Efficacy and safety of BCMA nanobody CAR T-cell therapy in relapsed or refractory plasma cell myeloma.

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising therapeutic efficacy in relapsed or refractory (R/R) multiple myeloma. However, distinct CAR T-cell constructs exhibit varying therapeutic outcomes. As the antigen-recognition domain, nanobodies offer a small, stable, single-domain structure with enhanced affinity and specificity compared with conventional single-chain variable fragments. We explored the use of nanobody-based BCMA(S103) CAR T-cell therapy for R/R plasma cell myeloma. The CAR construct incorporates dual-nanobody variable domain of the heavy chain of heavy chain antibody (VHHs) targeting BCMA. A cohort of 27 patients was treated with S103 CAR T-cell therapy, which included 4 patients of plasma cell leukemia, and 1 patient of anaplastic plasma cell myeloma. Eleven patients had multiple extramedullary lesions, and 11 patients exhibited high-risk genetic abnormalities, including 4 with TP53 mutations. One month after CAR T-cell infusion, the overall response rate (ORR) was 96.3% (26/27), with a complete response (CR) + very good partial response (VGPR) rate of 59.2% (16/27). At the 3-month follow-up, the ORR increased to 100% (27/27), with a CR + VGPR rate of 81.5% (22/27). The median duration of remission was 11 months (range, 2-36 months). The 1-year overall survival rate was 61.1%, and progression-free survival was 57.2%. In conclusion, BCMA CAR T-cell therapy, utilizing dual-nanobody VHHs targeting BCMA, demonstrates a high ORR and manageable safety profile in treating patients with R/R plasmacytic myeloma, including those with high-risk features such as extramedullary lesions, high-risk cytogenetic abnormalities, plasma cell leukemia, or anaplastic plasmacytoma. This trial was registered at www.ClinicalTrials.gov as #NCT04447573.