Concurrent Bcl-xL blockade outperforms venetoclax in the presence of stromal support. (A-B) Dose-response curves of S63845 in the presence or absence of stromal support: MSCT⁺ cells (A); HS-5 cells (B). (C) Dose-response curves of A-1210477 in the presence or absence of stromal support (MSCT⁺). (D) Efficacy studies of S63845 in MM cell monoculture, direct cell-cell contact coculture or Transwell coculture with MSCT⁺ or HS-5 stromal cells. (A-D) Graphs represent the mean ± standard deviation of 3 independent experiments performed in triplicate. *P < .05, **P < .01; ***P < .001. (E) Dose-response curves of S63845 in monoculture and coculture (MSCT⁺) in the presence or absence of the Bcl-xL inhibitor A-1331852 (100 nM) or the Bcl-2 inhibitor venetoclax (100 nM), respectively. Corresponding IC₅₀ values are indicated. Dose-response curves represent the mean of 3 independent experiments performed in triplicate. (F) Primary CD138⁺ MM cells (n = 10) escape S63845 therapy in the presence of stromal support (MSCT⁺). This effect is overcome by the concurrent treatment with A-1331852 (complete rescue) or venetoclax (partial rescue). Viable cells were determined via annexin V/7 AAD staining 24 hours after treatment initiation. Graph shows median viability with interquartile range. *P < .05; **P < .01.