The promise of bispecific antibodies in multiple myeloma faces a significant hurdle: nearly 40% of patients experience primary treatment failure. This challenge has prompted oncologists to seek predictable patterns in who responds and effective strategies to overcome resistance. A multi-center analysis of 90 patients reveals a practical solution that could transform treatment sequencing for this aggressive blood cancer. Researchers identified four clinical markers that collectively predict poor response to teclistamab, a BCMA-targeting bispecific antibody. The "Hi-MM" criteria include extramedullary disease spread, plasma cell leukemia, bone marrow plasma cell infiltration exceeding 50%, or recent blood transfusion requirements. Patients without these high-risk features achieved response rates between 84-96%, while those meeting Hi-MM criteria responded only 20-40% of the time. The survival differences were stark, with significantly prolonged progression-free and overall survival in the low-risk group. The breakthrough finding centers on debulking chemotherapy as an intervention strategy. Among 19 patients receiving chemotherapy before bispecific treatment, 79% subsequently responded to teclistamab. Most remarkably, patients who eliminated their Hi-MM status through debulking achieved 100% response rates. Even patients previously refractory to other BCMA bispecifics achieved deep responses after chemotherapy preparation. This represents a potential paradigm shift in multiple myeloma treatment sequencing. Rather than reserving bispecifics for heavily pretreated patients with high disease burden, these findings suggest strategic use of conventional chemotherapy to optimize the tumor microenvironment. The approach could maximize the substantial investment in bispecific antibody development while providing more patients access to these transformative but expensive therapies.