Anti-angiogenic and anti-multiple myeloma effects of oprozomib (OPZ) alone and in combination with pomalidomide (Pom) and/or dexamethasone (Dex)

•Oprozomib (OPZ) shows anti-tumor activity in human multiple myeloma (MM) xenograft models.•OPZ is an oral proteasome inhibitor that shows anti-angiogenic activity.•OPZ in combination with pomalidomide and dexamethasone markedly reduces MM xenograft growth.

Oprozomib (OPZ or ONYX 0912) is an irreversible, orally administered proteasome inhibitor (PI) and an analog of carfilzomib. We set out to determine the anti-angiogenic effect of OPZ using the choriollantoic membrane/feather bud (CAM/FB) model and its anti-MM effects using MM xenograft models (LAGκ-1A, LAGλ-1). OPZ significantly reduced blood vessel formation, endothelial gene and protein expression using the CAM/FB assay. In vivo, we determined the anti-MM effects of OPZ, dexamethasone (Dex) and pomalidomide (Pom) and showed that the combinations of two drugs (OPZ + Dex or OPZ + Pom) showed marked anti-MM effects when compared to monotherapy. Pom + Dex and the triplicate combination (OPZ + Pom + Dex) showed more anti-MM effects when compared to the doublets of either OPZ + Dex or OPZ + Pom; continued treatment with all three drugs (OPZ + Pom + Dex) was superior when compared to Pom + Dex, in both MM xenograft models tested. These studies show that OPZ has anti-angiogenic effects, and that the combination of OPZ, Dex and Pom produces greater anti-MM effects in vivo when compared to any of the doublet combinations. These studies provide further support for clinical trials evaluating OPZ in combination with Pom and Dex.