ImportancePatients with high-risk newly diagnosed multiple myeloma (NDMM) often have poor outcomes with standard treatments, necessitating novel effective frontline therapies to enhance clinical outcomes. GC012F, a B-cell maturation antigen/CD19 dual-targeting chimeric antigen receptor (CAR) T-cell therapy, has been developed on the novel FasTCAR platform. Notably, its use as a frontline therapy for patients with high-risk NDMM who are eligible for transplant has not been thoroughly explored.ObjectiveTo examine the safety, pharmacokinetics, and patient health and survival outcomes associated with GC012F in individuals with NDMM.Design, Setting, and ParticipantsPatients were enrolled in this single-arm, open-label phase 1 cohort study between June 28, 2021, and June 1, 2023 (the data cutoff date). All patients included in this study were treated at a single center, Shanghai Changzheng Hospital. The patients in the efficacy evaluation were followed up for a minimum period of 3 months.InterventionPatients underwent 2 cycles of induction therapy, followed by GC012F infusion (at 1 × 105 cells/kg, 2 × 105 cells/kg, or 3 × 105 cells/kg).Main Outcomes and MeasuresThe primary goals were to assess the safety, efficacy, and pharmacokinetics of GC012F at various dose levels.ResultsOf 22 patients receiving GC012F treatment, 6 experienced mild to moderate cytokine release syndrome (grade 1-2) and none experienced neurotoxic effects. Nineteen patients were included in the efficacy evaluation, and all 19 patients showed stringent complete responses and achieved minimal residual disease negativity. The treatment’s effectiveness was consistent across different dose levels. GC012F demonstrated a rapid response, with a median time to first stringent complete response of 84 days (range, 26-267 days) and achieving minimal residual disease negativity within 28 days (range, 23-135 days). The CAR T-cell expansion was robust, with a median peak copy number of 60 652 copies/μg genomic DNA (range, 8754-331 159 copies/μg genomic DNA), and the median time to median peak copy number was 10 days (range, 9-14 days).Conclusions and RelevanceThe findings of this single-arm, open-label phase 1 cohort study suggest that GC012F may be a safe treatment associated with positive health and survival outcomes for patients with high-risk NDMM eligible for transplant. Owing to the small sample size, further studies with larger cohorts and longer follow-up durations are needed.

中文翻译：

---

B 细胞成熟抗原/CD19 双靶点免疫治疗新诊断多发性骨髓瘤


重要性新诊断的高危多发性骨髓瘤 （NDMM） 患者在标准治疗下通常预后不佳，需要新型有效的一线疗法来增强临床预后。GC012F 是一种 B 细胞成熟抗原/CD19 双靶向嵌合抗原受体 （CAR） T 细胞疗法，已在新型 FasTCAR 平台上开发。值得注意的是，它作为符合移植条件的高危 NDMM 患者的一线治疗尚未得到彻底探索。目的检查 GC012F 在 NDMM.Design、环境和参与者个体中的安全性、药代动力学以及患者健康和生存结果患者在 2021 年 6 月 28 日至 2023 年 6 月 1 日（数据截止日期）期间参加了这项单臂、开放标签的 1 期队列研究。本研究纳入的所有患者均在上海长征医院接受治疗。疗效评价中的患者接受了至少 3 个月的随访。干预患者接受 2 个周期的诱导治疗，然后输注 GC012F （1 × 105 个细胞/kg，2 × 105 个细胞/kg，或 3 × 105 个细胞/kg）。主要结局和措施主要目标是评估 GC012F 在不同剂量水平下的安全性、有效性和药代动力学。结果接受 GC012F 治疗的 22 例患者中，6 例出现轻至中度细胞因子释放综合征 （1-2 级），无 1 例出现神经毒性作用。19 例患者纳入疗效评价，所有 19 例患者均表现出严格的完全缓解，并达到最小残留病阴性。治疗在不同剂量水平下的有效性是一致的。 GC012F 表现出快速反应，首次严格完全反应的中位时间为 84 天 （范围，26-267 天），并在 28 天内达到微小残留病阴性 （范围，23-135 天）。CAR T 细胞扩增稳定，中位峰拷贝数为 60 652 拷贝/μg 基因组 DNA （范围，8754-331 159 拷贝/μg 基因组 DNA），中位峰拷贝数为 10 天 （范围，9-14 天）。结论和相关性这项单臂、开放标签的 1 期队列研究结果表明，GC012F 可能是一种安全的治疗方法，与符合移植条件的高危 NDMM 患者的积极健康和生存结果相关。由于样本量小，需要对更大的队列和更长的随访时间进行进一步的研究。