Transplantation and induction/consolidation therapy: lenalidomide, bortezomib and dexamethasone

High dose chemotherapy (induction therapy) followed by autologous stem cell transplant (ASCT) has been the standard of care for adult patients with Multiple Myeloma (MM) aged 65 years or younger. However, with increased benefits observed from combination therapies, the timing of transplantation has been questioned, and was therefore addressed in a randomized, open-label, IFM 2009 phase III trial, carried out by Michel Attal and collaborators, and published in The New England Journal of Medicine in April 2017. Patients (pts) aged 65 years or younger were recruited from 69 centers in France, Belgium, and Switzerland between November 2010 and November 2012. The primary end-point was progression-free survival (PFS); secondary end-points were overall survival (OS) and analysis of adverse events (AEs).

Study Design

• Pts (n=700) were randomly assigned into one of two groups:
  • RVD alone: Eight cycles of RVD (lenalidomide (25 mg orally on day 1-14), bortezomib (1.3 mg/m² i.v. on day 1, 4, 8, and 11), and dexamethasone (20 mg orally on day 1, 2, 4, 5, 8, 9, 11, and 12)
  • Transplantation group: pre-treated with 3 cycles of RVD, followed by melphalan at a dose of 200 mg/m² plus ASCT, followed by two cycles of RVD with a reduced daily dose of dexamethasone of 10 mg
• Following induction, both groups underwent stem cell mobilization therapy and received lenalidomide maintenance therapy (10 mg/day for first 3 months; possible dose increase to 15 mg thereafter) for 1 year

Key Findings

• RVD-alone group = 331 pts (95%) entered the consolidation phase and 321 (92%) entered the maintenance phase
• Transplantation group = 323 pts (92%) underwent transplantation, 315 (90%) began to receive RVD therapy after transplantation, and 311 (89%) entered the maintenance phase

Data is given as RVD-alone group vs transplantation group:

• CRR = 48% vs 59% (P = 0.03)
• CR or vGPR: after the induction phase = 45% vs 47% (P = 0.87); after the consolidation phase = 69% vs 78% (P = 0.03); after the maintenance phase = 76% vs 85% (P = 0.009); after transplantation = 70%
• Minimal residual disease not detected = 65% vs 79% (P<0.001)
• Disease progression or death = 368 patients (211 vs 157)
• Data censored due to receiving a new therapy or a therapy not specified in the protocol, had consent withdrawn, or were lost to follow-up = 7.2% vs 9.8%
• Median PFS = 36 vs 50 months (adjusted HR for disease progression or death = 0.65; 95% CI, 0.53 to 0.80; P<0.001)
• PFS benefit was unaffected by age, sex, isotype of the monoclonal component, International Staging System (ISS) disease stage, and cytogenetic risk profile
• PFS and OS were longer for pts in whom minimal residual disease was not detected vs those in whom minimal residual disease was detected: adjusted HR for disease progression or death = 0.30; P<0.001 and 0.34; P<0.001, respectively
• Median TTP = 36 vs 50 months (adjusted HR for disease progression or death owing to myeloma = 0.62; P<0.001).
• OS (4 years) = 82% vs 81% (adjusted HR for death = 1.16; 95% CI, 0.80 to 1.68; P = 0.87)
• Median survival = not reached in either group
• Disease progression:
  • RVD alone group = 207 pts; 172 received a second line therapy and 136 of 172 (79%) were given salvage transplantation
  • Transplantation group = 149 pts; 123 patients received a second-line therapy; 21/123 (17%) underwent a second transplantation

Safety

• Treatment discontinuation due to AEs: 32 pts (9%) vs 39 patients (11%)
• Treatment-related deaths: 2 vs 6
• Grade 3 or 4 AEs: 83% vs 97% (P<0.001); blood and lymphatic disorders: 64% vs 95%; gastrointestinal disorders: 7% vs 28% (P<0.001), and infections: 9% vs 20% (P<0.001); neutropenia: 47% vs 92%; thrombocytopenia: 14% vs 83%
• Infections: 9% vs 20%
• Incidence of second primary cancers did not differ significantly between groups
• Incidence of acute myeloid leukemia: 1 vs 4 pts

In conclusion, RVD consolidation therapy followed by transplantation significantly improved PFS, but did not affect OS. Transplantation also led to a higher rate of CR, a lower rate of minimal residual disease detection and a longer median time to progression (TTP). However, the timing of transplantation (salvage transplantation in relapsed patients) led to similar outcomes, indicating that delayed transplantation is a feasible option.