What is the initial treatment for multiple myeloma?

Initial Treatment for Multiple Myeloma

The initial treatment for multiple myeloma should be a triplet regimen of bortezomib, lenalidomide, and dexamethasone (VRd) for both transplant-eligible and transplant-ineligible patients. 1, 2

Treatment Algorithm Based on Transplant Eligibility

For Transplant-Eligible Patients

Induction Phase:

• Administer VRd triplet therapy consisting of: 1, 2
  • Bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11 of 21-day cycles 3
  • Lenalidomide 25 mg orally on days 1-14 3
  • Dexamethasone 20 mg orally on days 1,2,4,5,8,9,11,12 3

Consolidation:

• Proceed to high-dose melphalan (200 mg/m²) with autologous stem cell transplantation (ASCT) after induction 1
• Use peripheral blood progenitor cells as the stem cell source 1

Maintenance:

• Continue lenalidomide until disease progression for standard-risk patients 1, 2
• For high-risk cytogenetics (del 17p, t(14;16), t(14;20)), use bortezomib-based maintenance therapy instead 1, 2

For Transplant-Ineligible Patients

Primary Regimen:

• VRd remains the standard triplet regimen 1, 2, 3
• Continue therapy until disease progression rather than fixed-duration treatment 2

Alternative Consideration:

• Daratumumab plus lenalidomide and dexamethasone (DRd) is an acceptable alternative, showing lower risk of progression versus VRd (HR 0.60) in meta-analysis 4
• The most recent 2025 CEPHEUS trial demonstrated that adding daratumumab to VRd (D-VRd quadruplet) achieved 60.9% MRD-negativity versus 39.4% with VRd alone, with 43% lower risk of progression 5

Risk Stratification Determines Maintenance Strategy

Standard-Risk Disease:

• Lenalidomide maintenance until progression 1, 2

High-Risk Disease (del 17p, t(4;14), t(14;16), t(14;20)):

• Bortezomib-based maintenance therapy preferred over lenalidomide alone 1, 2
• Continuous therapy is critical as progression-free survival is shorter in this population 6

Essential Supportive Care Measures

Thromboprophylaxis:

• Mandatory for all patients receiving lenalidomide-based regimens 1
• Use full-dose aspirin or therapeutic anticoagulation 2

Infection Prophylaxis:

• Herpes zoster prophylaxis required for all patients on proteasome inhibitors 2

Bone Protection:

• Administer bisphosphonates to reduce skeletal-related events 1

Neuropathy Prevention:

• Use subcutaneous bortezomib (rather than intravenous) for patients with pre-existing or high-risk peripheral neuropathy 2

Response Monitoring

Frequency:

• Assess response with each treatment cycle using serum and urine protein electrophoresis 1, 2
• Once best response achieved or on maintenance, assess at minimum every 3 months 2

Complete Response Criteria:

• Requires <5% plasma cells in bone marrow and negative immunofixation 1

Imaging:

• Use whole-body low-dose CT rather than conventional skeletal survey for bone assessment 1, 2

Critical Pitfall to Avoid

The ENDURANCE trial definitively showed that carfilzomib-based regimens (KRd) do not improve progression-free survival compared to VRd (34.6 vs 34.4 months, HR 1.04, p=0.74) and cause more toxicity, including higher rates of cardiotoxicity and treatment-related deaths 3. VRd remains the standard backbone for newly diagnosed multiple myeloma, not KRd. 3, 7