Aberrant BCMA Signaling Promotes Tumor Growth by Altering Protein Translation Machinery, a Therapeutic Target for the Treatment of Relapse/Refractory Multiple Myeloma

B-cell maturation antigen (BCMA) is critical for the viability of Multiple Myeloma (MM) tumor cells and targeting BCMA poses a remarkable opportunity as a potential therapeutic in this cancer. Recent approval of BCMA directed CAR-T and Antibody-Drug-Conjugates (ADCs) have revolutionized MM treatment landscape. Despite such clinical success, treatment resistance and dose limiting toxicity remain as major clinical challenges. Using ribosome profiling, we established a molecular link between BCMA signaling inhibition and protein translation machinery. In addition, BCMA signaling alters the translation efficiency of a transcriptional regulator ATMIN without changing the total mRNA transcript level. Furthermore, ATMIN can transcriptionally regulate IL-6, a critical survival factor for MM. To inhibit the BCMA signaling pathway, we devised both genetic knockdown strategy and pharmacological inhibition by using a soluble BCMA decoy receptor fusion protein (sBCMA-Fc) to trap both of its ligands, APRIL and BAFF. We demonstrated that treatment of MM tumor cells with sBCMA-Fc inhibits tumor progression in numerous in vivo and syngenic PDX tumors models without significant adverse effects. Furthermore, the addition of sBCMA-Fc treatment can restore bortezomib sensitivity in previously bortezomib resistant MM tumors, further adding to its therapeutic value in the treatment of relapse /refractory MM patients. Inhibiting BCMA signaling through neutralization of its ligands APRIL and BAFF with a sBCMA-Fc fusion protein represents a safe and efficacious treatment strategy for the treatment of relapse and refractory MM.