Step 1. Assess Transplant Eligibility
Transplant-eligible (TE): Age usually <65–70, good performance status, no prohibitive comorbidities. Transplant-ineligible (TI): Older, frail, or with significant comorbidities.
Step 2. Choose Induction Regimen
A. Transplant-Eligible (TE) Patients
Standard of care (SOC):
Quadruplet therapy (preferred, 2024+): Daratumumab + Bortezomib + Lenalidomide + Dexamethasone (Dara-VRd) Widely adopted after GRIFFIN and PERSEUS trials. Alternative if daratumumab not available: VRd (Bortezomib + Lenalidomide + Dexamethasone). KRd (Carfilzomib + Lenalidomide + Dexamethasone) in selected younger/high-risk patients (FORTE trial).
Algorithm:
👉 Dara-VRd (preferred) → stem cell mobilization & collection → autologous stem cell transplant (ASCT) → consolidation ± maintenance.
B. Transplant-Ineligible (TI) Patients
Therapy chosen based on frailty (fit, intermediate, frail). Fit / standard-risk TI: Daratumumab + Lenalidomide + Dexamethasone (Dara-Rd) → SOC after MAIA trial (improved OS & PFS). Dara-VMP (Daratumumab + Bortezomib + Melphalan + Prednisone) — option where melphalan is still used. Intermediate/frail: Rd (Lenalidomide + Dexamethasone) DR (Daratumumab + Rd with reduced-intensity dex) VRd-lite (weekly bortezomib, lower-intensity lenalidomide/dex).
Algorithm:
👉 Assess frailty →
Fit: Dara-Rd (preferred) Intermediate: Rd or Dara-Rd (dose adjusted) Frail: Rd-lite, supportive approach.
Step 3. High-Risk Disease Considerations
High-risk cytogenetics: del(17p), t(4;14), t(14;16), 1q gain. Preferred induction: Dara-VRd or KRd (more intensive). Avoid alkylators early if transplant planned. Early ASCT strongly recommended. Consider tandem ASCT in select ultra–high-risk patients (per EMN/DSMM data).
Step 4. Supportive Care
Bone disease: bisphosphonates (zoledronic acid, pamidronate) or denosumab. Infection prophylaxis: acyclovir/valacyclovir with proteasome inhibitors or daratumumab. Thromboprophylaxis: aspirin or anticoagulation with IMiD-based regimens. Vaccinations: influenza, pneumococcal, COVID-19, zoster.