PF594 BORTEZOMIB-LENALIDOMIDE-DEXAMETHASONE VS BORTEZOMIB-THALIDOMIDE-DEXAMETHASONE INDUCTION: INTEGRATED ANALYSIS OF RANDOMIZED CONTROLLED TRIALS IN TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA
Authors: L. Rosiñol, B. Hebraud, A. Oriol, A.-L. Colin, R. Rios, C. Hulin, M.J. Blanchard, D. Caillot, A. Sureda, M. Teodoro Hernández, B. Arnulf, M.-V. Mateos, M. Macro, J. San Miguel, K. Belhadj, J.J. Lahuerta, M.B. Garelik, J. Bladé, P. Moreau, M. Attal
Journal: HemaSphere (2019)

Background: European and US guidelines recommend VRD and VTD for pts with TE NDMM. However, no RCTs have directly compared VRD vs VTD to date. Aims: To evaluate efficacy and safety of VRD vs VTD in TE NDMM via integrated analysis. Methods: Prospective, phase 3 RCTs evaluating VRD or VTD induction (every 3 or 4 wks) in TE NDMM before ASCT were included if they met pre-defined eligibility criteria (including access to pt-level data). Primary endpoint was noninferiority of ≥ VGPR rate post induction. Secondary endpoints included safety and ≥ VGPR rate during induction and post ASCT. Exploratory endpoints were PFS and MRD negativity. Statistical methods were based on propensity score (PS). Pts with missing baseline values for the variables used for the PS analyses were excluded. Results: Four studies met the eligibility criteria: VRD, PETHEMA GEM (GEM)2012 and IFM 2009; VTD, GEM2005 and IFM 2013–04. GEM2005 and GEM2012, used for the primary analysis, had a symmetrical induction design (six 4-wk cycles then ASCT). IFM studies were considered supportive due to their variable number of cycles (3 VRD cycles before ASCT vs 8 VRD cycles in IFM 2009 and 4 VTD cycles before ASCT in IFM 2013–04). IFM analyses compared the IFM 2009 VRD non-ASCT of vs IFM 2013–04 VTD arm. The VRD and VTD PS-stratified cohorts of the GEM and IFM studies had no clinically meaningful differences in baseline characteristics. The integrated analysis met its primary endpoint (non-inferiority) and demonstrated a statistically significant and clinically relevant ≥ VGPR rate improvement after 6 cycles of induction with VRD vs VTD (66.3% vs 51.2%; P = .00281; Figure) in the GEM studies. IFM non-inferiority results had similar ≥ VGPR rates for VRD vs VTD by 4 cycles (12 wks; 57.1% vs 56.5%). Responses deepened during induction in the GEM studies. Among the 378 VRD pts who started cycle 6, ≥ VGPR rate increased from 54.5% by 3 cycles of induction to 62.7% by 4 cycles, and to 70.1% by 6 cycles and post induction. Of the 111 VTD pts, these rates were 35.1%, 40.5%, and 55.9%, respectively. The ≥ VGPR rate post-ASCT (74.4% vs 53.5%) and MRD negativity (10–4) rates post induction (46.7% vs 34.9%) and post ASCT (62.4% vs 47.3%) support the benefit of VRD vs VTD. Safety was as previously reported for these studies. Peripheral neuropathy (PN) can limit VRD and VTD Tx duration. In GEM studies, SC vs IV administration of BORT may have contributed to lower rates of PN (grouped term) with VRD vs VTD (grade 3/4, 5.5% vs 15.4%; grade ≥ 2, 20.7% vs 44.6%). TEAEs led to dose reduction (21.6% vs 35.4%) and study or Tx discontinuation (3.1% vs 9.2%) less frequently in the VRD vs VTD cohorts. In IFM studies, TEAEs led to dose reduction more frequently (32.9% vs 18.3%) and Tx discontinuation less frequently (6.5% vs 11.2%) with VRD vs VTD. Grade 3/4 PN (grouped term) was 5.9% vs 15.4%, whereas grade ≥ 2 events were similar (30.3% vs 27.2%), which may reflect BORT administration in these IFM studies (IV for VRD vs SC for VTD, respectively).Summary/Conclusion: Six cycles of VRD induction led to a significantly higher ≥ VGPR rate than VTD in TE NDMM. Deepening responses and MRD negativity further support the benefit of VRD over VTD. TEAEs in the GEM and IFM studies were generally consistent with the known safety profiles of the individual agents. TEAEs with the VRD regimen were manageable, and the overall tolerability profile compared well with VTD, with lower rates of TEAEs leading to discontinuation. This analysis supports the favorable benefit-risk profile with VRD over VTD as induction Tx in TE pts with NDMM.