Debulking Chemotherapy Can Overcome Primary Resistance to Teclistamab in Relapsed Refractory Multiple Myeloma

Bispecific antibodies have revolutionized the treatment of multiple myeloma (MM), however primary treatment failure occurs in 30-40% of patients. In this study, we analyzed correlates of response to teclistamab and strategies to overcome primary resistance. Across two independent cohorts (n=90), we developed Hi-MM, defined by extramedullary disease, plasma cell leukemia, bone marrow plasmacytosis ≥50%, or transfusion within 30 days, as a composite correlate of non-response. Patients without Hi-MM had ORR of 84-96% (vs 20-40% with Hi-MM), and significantly superior progression-free (p<0.001) and overall survival (p<0.001). Debulking chemotherapy was utilized in 19 patients; 79% then responded to teclistamab, including 100% who no longer had Hi-MM. All four patients who were primary refractory to a BCMA bispecific immediately prior to debulking then achieved deep responses to teclistamab. In conclusion, simple clinical parameters correlate with response to teclistamab, while debulking chemotherapy can overcome Hi-MM and successfully bridge patients to teclistamab or salvage non-responders.