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, followed by autologous stem cell transplantation (if eligible) and maintenance therapy. 1, 2

Risk Stratification and Initial Assessment

• All newly diagnosed multiple myeloma patients should undergo comprehensive risk stratification to guide treatment decisions, including cytogenetic analysis to identify high-risk features such as del(17p), t(4;14), t(14;16), or t(14;20) 1, 2
• Evaluation should include serum and urine electrophoresis, serum free light chain levels, bone marrow examination, and whole-body imaging (preferably low-dose CT) to assess disease burden and bone involvement 1, 2
• Patient-specific factors including age, comorbidities, and frailty status should be assessed to determine transplant eligibility and treatment intensity 3

Treatment for Transplant-Eligible Patients

• The standard initial treatment for transplant-eligible patients is bortezomib, lenalidomide, and dexamethasone (VRd), which has demonstrated high response rates with 74% of patients achieving very good partial response (VGPR) or better 2
• Following induction therapy with VRd, patients should proceed to high-dose melphalan (200 mg/m²) with autologous stem cell transplantation 1
• After transplantation, maintenance therapy with lenalidomide should be continued until disease progression to improve progression-free and overall survival 1, 2
• For high-risk patients (with del 17p, t(14;16), t(14;20)), bortezomib-based maintenance therapy is preferred over lenalidomide alone 1, 2

Treatment for Transplant-Ineligible Patients

• For transplant-ineligible patients, triplet therapies including VRd or daratumumab plus bortezomib plus melphalan plus prednisone (D-VMP) are recommended 3
• VRd has demonstrated superior outcomes compared to Rd (lenalidomide and dexamethasone) with median progression-free survival of 43 months vs. 30 months and median overall survival of 75 months vs. 64 months 3
• Daratumumab in combination with lenalidomide and dexamethasone (DRd) has emerged as a preferred option for transplant-ineligible patients, showing superior progression-free survival compared to VRd in meta-analyses (HR: 0.56; 95% CI: 0.39,0.82) 4, 5
• The DRd regimen demonstrated significant improvement in progression-free survival compared to Rd alone, with median PFS of 61.9 months vs. 34.4 months after 64 months of follow-up 4

Emerging Treatment Options

• Recent evidence supports the addition of anti-CD38 monoclonal antibodies to standard regimens, with isatuximab plus VRd showing superior progression-free survival compared to VRd alone in transplant-ineligible patients (63.2% vs. 45.2% at 60 months) 6
• Higher rates of complete response (74.7% vs. 64.1%) and MRD negativity (55.5% vs. 40.9%) were observed with isatuximab-VRd compared to VRd alone 6

Administration Considerations and Supportive Care

• Subcutaneous administration is the preferred route for bortezomib to reduce peripheral neuropathy while maintaining efficacy 2
• Weekly bortezomib dosing (rather than twice weekly) can further reduce neuropathy risk 2
• Thromboprophylaxis is essential for patients on immunomodulatory drugs like lenalidomide 1, 2
• Bisphosphonates should be administered to reduce skeletal-related events 1

Response Assessment and Monitoring

• 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 1, 2
• Regular monitoring for treatment-related toxicities is essential, particularly carfilzomib-related cardiac, renal, and pulmonary toxicities 2

Common Pitfalls and Caveats

• Inadequate risk stratification may lead to suboptimal treatment selection, particularly for high-risk patients who benefit from bortezomib-based maintenance 1, 2
• Failure to provide appropriate thromboprophylaxis for patients on immunomodulatory drugs increases risk of thrombotic events 1, 2
• Peripheral neuropathy is a common adverse effect of bortezomib that can lead to treatment discontinuation; using subcutaneous administration and weekly dosing can mitigate this risk 2
• Age alone should not determine transplant eligibility; comprehensive geriatric assessment including functional status and comorbidities provides better guidance for treatment intensity 3