Abstract 2772: BCL-2 family expression profiling may identify distinct molecular subtypes of multiple myeloma with increased susceptibility to single agent Venetoclax
Authors: Wu Jenny , Stein Caleb , Ross Jeremy A. , Peale Franklin , Shaughnessy John D. , Laar Ryan Van , Morgan Gareth , Venstrom Jeffrey M. , Punnoose Elizabeth A. , Jiang Yanwen Yanwen 
Published: July 2017

Abstract
Venetoclax (VEN) is being evaluated in relapsed/refractory multiple myeloma (R/R MM) patients as a single agent (NCT01794520). Improved objective response rates were observed in t(11;14) patients (40% in t(11;14)+ vs 6% in t(11;14)-), which were shown to associate with a favorable BCL-2 family expression profile (high BCL2:BCL2L1 (BCL-XL). Forty percent of t(11;14)+ population exhibited VEN favorable biomarker profile with an 88% ORR compared to 20% in t(11;14)+ patients with unfavorable profile. Thus, a favorable BCL-2 family expression profile may identify certain MM subgroups with increased sensitivity to the anti-tumor activity of VEN as a single agent. To better understand and identify the patient populations that may benefit from VEN, we retrospectively analyzed the prevalence of a favorable BCL-2 family expression profile in t(11;14)+ and other MM molecular subtypes in two published cohorts (GSE4581 and GSE9782). Our results showed that BCL2 expression varied significantly across molecular and cytogenetic subgroups. The t(11;14)+ subgroup expressed high BCL2 and the lowest BCL2L1 and MCL1 in both newly diagnosed (NDMM) and R/R MM patients. Correspondingly, the t(11;14) MM was enriched for the highest ratios of BCL2/MCL1 and BCL2/BCL2L1, further supporting the single agent VEN activity observed in this patient population. Based on prevalence study in cohort GSE9782, we observed 40% of t(11;14)+ R/R MM patients exhibited a favorable BCL-2 family expression profile, using clinical defined cutoffs, thus highly consistent with the VEN single agent trial. Furthermore, this favorable profile existed in other molecular subtypes, especially the ones that harbor abnormal MAF (23%) and D3 (37.5%) translocations, as well as dysregulated expression of cyclinD1 (21.2%)/D1+D2 (26.7%). The molecular subgroup with overexpression of cyclin D2 had the lowest prevalence of the favorable profile (7.5%). In the NDMM cohort, overall 27% patients had favorable profile. More specifically, the t(11;14) patients had the highest (61%) and D2 patients had the lowest (13%) prevalence of a favorable BCL-2 family profile. Collectively, our data suggests that MM subgroups are associated with distinct BCL-2 family expression profiles, and that the t(11;14) subgroup is particularly suited for single agent VEN treatment as indicated by the high prevalence of a favorable BCL-2 family expression profile. In addition, we further identified patients in the non t(11;14) MM subgroups with a favorable BCL-2 family expression profile that may also potentially benefit from VEN monotherapy.
Citation Format: Jenny Wu, Caleb Stein, Jeremy A. Ross, Franklin Peale, John D. Shaughnessy, Ryan Van Laar, Gareth Morgan, Jeffrey M. Venstrom, Elizabeth A. Punnoose, Yanwen Yanwen Jiang. BCL-2 family expression profiling may identify distinct molecular subtypes of multiple myeloma with increased susceptibility to single agent Venetoclax [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2772. doi:10.1158/1538-7445.AM2017-2772