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

Initial Treatment for Multiple Myeloma

For transplant-eligible patients with newly diagnosed multiple myeloma, 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, then continuous lenalidomide maintenance until disease progression. 1, 2, 3

Treatment Algorithm Based on Transplant Eligibility

Transplant-Eligible Patients (Age <65 years or fit patients)

Induction Phase:

• Administer VRd triplet regimen consisting of: 4, 1
  • Bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11 of 21-day cycles 4
  • Lenalidomide 25 mg orally on days 1-14 4
  • Dexamethasone 20 mg orally on days 1,2,4,5,8,9,11,12 4
• Continue for 4-6 cycles before proceeding to transplant 1, 2
• VRd is superior to older VAD regimens (vincristine, adriamycin, dexamethasone) and should be the backbone of induction 4

Consolidation Phase:

• High-dose melphalan 200 mg/m² intravenously is the standard preparative regimen 4, 2
• Use peripheral blood progenitor cells rather than bone marrow as the stem cell source 4
• ASCT provides median progression-free survival of 50 months versus 36 months with delayed transplant 2

Maintenance Phase:

• Continuous lenalidomide until disease progression 1, 2, 3
• 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 (Age ≥65 years or significant comorbidities)

Standard Regimens (choose one):

• Melphalan/prednisone/thalidomide (MPT): Melphalan 9 mg/m²/day for 4 days, prednisone 30 mg/m²/day for 4 days, thalidomide 100 mg daily, repeated every 4-6 weeks 4
• Bortezomib/melphalan/prednisone (VMP): Both MPT and VMP are approved by European Medicines Agency and considered standards of care 4
• Daratumumab/lenalidomide/dexamethasone (DRd): For patients ineligible for ASCT, DRd demonstrated median PFS of 61.9 months versus 34.4 months with lenalidomide/dexamethasone alone, with 44% reduction in risk of progression or death 5

The 2013 ESMO guidelines note that lenalidomide/dexamethasone is widely used in US centers but was not approved in Europe at that time 4. However, the more recent FDA label data from the MAIA trial (median follow-up 64 months) demonstrates superior outcomes with DRd in transplant-ineligible patients 5, making this a preferred option when available.

Alternative for patients with pre-existing neuropathy:

• Bendamustine plus prednisone is approved when clinical neuropathy precludes use of thalidomide or bortezomib 4

Risk Stratification Impact on Treatment Selection

Standard-risk patients:

• VRd induction → ASCT (if eligible) → lenalidomide maintenance 1, 3

High-risk patients (del 17p, t(4;14), t(14;16), t(14;20)):

• VRd induction → ASCT (if eligible) → bortezomib-based maintenance therapy preferred over lenalidomide alone 1, 3
• High-risk cytogenetics should be obtained by conventional karyotyping or FISH analysis 4, 3

Essential Supportive Care Measures

Mandatory interventions:

• Thromboprophylaxis: Full-dose aspirin or therapeutic anticoagulation for all patients receiving immunomodulatory drugs (lenalidomide, thalidomide, pomalidomide) 2, 3
• Herpes zoster prophylaxis: Acyclovir or valacyclovir for all patients on proteasome inhibitors 2, 3
• Bisphosphonates: Long-term administration (oral or intravenous) reduces skeletal events and should be given to patients with stage III or relapsed disease 4, 1
• Pneumocystis prophylaxis: For patients receiving high-dose glucocorticosteroids 2

Response Monitoring Protocol

• Assess response with each treatment cycle using serum and urine protein electrophoresis and serum free light chains 1, 2, 3
• Once best response achieved or on maintenance therapy, assess at minimum every 3 months 2, 3
• Complete response requires <5% plasma cells in bone marrow and negative immunofixation 1, 2
• Whole-body low-dose CT is preferred over conventional skeletal survey for bone assessment 1, 3

Critical Pitfalls to Avoid

Do not treat asymptomatic/smoldering myeloma:

• Immediate treatment is not recommended for patients with indolent myeloma who lack CRAB criteria (hypercalcemia >11.0 mg/dl, creatinine >2.0 mg/ml, anemia with Hb <10 g/dl, active bone lesions) 4

Avoid suboptimal regimens:

• Do not use single or doublet therapy when triplet combinations are tolerated—triplet regimens consistently demonstrate superior outcomes 2
• Multiagent chemotherapy beyond standard regimens has not proven superior and may be inferior in elderly patients 4
• The ENDURANCE trial demonstrated that carfilzomib/lenalidomide/dexamethasone (KRd) did not improve progression-free survival compared to VRd (median PFS 34.6 vs 34.4 months, HR 1.04, p=0.74) and had more toxicity, confirming VRd as the standard of care 6

Neuropathy management:

• Use subcutaneous bortezomib preferentially for patients with pre-existing or high-risk peripheral neuropathy 3
• Grade 3-4 peripheral neuropathy occurred in 8% with VRd versus <1% with KRd, but overall VRd remains preferred due to equivalent efficacy and better overall safety profile 6

Stem cell preservation:

• Induction chemotherapy should avoid prolonged alkylating agent exposure to ensure adequate hematopoietic quality of the graft 4