What is the recommended initial treatment approach for patients with Multiple Myeloma?

Initial Treatment for Multiple Myeloma

For newly diagnosed multiple myeloma, initiate treatment with the triplet regimen of bortezomib, lenalidomide, and dexamethasone (VRd), which is the standard of care for both transplant-eligible and transplant-ineligible patients. 1, 2

Transplant-Eligible Patients (Age <65 or Fit)

Induction therapy with VRd for 4-6 cycles followed by high-dose melphalan (200 mg/m²) with autologous stem cell transplantation (ASCT) and continuous lenalidomide maintenance until progression is the recommended approach. 1, 2

Specific VRd Dosing Regimen

• Bortezomib: 1.3 mg/m² subcutaneously (preferred over IV to reduce neuropathy risk) on days 1,4,8, and 11 of 21-day cycles for cycles 1-8, then days 1 and 8 for cycles 9-12 3, 4
• Lenalidomide: 25 mg orally on days 1-14 of each 21-day cycle 3
• Dexamethasone: 20 mg orally on days 1,2,4,5,8,9,11, and 12 3

Critical Timing Considerations

Harvest peripheral blood stem cells within the first 4 cycles of lenalidomide-based therapy to prevent collection failure. 3 Prolonged lenalidomide exposure decreases CD34-positive cell yield, though plerixafor can rescue failed conventional mobilization. 3

Transplant Outcomes

VRd induction followed by ASCT provides median progression-free survival of 50 months versus 36 months with VRd alone (HR 0.65, p<0.001), with complete response rates of 59% versus 48%. 5 However, overall survival at 4 years was similar (81% vs 82%), making delayed transplant a reasonable alternative for patients preferring to defer this approach. 5

Transplant-Ineligible Patients (Age ≥65, Frail, or Significant Comorbidities)

Triplet therapy with VRd or daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) should be administered, with continuous therapy preferred over fixed-duration treatment. 3, 1

VRd Regimen for Non-Transplant Patients

The same VRd dosing applies, but dexamethasone should be reduced to 20 mg weekly for patients >75 years or with significant comorbidities. 6 Treatment continues until progression or unacceptable toxicity. 3

Alternative: Daratumumab-Based Quadruplet

D-VMP demonstrated 91.3% overall response rate with median PFS of 61.9 months versus 34.4 months with melphalan-prednisone alone (HR 0.56, p<0.0001). 6 This represents a 44% reduction in disease progression risk and 32% reduction in death risk. 6

High-Risk Cytogenetics Management

For patients with del(17p), t(4;14), t(14;16), or t(14;20), bortezomib-based induction is mandatory as it overcomes some adverse prognostic effects, particularly for t(4;14). 3, 2

• Use VRd induction followed by ASCT if eligible 2
• Switch to bortezomib-based maintenance rather than lenalidomide alone for high-risk patients 2
• High-risk patients benefit most from achieving complete response, so therapy should be intensified if only partial response after 2 cycles 3

Special Populations

Renal Failure (Creatinine >2 mg/dL or eGFR <30)

Start bortezomib-based regimens immediately, as bortezomib has primarily non-renal clearance and produces rapid responses. 3 VRd or bortezomib-dexamethasone with cyclophosphamide or doxorubicin are preferred. 3 Avoid nephrotoxic agents and maintain euvolemia. 3

Standard-Risk t(11;14) Patients

Use standard VRd induction—t(11;14) is NOT high-risk cytogenetics. 4 Venetoclax-based regimens are reserved for relapsed/refractory disease, not initial treatment. 4

Essential Supportive Care (Non-Negotiable)

• Thromboprophylaxis: Full-dose aspirin or therapeutic anticoagulation for all patients on lenalidomide 2, 4
• Herpes zoster prophylaxis: Acyclovir or valacyclovir for all patients on bortezomib 2
• Bisphosphonates: Administer to reduce skeletal-related events 1, 4
• Pneumocystis prophylaxis: For patients receiving high-dose glucocorticosteroids 2

Response Monitoring

Assess response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains. 1, 2 Once best response is achieved or on maintenance, assess minimally every 3 months. 3, 2

• Complete response criteria: <5% plasma cells in bone marrow AND negative immunofixation 1, 2
• Imaging: Whole-body low-dose CT is superior to skeletal survey and is the preferred method for baseline and routine bone surveillance 3, 1

Critical Pitfalls to Avoid

• Do not use carfilzomib-lenalidomide-dexamethasone (KRd) instead of VRd for initial therapy—the ENDURANCE trial showed no PFS benefit (34.6 vs 34.4 months, HR 1.04, p=0.74) with significantly more toxicity including 2% treatment-related deaths versus <1% with VRd. 7
• Do not delay stem cell collection beyond 4 cycles of lenalidomide therapy in transplant-eligible patients 3
• Do not use lenalidomide-based regimens in patients with severe renal failure without dose adjustment—bortezomib-based regimens are preferred 3
• Do not use single or doublet therapy when triplet regimens are tolerated—triplet therapy consistently demonstrates superior outcomes 3, 2