Superior PFS2 with VTD Vs TD for Newly Diagnosed, Transplant Eligible, Multiple Myeloma (MM) Patients: Updated Analysis of Gimema MMY-3006 Study
Authors: Tacchetti Paola , Pantani Lucia , De Stefano Valerio , Zamagni Elena , Peccatori Jacopo , Pezzi Annalisa , Califano Catello , Nozza Andrea , Tosi Patrizia , Terragna Carolina , Ciambelli Fabrizio , Cangini Delia , Galieni Piero , Cangialosi Clotilde , De Sabbata Giovanni , Elice Francesca , Palumbo Antonio , Cavo Michele 
Published: October 2019

Abstract
Background: The phase 3 GIMEMA-MMY-3006 study comparing bortezomib-thalidomide-dexamethasone (VTD) vs. thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) provided demonstration of superior CR/nCR rates after induction (the primary study endpoint) and across all subsequent treatment phases, a gain which translated into significantly longer PFS for patients randomized to the VTD arm (Cavo, Lancet 2010; Blood 2012). We herein report an updated analysis of the study with a focus on PFS2, time to second anti-myeloma therapy, treatment-free interval, post-relapse OS and long term outcomes.
Methods: Overall, 474 patients were included in the trial. After a median follow up of 65 months, 251 patients (53%) have progressed and of these 221 (88%) had available data on salvage therapy after relapse.
Results: On an intention-to-treat basis, median PFS was 57 months for patients randomized to the VTD arm as compared to 42 months for those assigned in the TD arm (HR 0.67; p=0.001). No statistically significant difference in 5-years estimates of OS was observed between VTD and TD groups (80% vs 73%). PFS2, defined as the time from initial randomization to second disease progression or death from any cause, was significantly longer for patients randomised to VTD than for those in the TD group (76% vs. 63% at 5 years, respectively; HR 0.64, p=0.009). Globally, 73% and 83% of patients in the VTD and TD arms required the start of salvage therapy due to symptomatic relapse. Median time to subsequent anti-myeloma therapy (defined as the interval between start of induction treatment and the first dose of second-line therapy) was significantly longer for patients assigned to VTD than for those who experienced relapse in the TD cohort (40 vs 31 months, p=0.014). Similarly, median treatment-free interval (defined as the time between last administration of front-line therapy and start of salvage treatment) was 26 months in VTD group vs 16 months in TD arm (p=0.016). Most of the patients received a novel agent-containing salvage therapy, while 18% was treated with conventional chemotherapy. As expected, a greater percentage of patients in the TD arm were treated with second-line bortezomib-based combinations in comparison with those relapsing in the VTD arm (72% vs 46%, respectively, p=0.001). Within the VTD group, no statistically significant difference in PFS2 was seen regarding the use of bortezomib or an IMiD as (part of) second-line therapy (64 vs 57 months, respectively). Clinical benefit from primary randomization to VTD vs TD was also observed in terms of second PFS (defined as the interval between first and second progression) (HR 0.61, p=0.032). The median OS after relapse was 36 months for both TD and VTD groups. No differences in post relapse OS were observed for patients primarily assigned to VTD or TD who received a subsequent bortezomib-based salvage therapy.
Conclusion: With an extended follow-up of approximately 5 years, VTD was superior to TD in terms of extended PFS2, time to subsequent anti-MM therapy and treatment-free interval. PFS2 was significantly longer for patients randomized to VTD, with no difference regardless of the use of bortezomib or an IMiD as part of second-line therapy. This finding, along with similar post-relapse OS values across the two groups, suggest that induction and consolidation therapy with VTD did not select the emergence of bortezomib- resistant clones at the time of relapse.

Disclosures
Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Sanofi Aventis: Honoraria. Cavo:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharm.: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Onyx: Honoraria.