Long-Term Follow-up of a Phase 1, First-in-Human Open-Label Study of LCAR-B38M, a Structurally Differentiated Chimeric Antigen Receptor T (CAR-T) Cell Therapy Targeting B-Cell Maturation Antigen (BCMA), in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Background: In RRMM, the median overall survival (OS) of pts with RRMM who progressed after exposure to ≥3 prior therapies is ~13 mo, indicating a high unmet need. LCAR-B38M is a structurally differentiated CAR-T cell therapy containing a 4-1BB co-stimulatory domain and 2 BCMA-targeting single-domain antibodies designed to confer avidity. Earlier results from LEGEND-2 (NCT03090659), a first-in-human phase 1 study using LCAR-B38M CAR-T cells in 74 pts with RRMM conducted in 4 hospitals in China (Jiangsu Provincial People's Hospital; Ruijin Hospital; Changzheng Hospital; and the Second Affiliated Hospital of Xi'an Jiaotong University), showed encouraging efficacy and manageable safety. Key eligibility criteria included RRMM with ≥3 prior lines of therapy. Here, we present long-term follow-up data on safety and efficacy from the Xi'an site. Methods: In the Xi'an site-specific protocol (n=57), lymphodepletion was performed using cyclophosphamide (Cy; 300 mg/m2)alone for 3 days. LCAR-B38M (median CAR+ T cells, 0.5×106 cells/kg; range, 0.07-2.1 × 106) was infused in 3 split infusions. The primary objective was to evaluate the safety of LCAR-B38M; the secondary objective was to evaluate anti-myeloma response of treatment. Adverse events (AEs) were graded using the NCI-CTCAE v4.03, cytokine release syndrome (CRS) was assessed per Lee et al. 2014, and response was evaluated using IMWG criteria. Results: As of the 12/31/18 cutoff date (median follow-up, 19 mo; 95% confidence interval [CI], 17-22), enrollment at Xi'an is complete, and 57 pts have been infused with LCAR-B38M. AEs were reported by all pts: pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts: leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 events; no grade 4/5 CRS was observed. Neurotoxicity was observed in 1 pt (grade 1 aphasia, agitation, seizure-like activity). The median time to onset of CRS was 9 days (range, 1-19) with a median duration of 9 days (range, 3-57); all but 1 CRS events resolved. Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M was not detectable in peripheral blood in 71% of pts at 4 mo; 5 pts showed CAR-T cell persistence for up to 10 months. The overall response rate (partial response [PR] or better) was 88% (95% CI, 76-95), co