Niamh McAuley, Roisin McAvera, Dimitri Bong, Lara Donnelly, Izabela Cymer, Marian Brennan, Joanna Fay, Lance Hudson, John Quinn, Siobhan V. Glavey, Ann M. Hopkins
ABSTRACT Multiple myeloma (MM) is an incurable malignancy of terminally‐differentiated plasma cells that represents a major clinical challenge despite unprecedented therapeutic advances, particularly for patients with cytogenetically‐defined high‐risk MM (HR‐MM). Updated in 2025, the evolving cytogenetic classification of HR‐MM includes gains or amplifications in chromosome 1q. One gene of emerging interest on chromosome 1q is F11R, which codes for a protein called Junctional Adhesion Molecule‐A (JAM‐A). Upregulation of JAM‐A has been linked with the development of several aggressive malignancies, most recently MM. In the current study, F11R gene expression was found to be significantly higher in gain/amp(1q) MM patients from the CoMMpass database, and to correlate with poorer overall survival in MM patients. Furthermore, elevated F11R expression was accompanied by an increased burden of circulating CD138 + cells, potentially an early hallmark of extramedullary disease (EMD). As JAM‐A signalling putatively promotes tumorigenic behaviour through cis‐ dimerization‐dependent adhesion signalling, structure‐based rational design principles were utilised to design novel peptide inhibitors that selectively disrupt JAM‐A cis ‐dimerization. In vitro testing of novel peptides across a panel of MM cell lines and primary CD138+ cells from MM patients demonstrated anti‐proliferative and pro‐senescence properties of the novel peptides. Moreover, candidate peptide P4 significantly inhibited the growth of CD138+ plasmacytoma‐like tumours in an in vivo xenograft model involving implantation onto the chick chorioallantoic membrane. Collectively, these findings support the validity of JAM‐A as an emerging druggable target and provide a strong rationale for further preclinical investigations of JAM‐A inhibitors in MM.