Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Lancet. 2021 Aug 21;398(10301):665-674. doi: 10.1016/S0140-6736(21)01338-6. Epub 2021 Aug 10.
There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma.
This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0·3-19·2 μg/kg [once every 2 weeks] or 19·2-720 μg/kg [once per week]) or subcutaneously (range 80-3000 μg/kg [once per week]) in different cohorts, with step-up dosing for 38·4 μg/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181.
Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 μg/kg, after 60 μg/kg and 300 μg/kg step-up doses (median follow-up 6·1 months, IQR 3·6-8·2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 [40%]). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48-79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7·1 months' median follow-up (IQR 5·1-9·1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported.
Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development.
Janssen Research & Development.
对于复发或难治性多发性骨髓瘤，需要新的治疗方法，B 细胞成熟抗原（BCMA）是一个已验证的靶点。Teclistamab 是一种双特异性抗体，可与 BCMA 和 CD3 结合，将 T 细胞重新定向到多发性骨髓瘤细胞。MajesTEC-1 研究的目的是评估复发或难治性多发性骨髓瘤患者接受 teclistamab 的安全性、耐受性和初步疗效。
这项开放标签、单臂、I 期研究纳入了复发、难治或对现有治疗不耐受的多发性骨髓瘤患者。Teclistamab 以静脉输注（范围 0·3-19·2 μg/kg[每 2 周一次]或 19·2-720 μg/kg[每周一次]）或皮下注射（范围 80-3000 μg/kg[每周一次]）的方式在不同队列中给药，对于 38·4 μg/kg 或更高剂量进行逐步加量。主要目标是确定 II 期推荐剂量（第一部分），并在 II 期推荐剂量（第二部分）下描述 teclistamab 的安全性和耐受性。在至少接受过一次 teclistamab 治疗的所有患者中评估安全性。在可评估疗效的患者（即至少接受过一次 teclistamab 治疗且至少有一次基线后疗效评估的患者）中分析疗效。这项正在进行的试验在 ClinicalTrials.gov 上注册，NCT03145181。
2017 年 6 月 8 日至 2021 年 3 月 29 日，有 219 名患者接受了研究纳入筛选，有 157 名患者（中位数为 6 线既往治疗）入组并接受了至少一次 teclistamab 治疗（静脉内 n=84；皮下 n=73）。40 名患者接受了 II 期推荐剂量，确定为每周一次皮下注射 teclistamab 1500 μg/kg，60 μg/kg 和 300 μg/kg 逐步加量后（中位随访 6·1 个月，IQR 3·6-8·2）。在第一部分中，在 II 期推荐剂量下未观察到剂量限制毒性。在接受 II 期推荐剂量治疗的 40 名患者中，最常见的治疗相关不良事件是 28 名（70%；所有为 1 级或 2 级事件）患者的细胞因子释放综合征和 26 名（65%）患者的中性粒细胞减少症（16 名[40%]为 3 级或 4 级）。在接受 II 期推荐剂量治疗的可评估疗效患者中，总体缓解率为 65%（95%CI 48-79%）；58%的患者达到了非常好的部分缓解或更好。在 II 期推荐剂量下，中位缓解持续时间未达到。在 26 名应答者中，有 22 名（85%）在 7.1 个月的中位随访（IQR 5.1-9.1）后仍存活并继续接受治疗。在 II 期推荐剂量下，teclistamab 的暴露量维持在目标暴露水平以上，并报告了一致的 T 细胞激活。
Teclistamab 是一种治疗复发或难治性多发性骨髓瘤的新方法。在 II 期推荐剂量下，teclistamab 显示出有希望的疗效，疗效随着时间的推移而加深，且耐受性良好，支持进一步的临床开发。
杨森研究与开发公司。
