Sustainable Efficacy and Safety Results from Lummicar Study 1: A Phase 1/2 Study of Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Chinese Subjects with Relapsed and/or Refractory Multiple Myeloma

Background: CT053 is a fully human autologous chimeric antigen receptor (CAR) T-cell therapy comprising a B-cell maturation antigen (BCMA)-specific single-chain variable fragment (25C2). A clinical trial of CT053 is ongoing in LUMMICAR STUDY 1 (NCT03975907) for patients with relapsed and refractory multiple myeloma (RRMM) in China. The pivotal Phase 2 of LUMMICAR STUDY 1 is actively enrolling patients. Here, we report clinical data from Phase 1 with 12 months of follow-up. Methods: Subjects with RRMM who had received ≥3 prior therapies, including at least one proteasome inhibitor and one immunomodulatory drug were enrolled in Phase 1 study. Adverse events (AEs) were graded according to CTCAE, v5.0; Cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). Response was assessed per IMWG 2016 criteria. Minimal residual disease (MRD) was tested by next-generation flow cytometry on bone marrow aspirates by the EuroFlow assay with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher, and CAR copies in the subject peripheral blood were monitored by quantitative real-time polymerase chain reaction (qPCR). Results: Fourteen subjects with a median age of 54 years (range 34-62) received CT053 infusion. Three subjects received 1.0×10 8 CAR+ T cells and eleven subjects received 1.5×10 8 CAR+ T cells. As of July 8, 2021, 14 subjects with a median follow-up of 13.6 months since infusion. Of the 14 subjects, 11 (78.6%) had received autologous stem cell transplantation, 2 (14.2%) had extramedullary disease at baseline, 2 (14.3%) had ISS stage III, and 5 (35.7%) had high-risk cytogenetics. The median prior therapies was 6 (range 3-7) and no subject received bridging therapy. The most common AEs were expected hematological toxicities. All subjects (100%) experienced ≥ grade 3 neutropenia, 91.7% experienced ≥ grade 3 thrombocytopenia, and most recovered to ≤ grade 2 within 2 weeks. No dose limiting toxicity or treatment-related death was reported. Additionally, no ≥ grade 3 CRS or neurotoxicity was observed, 92.9% subjects (13/14) experienced grade 1 or 2 CRS (9 grade 1, 4 grade 2). CRS occurred at a median of 6 days (range 2-12) post-infusion with a median duration of 7 days. No severe infections were reported except one case of grade 3 lung infection. A 100% overall response rate was achieved in 14 subjects, with 11 stringent complete responses (sCR, 78.6%), 2 very good partial responses (VGPR), and 1 partial response, with a ≥VGPR rate of 92.9%. Four subjects achieved sCR at week 52. As of July 8, 2021, 12 subjects with at least 12 months of efficacy assessment were still in the study, and the 12-month progression-free survival (PFS) rate was 85.7%. With a median follow-up of 13.6 months, the median duration of response and the median PFS had not been reached. All 11 subjects with sCR were MRD-negative, and 9 subjects reached sustained CR/sCR for more than 12 months (Figure 1). Three subjects had disease progressed including two subjects with extramedullary disease progressed at week 16. Interestingly, the CR/sCR rate for the subjects without extramedullary disease is 91.7% (11/12). The 1-year PFS rate for subjects without extramedullary disease reached 100%。 CT053 cells expanded and persisted well. No immunogenicity was detected. Conclusion: These results demonstrate that CT053 CAR T cells at a dose of 1.0-1.5×10 8 cells achieve a deep and durable response, including a high MRD-negative sCR rate, with an acceptable safety profile in subjects with heavily pretreated RRMM. Figure 1 Figure 1. Disclosures Li: CARsgen: Current Employment, Current equity holder in publicly-traded company. Wang: CARsgen Therapeutics Corp: Current Employment. Xiao: CARsgen Therapeutics Corp: Current Employment. Wang: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in publicly-traded company. Tang: CARsgen Therapeutics Corp: Current Employment.

Anti-BCMA CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma Patients With Extramedullary Disease: A Single Center Analysis of Two Clinical Trials

BackgroundThe prognosis of relapsed/refractory multiple myeloma (RRMM) patients with the extramedullary disease was significantly poor. Extramedullary multiple myeloma (EMM) patients gained limited benefits from traditional drugs. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy seems to be a promising approach to treat RRMM patients. However, very few clinical studies are designed for EMM. Our study aimed to compare and assess the safety, efficacy, and pharmacokinetics of anti-BCMA CAR-T cell therapy in EMM and non-EMM.MethodsThe results from published anti-BCMA CAR-T clinical trials, in which raw data of EMM patients were available, were reviewed and summarized. Two trials conducted in our clinical centers were analyzed and presented with detailed data.ResultsAccording to published anti-BCMA CAR-T clinical trials, the ORR of EMM ranged from 57% to 100%, with the complete remission (CR) rate of 29% to 60%. Between February 22, 2017, and September 26, 2019, a total of 61 subjects (EMM 25; non-EMM 36) received anti-BCMA CAR-T cell infusion. The data-cutoff date was April 1, 2021. There were no statistical differences between EMM and non-EMM groups in adverse events (AEs), including cytokine release syndrome (CRS). The most common AEs of grade ≥ 3 in both groups were hematologic toxicities. There was no significant difference in the objective response rate (ORR) and ≥ complete remission (CR) rate between both groups. However, the ≥ CR rate of the EMM group was lower than the non-EMM group receiving the fully human anti-BCMA CAR-T cell therapy (p = 0.026). The median progression-free survival (PFS) for EMM and the non-EMM group was 121 days and 361 days, respectively (p = 0.001). The median overall survival (OS) for EMM and the non-EMM group was 248 days and 1024 days, respectively (p = 0.005). The Cmax and AUC0-28d for EMM group were lower than non-EMM group (Cmax, p = 0.016; AUC0-28d, p = 0.016). Extramedullary disease was an independent prognostic risk factor for PFS (hazard ratio, 2.576; 95% CI, 1.343 to 4.941; p = 0.004) and OS (hazard ratio, 2.312; 95% CI, 1.165 to 4.592; p = 0.017) in RRMM patients receiving anti-BCMA CAR-T cell therapy.ConclusionsBased on our results, EMM patients could benefit from the two anti-BCMA CAR products, although they had a shorter PFS and OS compared with non-EMM patients.Clinical Trial Registrationhttp://www.chictr.org.cn, identifier ChiCTR-OPC-16009113 and ChiCTR1800018137.