The Clinical Challenge of Triple-Class–Refractory Myeloma and the Central Role of BCMA

Drs Paul Richardson and Hans Lee explore why patients with relapsed or refractory multiple myeloma who are refractory to proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies remain particularly difficult to treat in clinical practice. The discussion highlights how traditional strategies of recycling or switching within the same drug classes have become less effective in the modern era, especially after CD38-directed therapy. Against this backdrop, the faculty explain why novel targets are essential and why BCMA has emerged as a cornerstone in advanced myeloma care. Dr Lee reviews the biological rationale for targeting BCMA, including its high and relatively specific expression on malignant plasma cells and its role in key survival signaling pathways. The conversation also contrasts different BCMA-directed modalities, including CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates, emphasizing how safety considerations, off-target effects, and real-world tolerability influence treatment selection. Together, this segment underscores why BCMA-directed approaches offer a critical, non–cross-resistant strategy for heavily pretreated patients.