In patients with t(11;14) myeloma, a loss of a “B-cell–like” epigenetic and transcriptomic signature with a gain of canonical plasma cell transcription factors (TFs) is observed at the time of resistance to venetoclax. MCL1 and BCL2L1 copy number gains and structural rearrangements are also linked to venetoclax resistance. See the visual abstract in the online version of the article by Leblay et al that begins on page 42.