BACKGROUND Indatuximab ravtansine (BT062) is an antibody-drug conjugate that binds to CD138 and synergistically enhances the antitumor activity of lenalidomide in preclinical models of multiple myeloma. This phase 1/2a study was done to determine the safety, activity, and pharmacokinetics of indatuximab ravtansine in combination with immunomodulatory drugs in patients with relapsed or refractory multiple myeloma. METHODS This open-label, phase 1/2a study took place at nine hospital sites in the USA. Eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and ECOG performance status or Zubrod score of 2 or below. Patients who received indatuximab ravtansine with lenalidomide and dexamethasone (indatuximab ravtansine plus lenalidomide) had failure of at least one previous therapy. Patients treated with indatuximab ravtansine with pomalidomide and dexamethasone (indatuximab ravtansine plus pomalidomide) had failure of at least two previous therapies (including lenalidomide and bortezomib) and had progressive disease on or within 60 days of completion of their last treatment. In phase 1, patients received indatuximab ravtansine intravenously on days 1, 8, and 15 of each 28-day cycle in escalating dose levels of 80 mg/m2, 100 mg/m2, and 120 mg/m2, with lenalidomide (25 mg; days 1 to 21 every 28 days orally) and dexamethasone (20-40 mg; days 1, 8, 15, and 22 every 28 days). In phase 2, the recommended phase 2 dose of indatuximab ravtansine was given to an expanded cohort of patients in combination with lenalidomide and dexamethasone. The protocol was amended to allow additional patients to be treated with indatuximab ravtansine plus pomalidomide (4 mg; days 1 to 21 every 28 days orally) and dexamethasone, in a more heavily pretreated patient population than in the indatuximab ravtansine plus lenalidomide group. The phase 1 primary endpoint was to determine the dose-limiting toxicities and the maximum tolerated dose (recommended phase 2 dose) of indatuximab ravtansine, and the phase 2 primary endpoint was to describe the objective response rate (ORR; partial response or better) and clinical benefit response (ORR plus minor response). All patients were analysed for safety and all patients with post-treatment response assessments were analysed for activity. This study is registered with ClinicalTrials.gov, number NCT01638936, and is complete. FINDINGS 64 (86%) of 74 screened patients were enrolled between July 3, 2012, and June 30, 2015. 47 (73%) patients received indatuximab ravtansine plus lenalidomide (median follow-up 24·2 months [IQR 19·9-45·4]) and 17 (27%) received indatuximab ravtansine plus pomalidomide (24·1 months [17·7-36·7]). The maximum tolerated dose of indatuximab ravtansine plus lenalidomide was 100 mg/m2, and defined as the recommended phase 2 dose for indatuximab ravtansine plus pomalidomide. An objective response for indatuximab ravtansine plus lenalidomide was observed in 33 (71·7%) of 46 patients and in 12 (70·6%) of 17 patients in the indatuximab ravtansine plus pomalidomide group. The clinical benefit response for indatuximab ravtansine plus lenalidomide was 85% (39 of 46 patients) and for indatuximab ravtansine plus pomalidomide it was 88% (15 of 17 patients). The most common grade 3-4 adverse events in both groups were neutropenia (14 [22%] of 64 patients), anaemia (10 [16%]), and thrombocytopenia (seven [11%]). Treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 35 (55%) of the 64 patients. Five (8%) patients with a TEAE had a fatal outcome; none was reported as related to indatuximab ravtansine. INTERPRETATION Indatuximab ravtansine in combination with immunomodulatory drugs shows preliminary antitumor activity, is tolerated, and could be further evaluated in patients with relapsed or refractory multiple myeloma. FUNDING Biotest AG.

中文翻译：

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Indatuximab ravtansine 加地塞米松联合来那度胺或泊马度胺治疗复发或难治性多发性骨髓瘤：一项多中心、1/2a 期研究。

