Carfilzomib-based induction/consolidation with or without autologous transplant (ASCT) followed by lenalidomide (R) or carfilzomib-lenalidomide (KR) maintenance: Efficacy in high-risk patients.
Authors: Francesca Gay, Roberto Mina, Delia Rota-Scalabrini, Monica Galli, Angelo Belotti, Elena Zamagni, Luca Bertamini, Renato Zambello, Barbara Gamberi, Giovanni De Sabbata, Giuseppe Pietrantuono, Andrea Capra, Anna Pascarella, Anna Marina Liberati, Salvatore Palmieri, Angela Cuoghi, Massimo Offidani, Michele Cavo, Pellegrino Musto, Mario Boccadoro
Journal: Journal of Clinical Oncology (2021)

8002 Background: Cytogenetic abnormalities (CA) are one of the most powerful prognostic factors in multiple myeloma (MM). In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd_ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12, HR 0.64) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd_ASCT, HR 0.53). KR maintenance significantly improved PFS vs R (HR 0.63). Methods: MM patients (pts) were randomized to KRd_ASCT vs KCd_ASCT vs KRd12 and, thereafter, to KR vs R maintenance. Subgroup analyses according to FISH evaluated the impact of each single high-risk (HiR) CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)] and that of combined CA, defining HiR by the presence of ≥1 HiR CA and double-hit (DH) by the presence of ≥2 HiR CA. Pts negative for all the HiR CA were considered at standard risk (SR). The primary objective was the impact of treatment on PFS according to pt risk. Results: 396 out of 474 enrolled pts were included in the analysis with complete FISH data: 243 HiR, 105 DH and 153 SR. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd_ASCT vs KRd12 (HR 0.47, p = 0.05) and KCd_ASCT (HR 0.38, p = 0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd_ASCT improved PFS vs KRd12 (HR 0.6, p = 0.04) and KCd_ASCT (HR 0.57, p = 0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd_ASCT vs KRd12 (HR 0.53, p = 0.07) and KCd_ASCT (HR 0.49; p = 0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Analyses by single CA were limited by the small number of pts in each subgroup, but a trend towards a PFS benefit from KRd_ASCT vs KRd12 was seen in pts with del17p (HR 0.61, p = 0.3), t(4;14) (HR 0.59, p = 0.2) and 1q gain (HR 0.45, p = 0.02). In pts with del1p, KRd_ASCT (HR 0.24, p = 0.06) and KRd12 (HR 0.33, p = 0.09) showed superiority over KCd_ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd_ASCT vs KCd_ASCT, HR 1.16, p = 0.73; KRd12 vs KCd_ASCT, HR 1.34, p = 0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p = 0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p = 0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p = 0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p = 0.37), t(4;14) (HR 0.59, p = 0.3), 1q gain (HR 0.54, p = 0.07) and del1p (HR 0.23, p = 0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p = 0.7). Conclusions: KRd_ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd_ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus supporting their use in HiR pts, who represent an unmet medical need. Clinical trial information: NCT02203643.