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美国莱文癌症研究所Saad Z Usmani团队研究了B细胞成熟抗原双特异性抗体teclistamab治疗复发或难治性多发性骨髓瘤的效果。2021年8月10日出版的《柳叶刀》杂志发表了这项成果。

复发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）是一个有效靶点。Teclistamab是一种双特异性抗体，可结合BCMA和CD3，引导T细胞定向至多发性骨髓瘤细胞。该研究旨在评估teclistamab治疗复发或难治性多发性骨髓瘤患者的安全性、耐受性和初步疗效。

这项开放标签、单臂、临床1期研究纳入了复发、难治性或对现有治疗不耐受的多发性骨髓瘤患者，均接受静脉注射或皮下注射不同剂量的teclistamab，递增剂量为38.4 μg/kg或更高。主要目标是确定推荐临床2期剂量（第一部分），并在推荐2期剂量（第二部分）下确定teclistamab的安全性和耐受性。对所有接受至少一剂teclistamab治疗的患者进行安全性评估和相应的疗效分析。

2017年6月8日至2021年3月29日，研究组共筛查了219名患者，有157名被纳入研究并接受了至少一剂teclistamab，其中静脉注射84例，皮下注射73例。40例患者给予推荐的2期剂量，在60 μg/kg和300 μg/kg剂量递增后，确定为每周一次皮下给药，剂量为1500 μg/kg。第一部分中推荐的2期剂量没有剂量限制毒性。

在推荐2期剂量治疗的40名患者中，最常见的治疗紧急不良事件为28名患者发生细胞因子释放综合征（70%），26名（65%）患者发生中性粒细胞减少（16例为3级或4级）。在可评价疗效的患者中，推荐2期剂量治疗的总体缓解率为65%，58%达到了非常好的部分缓解或更好。推荐2期剂量的中位缓解持续时间未达到。26名缓解者中有22名（85%）在7.1个月的中位随访时仍然存活并继续接受治疗。在推荐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细胞激活。

研究结果表明，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疗效较好，随时间推移，缓解持续加深，耐受性良好。

附：英文原文

Title: Teclistamab, a B-cell maturation antigen×CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study

Author: Saad Z Usmani, Alfred L Garfall, Niels W C J van de Donk, Hareth Nahi, Jesus F San-Miguel, Albert Oriol, Laura Rosinol, Ajai Chari, Manisha Bhutani, Lionel Karlin, Lotfi Benboubker, Lixia Pei, Raluca Verona, Suzette Girgis, Tara Stephenson, Yusri Elsayed, Jeffrey Infante, Jenna D Goldberg, Arnob Banerjee, María-Victoria Mateos, Amrita Krishnan

Issue&Volume: 2021-08-10

Abstract:

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 0·319·2 μg/kg [once every 2 weeks] or 19·2720 μg/kg [once per week]) or subcutaneously (range 803000 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 3·68·2). 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 4879); 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 5·19·1). 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.

DOI: 10.1016/S0140-6736(21)01338-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01338-6/fulltext

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