Incorporation of Thalidomide-Dexamethasone (Thal-Dex) into up-Front Double Autologous Stem-Cell Transplantation (ASCT) for multiple Myeloma: Final analysis of phase II “Bologna 2002” Study.
Authors: Zamagni Elena , Testoni Nicoletta , Terragna Carolina , Tacchetti Paola , Nicci Chiara , Tosi Patrizia , Fiacchini Mauro , Patriarca Francesca , Raimondo Francesco Di , Catalano Lucio , Casulli Francesco , Volpe Silvestro , Masini Luciano , Ledda Antonio , Brioli Annamaria , Cangini Delia , Gozzetti Alessandro , Califano Catello , Cellini Claudia , Carubelli Affra , Petrucci Alessandro , Leopardi Giuliana , Pantani Lucia , Ceccolini Michela , Offidani Massimo , Perrone Giulia , Baccarani Michele , Cavo Michele 
Published: October 2019

Abstract
Abstract 349
We report here on the final analysis of the multicenter phase II “Bologna 2002” study which incorporated thal-dex into double ASCT with high-dose melphalan (200 mg/m2) as front-line therapy for younger patients with symptomatic multiple myeloma (MM). By study design, thal (200 mg/day) and pulsed low-dose dex (160 mg/month, with two added 4-day courses on the first and third cycle of induction therapy) were administered from the outset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 357 patients who were followed for a median of 43 months. Their median age was 57 years, 86% had advanced disease stage. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities (FISH) on CD138+ bone marrow plasma cells, including del(13q) (45%), t(4;14) (14%) and del(17p) (6%). The rate of at least VGPR increased from 31% after thal-dex induction therapy to 60% after the second ASCT. The final CR rate was 33% for all the patients and 44% for those who actually received pre planned double ASCT. Median TTP and PFS were 68 and 47 months, respectively, with 5-year projected rates of 45% and 33%. The 5-year projected OS rate was 65%. TRM after the first and second ASCT was 0.5% and 2%, respectively. Median OS after relapse or progression was 30 months, suggesting that short-term thal exposure had no adverse influence on response to salvage therapies. The quality of response following ASCT(s) influenced clinical outcomes. In particular, patients achieving CR had significantly longer PFS and OS than patients in VGPR (PFS: median 68 vs 48 months, respectively, P=0.04; 5-year projected OS 84% vs 72%, respectively, P=0.02). Similarly, patients in VGPR had better outcomes compared with patients achieving PR (P=0.02 and 0.04 for PFS and OS comparisons, respectively). In a multivariate analysis, best response (at least VGPR) ever achieved and low beta2-m were the most important variables significantly extending TTP (P=0.04), PFS (P=0.000) and OS (P=0.003). Additional variables predicting for prolonged PFS were the absence of del(13q) (P=0.002) and del(17p) with or without t(4;14)(P=0.03). OS was favourably influenced also by IgG isotype (P=0.04) and absence of high-risk cytogenetic abnormalities [del (17p) +/- t(4;14)(P=0.03)]. A case match comparison of 135 patients enrolled in “Bologna 2002” study with an equal number of pair mates included in the previous “Bologna 96” study of double ASCT without thal confirmed the benefits from the addition of thal-dex to double autotransplantation in terms of rate (P=0.001) and duration (p<0.001) of at least VGPR, TTP (P<0.001) and PFS (P=0.001). In conclusion, attainment of CR and VGPR was a major determinant of favorable outcomes for patients treated with thal-dex and double ASCT. Poor prognosis conferred by del(13q) and del (17p)+/- t(4;14) was not overcome by thalidomide, consistently with previous data reported in refractory MM patients and with thal as maintenance therapy after double ASCT. Short-term thal therapy, as applied in “Bologna 2002” study, was generally well tolerated, with limited toxicities leading to less than 10% discontinuation rate due to drug-related adverse events, and had no adverse impact on OS after relapse.

Disclosures:
Off Label Use: Thalidomide was incorporated into up-front treatment for patients with newly diagnosed multiple myeloma.