, dexamethasone) 6
• DRd has demonstrated superior progression-free survival compared to Rd (lenalidomide, dexamethasone) with median PFS of 61.9 months vs. 34.4 months (HR=0.56) 6
• Recent meta-analysis suggests DRd may be superior to VRd in transplant-ineligible patients (HR: 0.56; 95% CI: 0.39,0.82) 7

Evidence-Based Comparison of Initial Regimens

VRd Regimen

• Demonstrated high response rates with 70.4% of patients achieving very good partial response or better after 6 cycles 5
• Complete response rate of 33.4% after induction, which deepens to 50.2% after consolidation 5
• Most common grade ≥3 adverse events: neutropenia (12.9%) and infection (9.2%) 5
• Grade ≥2 peripheral neuropathy occurs in 17% of patients 5

DRd Regimen

• Superior overall response rate of 92.9% compared to 81.3% with Rd 6
• Higher rates of stringent complete response (30.4% vs 12.5%) 6
• 32% reduction in risk of death compared to Rd (HR=0.68) 6
• Higher rates of minimal residual disease negativity (24.2% vs 7.3%) 6

Special Considerations

• For high-risk cytogenetics (del 17p, t(14;16), t(14;20)), bortezomib-based maintenance therapy is preferred over lenalidomide alone 1, 2
• Subcutaneous administration is the preferred route for bortezomib to reduce peripheral neuropathy 2
• Weekly bortezomib dosing (rather than twice weekly) reduces neuropathy while maintaining efficacy 2
• Thromboprophylaxis is essential for patients on immunomodulatory drugs like lenalidomide 1, 2

Monitoring Response

• Response should be assessed with each treatment cycle using serum and urine electrophoresis 1, 2
• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 2
• Minimal residual disease assessment should be considered to evaluate depth of response 6, 5

Common Pitfalls and Caveats

• Peripheral neuropathy is a significant concern with bortezomib-based regimens; subcutaneous administration and weekly dosing can mitigate this risk 2, 5
• Thrombotic events are associated with immunomodulatory drugs; appropriate prophylaxis is essential 1, 2
• Carfilzomib was evaluated as an alternative to bortezomib in the ENDURANCE trial but did not improve progression-free survival and had more toxicity, particularly cardiotoxicity 8
• Treatment decisions should account for patient frailty, as frail patients experience higher rates of treatment discontinuation and non-hematologic toxicity 3