What is the recommended initial treatment approach for patients with multiple myeloma?

Initial Treatment for Multiple Myeloma

For transplant-eligible patients under 65 years, initiate induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) for 4-6 cycles, followed by high-dose melphalan (200 mg/m²) with autologous stem cell transplantation (ASCT), then continuous lenalidomide maintenance until progression. 1, 2, 3

Treatment Algorithm Based on Transplant Eligibility

Transplant-Eligible Patients (<65 years, good functional status)

Induction Phase:

• Administer VRd triplet regimen consisting of: 1, 2
  • Bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11 4
  • Lenalidomide 25 mg orally on days 1-21 5
  • Dexamethasone 40 mg weekly (20 mg on infusion days as pre-medication) 4, 5
• Continue for 4-6 cycles before proceeding to transplant 1, 2
• This approach achieves 59% complete response rates and 79% minimal residual disease negativity 5

Consolidation Phase:

• High-dose melphalan 200 mg/m² intravenously as preparative regimen 4
• Use peripheral blood progenitor cells rather than bone marrow as stem cell source 4
• ASCT provides median progression-free survival of 50 months versus 36 months without transplant 2, 6

Maintenance Phase:

• Continuous lenalidomide until disease progression 1, 2
• For high-risk cytogenetics (del 17p, t(4;14), t(14;16), t(14;20)), consider bortezomib-based maintenance instead 1, 3

Transplant-Ineligible Patients (≥65 years or significant comorbidities)

Primary Treatment:

• Daratumumab, lenalidomide, and dexamethasone (DRd) is the preferred triplet regimen 1, 2, 7
  • Daratumumab 16 mg/kg intravenously per FDA-approved schedule 5
  • Lenalidomide 25 mg orally days 1-21 of 28-day cycles 5
  • Dexamethasone 40 mg weekly (20 mg for patients >75 years) 5
• DRd achieves median progression-free survival of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone 5
• Overall response rate of 92.9% with 47.6% achieving complete response or better 5

Alternative for Transplant-Ineligible:

• Melphalan-prednisone-thalidomide remains an option but is inferior to DRd 4
• Melphalan 9 mg/m²/day for 4 days plus prednisone 30 mg/m²/day for 4 days, repeated every 4-6 weeks 4

Essential Supportive Care Measures

Mandatory prophylaxis includes: 2, 3

• Thromboprophylaxis: Full-dose aspirin or therapeutic anticoagulation for all patients receiving immunomodulatory drugs (lenalidomide) 2, 3
• Herpes zoster prophylaxis: Acyclovir or valacyclovir for all patients on proteasome inhibitors (bortezomib) 2, 3
• Pneumocystis prophylaxis: For patients receiving high-dose glucocorticosteroids 2
• Bisphosphonates: To reduce skeletal-related events 1

Neuropathy prevention:

• Use subcutaneous rather than intravenous bortezomib administration to reduce peripheral neuropathy risk 3

Response Monitoring Protocol

• Assess response with each treatment cycle using serum and urine protein electrophoresis plus serum free light chains 1, 2, 3
• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 1, 2
• Once best response achieved or on maintenance, assess minimally every 3 months 2, 3
• Use whole-body low-dose CT rather than conventional skeletal survey for bone assessment 1, 3

Critical Risk Stratification

Obtain cytogenetics via FISH at diagnosis to identify: 4, 3

• High-risk abnormalities: del(17p), t(4;14), t(14;16), t(14;20) 4, 1
• These patients require intensified therapy with bortezomib-based maintenance rather than lenalidomide alone 1, 2

Use International Staging System (ISS) combining: 4

• β2-microglobulin and serum albumin levels 4
• Stage I (β2M <3.5 mg/L and albumin >3.5 g/dL) has 82% 5-year survival 8
• Stage III (β2M >5.5 mg/L) requires more aggressive approach 4

Asymptomatic/Stage I Disease

Do not initiate treatment for asymptomatic myeloma without CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions). 4

• Immediate treatment is not recommended for indolent myeloma 4
• Monitor closely for progression to symptomatic disease 4

Key Clinical Pitfalls to Avoid

• Never use lenalidomide-based regimens in patients progressing on lenalidomide maintenance—switch to proteasome inhibitor with monoclonal antibody 2
• Never delay restaging at relapse—evaluate for plasma cell leukemia or extramedullary disease as treatment approach differs dramatically 2
• Never use single or doublet therapy when triplet combinations are tolerated—triplet regimens consistently demonstrate superior outcomes 2
• Never overlook high-risk cytogenetics—these patients require bortezomib-based maintenance, not lenalidomide alone 1, 2, 3
• Never use intravenous bortezomib in patients with pre-existing neuropathy—subcutaneous administration significantly reduces neuropathy risk 3