Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

Janssen Research & Development.

中文翻译：

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Teclistamab，一种 B 细胞成熟抗原 × CD3 双特异性抗体，用于治疗复发性或难治性多发性骨髓瘤 (MajesTEC-1)：一项多中心、开放标签、单臂、1 期研究

背景

复发性或难治性多发性骨髓瘤需要新的治疗方法，而 B 细胞成熟抗原 (BCMA) 是一个经过验证的靶点。Teclistamab 是一种双特异性抗体，可结合 BCMA 和 CD3，将 T 细胞重定向到多发性骨髓瘤细胞。MajesTEC-1 研究的目的是评估 teclistamab 在复发或难治性多发性骨髓瘤患者中的安全性、耐受性和初步疗效。

方法

这项开放标签、单臂、1 期研究招募了复发、难治或对既定疗法不耐受的多发性骨髓瘤患者。Teclistamab 静脉给药（范围 0·3-19·2 μg/kg [每 2 周一次] 或 19·2-720 μg/kg [每周一次]）或皮下给药（范围 80-3000 μg/kg [每 2 周一次]）周]）在不同的队列中，递增剂量为 38·4 μg/kg 或更高剂量。主要目标是确定推荐的 2 期剂量（第一部分）并描述 teclistamab 在推荐的 2 期剂量下的安全性和耐受性（第二部分）。在所有接受至少一剂 teclistamab 治疗的患者中评估了安全性。在可评估反应的患者（即，接受至少一剂 teclistamab 并进行至少一次基线后反应评估的患者）中分析疗效。

发现

2017 年 6 月 8 日至 2021 年 3 月 29 日期间，对 219 名患者进行了研究纳入筛选，157 名患者（中位数为 6 个既往治疗线）被纳入并接受了至少一剂 teclistamab（静脉注射 n=84；皮下注射 n=73 ）。40 名患者接受了推荐的 2 期剂量，确定为每周一次皮下注射 teclistamab 1500 μg/kg，在 60 μg/kg 和 300 μg/kg 递增剂量后（中位随访 6·1 个月，IQR 3·6-8·2）。在第一部分中推荐的 2 期剂量下没有剂量限制性毒性。在以推荐的 2 期剂量治疗的 40 名患者中，最常见的治疗中出现的不良事件是 28 名（70%；所有 1 级或 2 级事件）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（3 级或16 个中有 4 个 [40%]）。以推荐的 2 期剂量（n=40）治疗的反应可评估患者的总体反应率为 65%（95% CI 48-79）；58% 达到了非常好的部分响应或更好。在推荐的 2 期剂量下，未达到中位反应持续时间。在 7·1 个月的中位随访（IQR 5·1-9·1）后，26 名应答者中有 22 名（85%）存活并继续接受治疗。在推荐的 2 期剂量下，teclistamab 暴露维持在目标暴露水平以上，并报告了一致的 T 细胞活化。

解释

Teclistamab 是一种治疗复发或难治性多发性骨髓瘤的新方法。在推荐的 2 期剂量下，teclistamab 显示出有希望的疗效，持久的反应随着时间的推移而加深，并且耐受性良好，支持进一步的临床开发。

资金

杨森研发。