Abstract 4067: Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14)
Authors: Chaudhry Sana , Nguyen Nina , Khurana Rimpi , Totiger Tulasigeri M. , Montoya Skye , Afaghani Jumana , Bradley Terrence , Maura Francesco , Kazandjian Dickran , Chapman Jennifer , Schürer Stephan , Landgren Ola , Hoffman James , Taylor Justin 
Published: June 2022

Abstract
Translocation t(11;14) positive multiple myeloma (MM) is sensitive to venetoclax, yet the drug lacks FDA approval in MM. Selinexor is an inhibitor of nuclear exporter XPO1 and is approved in relapsed refractory MM. We recently analyzed RNA-seq from 859 MM patient samples (MMRF CoMMpass study) and compared them to healthy bone marrow samples (GSE114922). After correcting for batch effects, differential gene expression analysis found apoptosis and cell cycle regulation amongst the top upregulated gene pathways in MM. We therefore hypothesized that MM would be sensitive to the combination of the pro-apoptotic drug, venetoclax, and selinexor, which causes cell cycle arrest.
Using a panel of 8 MM cell lines (U266-B1, KMS12BM, SKMM2, RPMI-8226, LP1, OPM2, KMS12PE, and NCIH929), we performed cell viability assays in increasing concentrations of selinexor, venetoclax, and a combination of the two drugs at 72 hours. Overall, the combination showed synergy in MM cell lines but strikingly, cell lines that possessed t(11;14) were more sensitive to the drug combination and showed enhanced synergy compared to the non-t(11;14). Average Bliss model synergy score were 0.5 in non-t(11;14) and 10.2 in t(11;14) MM cells (&gt;10 indicates synergistic effects and &lt;-10 indicates antagonistic drug effects).
To better understand molecular mechanisms underlying the observed synergistic effect in t(11;14), we performed western blot analysis in these cell lines treated with selinexor, venetoclax, the combination, or DMSO control for 24 hours. We measured protein levels of Cyclin D1, which is overexpressed in t(11;14) and a cargo of XPO1. We confirmed Cyclin D1 overexpression in t(11;14) cells lines but not in non-t(11;14) cells. Cyclin D1 levels decreased with selinexor, and the reduction was enhanced by adding venetoclax. Additionally, we measured levels of XPO1, p53, MCL-1, and p65, which we have previously shown to be altered by selinexor treatment. While venetoclax monotherapy caused increased MCL-1 expression, this was abrogated by combining with selinexor and the effects were statistically more significant in t(11;14) cell lines.
Concurrently, two patients with relapsed, refractory t(11;14) MM and disease progression after multiple lines of therapy were treated with venetoclax; however, after initial response, they developed resistance and progressive disease. Based off our preclinical results, selinexor was added to venetoclax and recaptured responses (VGPR and MR, respectively) suggesting a beneficial effect of the combination over single agent venetoclax. To our knowledge, this is the first report of patients with MM treated with the combination of selinexor and venetoclax. Further clinical evaluation of this combination in t(11;14) MM is planned and samples will be collected to better understand the mechanistic correlation between XPO1, BCL2/MCL-1, and Cyclin D1 levels and response.
Citation Format: Sana Chaudhry, Nina Nguyen, Rimpi Khurana, Tulasigeri M. Totiger, Skye Montoya, Jumana Afaghani, Terrence Bradley, Francesco Maura, Dickran Kazandjian, Jennifer Chapman, Stephan Schürer, Ola Landgren, James Hoffman, Justin Taylor. Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4067.