Initial Treatment of Newly Diagnosed Multiple Myeloma
For transplant-eligible patients with newly diagnosed multiple myeloma, initiate VRd (bortezomib, lenalidomide, dexamethasone) for 3-4 cycles, followed by autologous stem cell transplantation, then lenalidomide maintenance until progression. 1
Risk Stratification Before Treatment Selection
Perform cytogenetic risk assessment using FISH on bone marrow samples immediately at diagnosis to determine treatment intensity 1, 2:
Standard-risk features:
- Hyperdiploidy, t(11;14), t(6;14) 1
High-risk features:
- t(4;14), t(14;16), t(14;20), del(17p), 1q amplification/del(1p), ISS stage III, high LDH, plasma cell labeling index >3%, extramedullary disease 1, 2
Transplant-Eligible Patients
Standard-Risk Disease
Induction therapy: VRd (bortezomib, lenalidomide, dexamethasone) for 3-4 cycles achieves 58% VGPR or better and 52% complete response rates 1. This regimen produces an overall response rate of 87% and 30% complete response 2.
Consolidation: High-dose melphalan with autologous stem cell transplantation 1, 2
Maintenance: Lenalidomide maintenance until progression increases progression-free survival and possibly overall survival 3, 1, 4
High-Risk Disease
Add daratumumab to VRd (Dara-VRd) for high-risk cytogenetics 1. The addition of daratumumab to VTd improves 18-month progression-free survival to 93% versus 85% with VTd alone (P<0.0001) 2. Bortezomib-based regimens partially overcome the adverse prognosis of high-risk cytogenetics including t(4;14) and del(17p) 2.
Post-transplant: Consider tandem autologous transplantation for high-risk disease, though data remain conflicting 3. Use proteasome inhibitor-based maintenance (with or without immunomodulatory drug) rather than lenalidomide alone, as lenalidomide maintenance shows limited benefit in high-risk disease 3.
Transplant-Ineligible Patients
Standard-Risk Disease
DRd (daratumumab, lenalidomide, dexamethasone) until progression is the preferred regimen 1. The MAIA trial demonstrated median PFS of 61.9 months with DRd versus 34.4 months with Rd alone (HR=0.56), representing a 44% reduction in risk of disease progression or death 5. Overall response rate was 92.9% with DRd versus 81.3% with Rd (p<0.0001) 5.
Alternative regimens include VMP (bortezomib, melphalan, prednisone) or MPT (melphalan, prednisone, thalidomide), which are standards of care 3. Weekly bortezomib schedules are preferred over twice-weekly dosing to reduce polyneuropathy, especially in elderly or frail patients 3.
High-Risk Disease
VRd for 8-12 cycles followed by bortezomib-based maintenance until progression 1. This approach leverages the ability of proteasome inhibitors to overcome adverse cytogenetics 2.
Special Clinical Situations
Renal Failure
Start bortezomib-based regimens immediately without dose adjustment 1. Lenalidomide requires dose modification based on creatinine clearance using the Cockroft-Gault formula 3.
Pre-existing Neuropathy
Use DRd instead of VRd to avoid bortezomib-related neuropathy 1. If bortezomib is necessary, use weekly rather than twice-weekly dosing 3.
Frail or Elderly Patients (>75 years)
Reduce dexamethasone dose to 20 mg/week instead of 40 mg/week 5. Consider two-drug combinations rather than triplet therapy based on geriatric assessment including Karnofsky Performance Status, organ impairment, and instrumental activities of daily living 3.
Essential Supportive Care
Bone protection: Administer intravenous bisphosphonates (zoledronic acid or pamidronate) for all patients requiring therapy, continued throughout active disease 3, 2. Zoledronic acid improves overall survival by 5.5 months independent of skeletal-related events, suggesting anti-myeloma properties 3.
Thromboprophylaxis: Use aspirin for standard-risk patients; use low-molecular weight heparin, warfarin, or direct thrombin inhibitors for high-risk patients (those receiving immunomodulatory drugs with steroids or anthracyclines) 1, 2.
Infection prophylaxis: Provide acyclovir for all patients on bortezomib-based regimens; consider levofloxacin during the first two cycles 2.
Critical Pitfalls to Avoid
Do not use carfilzomib-lenalidomide-dexamethasone (KRd) as initial therapy due to higher risk of serious cardiac, renal, and pulmonary toxicity 1.
Do not prolong induction beyond 4-6 cycles in transplant-eligible patients as this may impair stem cell collection 1.
Do not use age alone to determine transplant eligibility—perform comprehensive geriatric assessment including functional status, comorbidities, and frailty scoring 3.