BH3 mimetics are the most promising combination partners for MCL-1 inhibitors in myeloma. (A) Outline of the 72-hour drug combination screening and representative hit selection based on synergy (S) score and CSS in OPM2-S63845 cells. (B) Ranking of selected drug combination partners (drug classes) based on S scores in all 4 cell line variants. Horizontal lines indicate average S scores for each drug class. (C) Independent validation experiments confirm strong synergism of S63845 with Bcl-xL and Bcl-2 inhibitors. Results are based on dose-response curves obtained 72 hours after treatment (n = 3 biological replicates). Zero interaction potency scores were determined with SynergyFinder. (D) BH3 mimetics reactivate BAK in S63845-resistant cells, whereas individual cell lines show preferences for either concurrent Bcl-xL or Bcl-2 blockade. BAK activation status was determined 4 hours after treatment with BH3 mimetics at the indicated concentrations. Horizontal lines indicate mean BAK activity (mean fluorescence intensity [MFI]). Results are based on 3 independent experiments performed in triplicate. *P < .05; ***P < .001; n.s., not significant.