Bortezomib and High-Dose Melphalan Vs. High-Dose Melphalan As Conditioning Regimen before Autologous Stem Cell Transplantation in De Novo Multiple Myeloma Patients: A Phase 3 Study of the Intergroupe Francophone Du Myelome (IFM 2014-02)

Background: High dose melphalan (HDM) with autologous stem cell transplantation (ASCT) is a standard of care for multiple myeloma (MM) patients (pts). To date, no conditioning regimen has proven to be more effective or as well tolerated. Although outcomes have significantly improved over the past 15 years, relapse is thought to occur because of the persistence of resistant/dormant disease. Bortezomib (Bor) is a proteasome inhibitor that synergizes with alkylating agents due to its effects on DNA repair enzymes. It could improve the conditioning regimen before ASCT and increase the depth of tumor reduction. We previously reported (Roussel et al., Blood 2010) in a phase 2 study that Bor can safely and effectively be combined withHDM with 32% of complete response (CR) after a single ASCT, regardlessof the type of induction therapy. These data supported a randomized trial to assess whether this Bor-HDM regimen could enhance efficacy compared to HDM alone, in the settingof new-drug containing induction/consolidation therapies.

Methods: this phase 3, randomized, multicenter, open label trial was conducted within the IFM network (NCT02197221). Randomization was stratified according to ISS stage (I-II vs III), Fish analysis (standard vs high risk (HR=del17p or t(4;14)) vs fish failure) and response after induction (≥VGPR vs PR/SD). The experimental arm A, Bor-HDM, comprised Bor (1 mg/m², IV) on days -6, -3, +1, and +4; Melphalan (200 mg/m², IV) on day -2. Arm B consisted of HDM alone on day -2. Induction was free and non-progressive pts after ASCT further received 2 VTD cycles as consolidation. No maintenance was planned. Primary endpoint was CR rate at day 60 post ASCT, before consolidation. Secondary endpoints included overall responses, toxicities and outcomes.

Results: 300 pts were enrolled between 01/2015-09/2016 and 154 were allocated to the Bor-HDM arm. Pts characteristics were well balanced: median age=58 years; ISS stage I 57%, stage II 29%, stage III 14% ; HR cytogenetic 16% ; ≥VGPR at baseline 58%. 88% of pts received VTD as induction and 11% CyborD. In the Bor-HDM arm, 97.5% of pts received the planned conditioning regimen and underwent ASCT (98.5% in the HDM arm). On an intention to treat analysis, there was no difference regarding CR rates at day 60: 23% in the Bor-HDM arm vs 21% in the HDM arm (p=0.72). These results were homogenous across strata. At the completion of consolidation, 34% were in CR in the Bor-HDM arm vs 36% in the HDM arm. (p=0.70). Overall, all pts except 4 in the HDM arm responded. Best response achieved across the program were : 86% ≥VGPR and 44% ≥CR in the Bor/HDM arm vs 84% of ≥VGPR and 46% of ≥CR in the HDM arm. Results of minimal residual disease (MRD) are not yet available and will be presented during the meeting.

As of July 2017, median follow-up was 14 months. The 18-month PFS was 76% in the Bor-HDM arm versus 79% in the HDM arm (p= 0.53) and the 2-year OS was more than 93% in both arms.

Concerning toxicities, 1 pt died of influenza infection at day 4 after ASCT in the Bor-HDM arm. Sixty-two serious adverse events (AEs) occurred in 16% of pts treated with Bor-HDM and in 12% of HDM. Proportion of grade 3/4 AEs was slightly higher in patients treated with Bor-HDM (67% vs 63%). The most common grade 3/4 AEs were blood and gastrointestinal disorders. In the Bor-HDM arm, 4% of pts experienced grade 3/4 peripheral neuropathy (PNY) or grade 2 PNY with pain.

Conclusion: in this phase 3 randomized study, 97.5% of pts actually received the planned conditioning regimen with Bor-HDM. This conditioning regimen did not improve the CR rates after ASCT when compared to high dose Melphalan alone but MRD results are pending. No unexpected toxicities were reported.