Shared BME interactions across subclones indicate potentially actionable therapeutic targets. (A) Total number of cellular interactions between myeloma and BME cells in patients with RRMM. Predicted unshared (subclone-specific) and shared (interactions predicted in all subclones per patient) interactions are shown. (B) Total number of cellular interactions between specific subclones and BME cells in RRMM patients. Unshared interactions are colored based on the interaction type: (1) subclonal, interactions predicted to be specific for a subclone; (2) temporal, time point–specific interactions that are shared between ≥ 2 subclones; or (3) subclonal + temporal, interactions of a subclone that differ between time points T1 and T2. Sender-receiver interactions seen in all subclones as well as between BME cells are not indicated. (C) Circos plot and chord interaction diagram of ICAM1-(ITGAX + ITGB2) mediated interactions between subclones of patient RRMM15 and BME cells. The links start at a sender and end at a receiver. (D) Pathways based on CellChatDB²⁶ ranked based on the number of subclone-specific interactions across our patient cohort. (E) Bulk RNA-seq differential expression (log₂-fold change) of ICAM1 between time point T1 (before treatment initiation) and T2 (at relapse) of CD138⁺-enriched PCs isolated from serial samples of 16 patients with RRMM. (F) Chromatin accessibility at the ICAM1 promoter plus 50 kb upstream and downstream in patient RRMM15. The ICAM1 promoter peak is highlighted in light blue. (Top) Aggregated pseudobulk scATAC-seq tracks at both time points. (Right) Violin plots showing normalized ICAM1 expression per time point, with individual cells plotted as dots. (Middle) Peaks are colored based on the location of the peak in either promoter (orange), distal (red), exonic (blue), or intronic (green) regions. IRF4 ChIP-seq peaks from the MM cell line KMS12BM are shown in purple. (Bottom) Peak coaccessibility in the ICAM1 region at both time points colored based on the Pearson correlation coefficient. (G) The top TF motifs for patient RRMM15, which show a significantly higher motif deviation score at relapse (T2) compared with that at T1. TFs putatively binding to the ICAM1 promoter are labeled in blue.