背景 Indatuximab ravtansine (BT062) 是一种抗体-药物偶联物，可与 CD138 结合并在多发性骨髓瘤的临床前模型中协同增强来那度胺的抗肿瘤活性。这项 1/2a 期研究旨在确定 indatuximab ravtansine 与免疫调节药物联合治疗复发或难治性多发性骨髓瘤患者的安全性、活性和药代动力学。方法 这项开放标签的 1/2a 期研究在美国的九家医院进行。符合条件的患者年龄在 18 岁或以上，患有复发性或难治性多发性骨髓瘤，并且 ECOG 体能状态或 Zubrod 评分为 2 或以下。接受 indatuximab ravtansine 联合来那度胺和地塞米松（indatuximab ravtansine 加来那度胺）的患者至少一种既往治疗失败。接受 indatuximab ravtansine 和 pomalidomide 和地塞米松（indatuximab ravtansine 加 pomalidomide）治疗的患者至少有两种既往疗法（包括来那度胺和硼替佐米）失败，并且在完成最后一次治疗后 60 天内或之内出现疾病进展。在第 1 阶段，患者在每个 28 天周期的第 1、8 和 15 天以 80 mg/m2、100 mg/m2 和 120 mg/m2 的递增剂量水平静脉接受 indatuximab ravtansine 和来那度胺（25 mg；每 28 天口服 1 至 21 天）和地塞米松（20-40 毫克；每 28 天第 1、8、15 和 22 天）。在第 2 阶段，推荐的第 2 阶段剂量的 indatuximab ravtansine 与来那度胺和地塞米松联合用于扩大的患者队列。对方案进行了修订，以允许更多患者接受 indatuximab ravtansine 加泊马度胺（4 mg；每 28 天口服一次，第 1 至 21 天）和地塞米松，与 indatuximab ravtansine 加来那度胺组相比，预先治疗的患者群体更重。1 期主要终点是确定 indatuximab ravtansine 的剂量限制性毒性和最大耐受剂量（2 期推荐剂量），2 期主要终点是描述客观缓解率（ORR；部分缓解或更好）和临床获益反应（ORR 加轻微反应）。对所有患者进行安全性分析，并对所有接受治疗后反应评估的患者进行活性分析。该研究已在 ClinicalTrials.gov 注册，编号 NCT01638936，并且已完成。结果 2012 年 7 月 3 日至 2015 年 6 月 30 日期间，74 名接受筛查的患者中有 64 名 (86%) 入组。47 名 (73%) 患者接受了印达妥昔单抗加来那度胺治疗（中位随访时间为 24·2 个月 [IQR 19·9- 45·4]) 和 17 名 (27%) 接受 indatuximab ravtansine 加泊马度胺（24·1 个月 [17·7-36·7]）。indatuximab ravtansine 加来那度胺的最大耐受剂量为 100 mg/m2，并定义为 indatuximab ravtansine 加泊马度胺的推荐 2 期剂量。在 46 名患者中的 33 名 (71·7%) 和 17 名患者中的 12 名 (70·6%) 中观察到因达妥昔单抗 ravtansine 和来那度胺联合治疗的客观反应。Indatuximab ravtansine 加来那度胺的临床获益反应为 85%（46 名患者中的 39 名），indatuximab ravtansine 加泊马度胺的临床获益率为 88%（17 名患者中的 15 名）。两组中最常见的 3-4 级不良事件是中性粒细胞减少症（64 名患者中的 14 名 [22%]）、贫血（10 名 [16%]）和血小板减少症（7 名 [11%]）。64 名患者中有 35 名 (55%) 发生了导致停药的治疗紧急不良事件 (TEAE)。五名 (8%) TEAE 患者出现致命结果；没有报告与因达妥昔单抗 ravtansine 相关。解释 Indatuximab ravtansine 联合免疫调节药物显示出初步的抗肿瘤活性，可耐受，可在复发或难治性多发性骨髓瘤患者中进一步评估。资助 Biotest AG。64 名患者中有 35 名 (55%) 发生了导致停药的治疗紧急不良事件 (TEAE)。五名 (8%) TEAE 患者出现致命结果；没有报告与因达妥昔单抗 ravtansine 相关。解释 Indatuximab ravtansine 联合免疫调节药物显示出初步的抗肿瘤活性，可耐受，可在复发或难治性多发性骨髓瘤患者中进一步评估。资助 Biotest AG。64 名患者中有 35 名 (55%) 发生了导致停药的治疗紧急不良事件 (TEAE)。五名 (8%) TEAE 患者出现致命结果；没有报告与因达妥昔单抗 ravtansine 相关。解释 Indatuximab ravtansine 联合免疫调节药物显示出初步的抗肿瘤活性，可耐受，可在复发或难治性多发性骨髓瘤患者中进一步评估。资助 Biotest AG。