The cell-based antiproliferation studies suggested synergistic activity between alrizomadlin and IMiDs against wild-type TP53 (TP53WT) MM cell lines...alrizomadlin plus pomalidomide further 1) enhanced accumulation of p21 and decreased phosphorylation of retinoblastoma tumor suppressor protein (RB), which culminated in cell cycle arrest at G0/G1; 2) augmented BIM as well as cleavage of caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1), which trigger and/or serve as a hallmark of apoptosis (respectively); and 3) promoted antiproliferative effects....Preclinical research suggests that MDM2 inhibitor alrizomadlin in combination with pomalidomide has synergistic antitumor effects in MM tumors harboring TP53WT.

In cell-based antiproliferation studies, alrizomadlin demonstrated selective activity against WT TP53 MM cell lines, including MOLP-8, H929, and MM1S...In vivo studies showed that coadministration of alrizomadlin with proteasome inhibitor bortezomib or carfilzomib enhanced tumor regression (vs. single agents) in H929 xenograft models...the combination of MDM2 inhibitor APG-115 and proteasome inhibitors have synergistic antitumor effects on MM tumors harboring WT TP53.