Superior Efficacy of VTD over VCD As Induction Therapy for Autotransplantation-Eligible, Newly Diagnosed, Myeloma Patients
Authors: Cavo Michele , Pantani Lucia , Pezzi Annalisa , Cavallo Federica , Petrucci Maria Teresa , Di Raimondo Francesco , Patriarca Francesca , Waage Anders , Zamagni Elena , Montefusco Vittorio , Galli Monica , Gamberi Barbara , Rossi Giuseppe , Tacchetti Paola , Grasso Mariella , Zweegman Sonja , Offidani Massimo , Ballanti Stelvio , Zambello Renato , Liberati Anna Marina , Bassan Renato , Pregno Patrizia , Palumbo Antonio , Sonneveld Pieter 
Published: October 2019

Abstract
Introduction
Three-drug induction regimens including a first or second generation proteasome inhibitor are a current standard of care for autologous stem-cell transplantation (ASCT)-eligible, newly diagnosed, multiple myeloma (MM) patients (pts). In the absence of prospective randomized studies comparing different induction regimens, it is difficult to recommend one treatment over another, and the choice is ultimately based upon physician’s preference or single center’s policy. Bortezomib-thalidomide-dexamethasone (VTD) has been recently approved by EMA as induction for previously untreated, ASCT-eligible, MM pts. Bortezomib combined with cyclophosphamide and dexamethasone (VCD) is an attractive alternative to VTD, although efficacy results have not been backed by phase III studies. The present study aimed to evaluate the differences in response rates and toxicity between VTD and VCD induction regimens in preparation for subsequent ASCT.
Methods
Two hundred and thirty six pts who were randomized to the VTD arm of the GIMEMA-MMY-3006 study were compared with an equal number of pair mates who received induction therapy with VCD as part of the EMN02 trial designed to prospectively compare ASCT up front vs bortezomib-melphalan-prednisone followed by ASCT at the time of relapse or progression. Both groups of pts were treated in Italian centers participating in the two phase III studies. Case matching was performed with respect to the following pt characteristics at baseline: age (± 2 years), ISS stage (1 vs 2 vs 3), t(4;14) (detected by FISH in ≥ 10% vs < 10% CD138+ bone marrow plasma cells) and del(17p) (≥ 20% vs <20% positivity). The two groups were also comparable with respect to Hb concentration, Plts and M protein isotype. Induction treatment consisted of three 21-day cycles of either VTD (bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; thalidomide 100 mg daily for the first 14 days and 200 mg daily thereafter; dexamethasone 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) or VCD (bortezomib and dexamethasone as in VTD; cyclophosphamide 500 mg/m2 on days 1 and 8). Evaluation of response and toxicity was performed after the third cycle of induction or the last cycle actually received for those pts who discontinued earlier.
Results
On an intention-to-treat basis, the overall rate of partial response (PR) or higher, as established according to the IMWG criteria, was 93% (95% CI: 89-96%) with VTD and 84% (CI: 79-89%) with VCD (χ2test p value=0.003). In particular, the complete response (CR) rate was approximately three fold higher for pts randomized to VTD (19%, CI: 14-24%) as compared to those in the VCD group (7%; CI: 4-10%) (p<0.001), while the corresponding values for very good partial response (VGPR) were 43% (CI: 36-49%) vs 32% (CI: 26-38%), respectively (p<0.001). Overall, VTD induction therapy yielded a significantly higher rate of ≥ VGPR (61%, CI: 55-68%) as compared to VCD (39%, CI: 32-45%) (p<0.001), and a two fold lower probability to achieve less than PR (7%, CI: 4-11%) vs 16% (CI: 11-21%) (p=0.003). The superior rate of ≥ VGPR yielded by VTD over VCD was retained both in pts with ISS stage 2+3 (65%, CI: 57-73%) vs 37% (CI: 29-46%) (p<0.001), and in those with t(4;14) and/or del(17p) [79% (CI: 68-90%) vs 44% (CI: 30-58%), p<0.001]. Evaluation of toxicity induced by VTD and VCD induction therapy was focused on peripheral neuropathy (PN) (NCI CTCAE, version 3.0). Grade ≥ 2 PN was slightly higher for pts on VTD (13%, CI: 9-17%) as compared to those on VCD (9%, CI: 6-13%) (p=0.19). When the threshold of grade ≥ 3 PN was considered, the difference between the two groups significantly favoured pts treated with VCD [2% (CI: 0.1-3%) vs 7% (CI: 4-11%) (p=0.004) for pts on VTD]. However, it is worth noting that only a single pt on VCD and 2 pts on VTD discontinued treatment due to PN.
Conclusions
The triplet VTD induction therapy was associated with significantly higher CR and ≥ VGPR rates compared to VCD, confirming that VTD is one of the most active bortezomib-based induction regimens in preparation for ASCT. Grade ≥ 2 PN rate was similar between the two regimens, although VTD-induced grade ≥ 3 PN was higher with VTD. Data on the impact of VTD and VCD induction therapy on post-ASCT high-quality response rates and additional outcomes will be presented at the meeting. The superiority of VTD over VCD needs to be confirmed by prospective randomized studies, one of which is currently running in Europe.

Disclosures
Cavo: Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharm.: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Onyx: Honoraria. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Celgene, Janssen-Cilag, Sanofi, Bristol-Myers Squibb: Honoraria. Ballanti:Janssen: Honoraria. Palumbo:Sanofi Aventis: Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Array BioPharma: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Sonneveld:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.