What is the initial treatment for multiple myeloma?

Initial Treatment for Multiple Myeloma

For newly diagnosed multiple myeloma, initiate treatment with bortezomib, lenalidomide, and dexamethasone (VRd) as the standard triplet regimen, regardless of transplant eligibility. 1, 2

Treatment Pathway Based on Transplant Eligibility

Transplant-Eligible Patients

Administer 4-6 cycles of VRd induction therapy, followed by autologous stem cell transplantation (ASCT) with high-dose melphalan (200 mg/m²), then continuous lenalidomide maintenance until disease progression. 1, 2

• Standard-risk patients (absence of del(17p), t(14;16), t(14;20), t(4;14)): VRd × 4 cycles → stem cell collection → ASCT → lenalidomide maintenance 3, 1
• High-risk patients (del(17p), t(4;14), t(14;16), t(14;20)): VRd × 4-6 cycles → stem cell collection → ASCT → bortezomib-based maintenance therapy (not lenalidomide alone) 1, 2
• Peripheral blood progenitor cells are preferred over bone marrow as the stem cell source 1
• For patients >65 years or those receiving ≥4 cycles of lenalidomide-dexamethasone, consider chemotherapy plus G-CSF mobilization or plerixafor for stem cell collection 3

Transplant-Ineligible Patients

VRd remains the preferred triplet regimen, with continuous therapy until disease progression. 1, 2, 4

• The ENDURANCE trial demonstrated that VRd and carfilzomib-lenalidomide-dexamethasone (KRd) had equivalent progression-free survival (34.4 vs 34.6 months), but VRd had superior safety profile with less cardiotoxicity, dyspnea, and thromboembolic events 4
• Alternative for transplant-ineligible patients: Daratumumab-lenalidomide-dexamethasone (DRd) demonstrated superior outcomes compared to lenalidomide-dexamethasone alone in the MAIA trial, with median PFS of 61.9 months versus 34.4 months (HR 0.56) and 32% reduction in death risk 5
• Recent meta-analysis suggests DRd may be superior to VRd in transplant-ineligible patients (HR 0.60 for progression or death) 6
• Emerging option: Isatuximab-VRd showed 60-month PFS of 63.2% versus 45.2% with VRd alone in transplant-ineligible patients (HR 0.60), representing a newer quadruplet approach 7

VRd Dosing Regimen

For 12 cycles of 3 weeks each: 4

• Bortezomib 1.3 mg/m² subcutaneously (preferred) or IV on days 1,4,8,11 (cycles 1-8), then days 1,8 only (cycles 9-12)
• Lenalidomide 25 mg orally days 1-14
• Dexamethasone 20 mg orally on days 1,2,4,5,8,9,11,12

Essential Supportive Care Measures

All patients require comprehensive prophylaxis to prevent treatment-related complications: 2, 8

• Thromboprophylaxis: Full-dose aspirin or therapeutic anticoagulation for all patients on immunomodulatory drugs (lenalidomide) 2, 8
• Herpes zoster prophylaxis: Acyclovir or valacyclovir for all patients on proteasome inhibitors (bortezomib) 2, 8
• Pneumocystis prophylaxis: For patients receiving high-dose glucocorticosteroids 2
• Bisphosphonates: Administer to reduce skeletal-related events 1
• Subcutaneous bortezomib: Preferred route for patients with pre-existing or high-risk peripheral neuropathy 8

Response Monitoring

Assess response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains. 2, 8

• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 1, 2
• Once best response is achieved or on maintenance therapy, assess at minimum every 3 months 2, 8
• Whole-body low-dose CT is preferred over conventional skeletal survey for bone assessment 1

Critical Pitfalls to Avoid

• Do not use single or doublet therapy when triplet regimens are tolerated—triplet combinations consistently demonstrate superior outcomes 2
• Do not use lenalidomide-based regimens in patients progressing on lenalidomide maintenance—switch to proteasome inhibitor with monoclonal antibody 2
• Do not overlook high-risk cytogenetics—these patients require bortezomib-based maintenance rather than lenalidomide alone 2, 8
• Do not delay ASCT in eligible patients—ASCT provides median PFS of 50 months versus 36 months with delayed transplant 2