PURPOSE The anti-B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS In this first-in-human study, up to 10 cycles of AMG 420 were given (4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/104 bone marrow cells by flow cytometry. RESULTS Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 μg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year. CONCLUSION In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.

中文翻译：

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抗 B 细胞成熟抗原 BiTE 分子 AMG 420 在多发性骨髓瘤中诱导反应

目的 在复发/难治性多发性骨髓瘤患者中评估抗 B 细胞成熟抗原 BiTE 分子 AMG 420。患者和方法 在这项首次人体研究中，给予最多 10 个周期的 AMG 420（4 周输注/6 周周期）。患者在≥ 2 线既往治疗后出现进展，且无髓外疾病。通过流式细胞术将最小残留疾病 (MRD) 反应定义为 < 1 个肿瘤细胞/104 个骨髓细胞。结果 42 名患者接受了 0.2-800 μg/d 的 AMG 420。中位年龄为 65 岁，中位病程为 5.2 年。响应者的平均暴露时间为 1 个周期（范围，1-10 个周期）和 7 个周期（范围，1-10 个周期）。患者因疾病进展（n = 25）、不良事件（AE；n = 7）、死亡（n = 4）、完成 10 个周期（n = 3）和同意撤回（n = 1）而停药。两名患者仍在接受治疗。AE、流感/曲霉病和腺病毒相关肝炎导致 2 例非治疗相关死亡。严重 AE（n = 20；48%）包括感染（n = 14）和多发性神经病（n = 2）；治疗相关的严重 AE 包括 2 例 3 级多发性神经病和 1 例 3 级水肿。没有≥ 3 级的 CNS 毒性或抗 AMG 420 抗体。在这项研究中，800 μg/d 被认为是不可耐受的，因为 3 级细胞因子释放综合征和 3 级多发性神经病各有 1 例，两者均已解决。总体响应率为 31%（n = 13，共 42 个）。在 400 μg/d 的最大耐受剂量 (MTD) 下，反应率为 70%（n = 7 of 10）。其中，5 名患者出现 MRD 阴性完全反应，1 名部分反应，1 人部分反应非常好；所有 7 名患者在第一个周期内均有反应，有些反应持续时间 > 1 年。结论 在这项针对复发/难治性多发性骨髓瘤患者的 AMG 420 研究中，反应率为 70%，包括 50% 的 MRD 阴性完全反应，400 μg/d，本研究的 MTD。