Abstract 285: Ixazomib combined with the nuclear export inhibitors selinexor or eltanexor for the treatment of multiple myeloma
Authors: Turner Joel G. , Dawson Jana , Bauer Alexis , Gomez Juan , Baloglu Erkan , Landesman Yosef , Sullivan Daniel M. 
Published: August 2019

Introduction In the past decade, response and survival rates in multiple myeloma (MM) patients have been greatly increased by newer therapies. Nevertheless, most patients with MM eventually die from relapsed/refractory disease. Previous studies in our lab and in others have shown that exportin 1 inhibitors (XPO1i) are potent anti-MM drugs, whether used as single agents or in combination with proteasome inhibitors (PIs), immunomodulator drugs (IMiDs), anthracyclines, or alkylating agents. Ixazomib (IXA), an orally available PI, has been shown to be effective when combined with IMiDs, dexamethasone, alkylating agents, and/or prednisone for the treatment of patients with MM. We investigated whether the clinical XPO1i selinexor (SEL) or eltanexor (ELT) combined with IXA could overcome PI resistance in MM cell lines and in ex vivo bone marrow aspirates from PI-refractory patients.

Materials and Methods PI-resistant MM cell lines 8226B25 and U226PSR and their respective parental cell lines, 8226 and U266, were treated in vitro and in vivo (mice) with SEL/IXA or ELT/IXA combinations or with each drug as a single agent. Bone marrow aspirates from newly diagnosed and PI-refractory MM patients were treated ex vivo with SEL/IXA or ELT/IXA and assayed for apoptosis. Mechanistic studies included NFkB and IkBα protein assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assay. IkBα knockdown and NFkB transcriptional activity were measured in SEL/IXA- or ELT/IXA-treated MM cells.

Results SEL and ELT each sensitized parental and, to a lesser extent, PI-resistant MM cells to IXA, as measured by apoptosis. XPO1i/IXA treatments inhibited U266 and 8226 MM tumor growth and increased survival in mice; however, PI-resistant tumors were not sensitized by XPO1i/IXA treatment. Myeloma cells isolated from both newly diagnosed and PI-refractory MM patients were sensitized by XPO1i to IXA, as compared to untreated and single agent-treated MM cells, without affecting non-MM cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increased nuclear IkBα with the XPO1i/PI treatments. Proximity ligation found increased IkBα-NFkB complexes in treated MM cells. IkBα knockdown abrogated XPO1i/PI-induced cytotoxicity in MM cells. XPO1i/PI treatment decreased NFkB transcriptional activity.

Conclusions In previous studies, we found that SEL sensitized PI-resistant cell lines to carfilzomib and bortezomib; however, IXA was less effective in these same MM cells. SEL or ELT used in combination with IXA have the potential to overcome PI drug resistance in MM patients. Sensitization may be due to inactivation of the NFkB pathway by IkBα. Further investigation is underway to examine these mechanisms. The results presented in this study support combinatorial clinical trials in relapsed and refractory MM patients who use PI therapies.

Citation Format: Joel G. Turner, Jana Dawson, Alexis Bauer, Juan Gomez, Erkan Baloglu, Yosef Landesman, Daniel M. Sullivan. Ixazomib combined with the nuclear export inhibitors selinexor or eltanexor for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 285.