BACKGROUND Treatment of multiple myeloma is not curative, but targeting CD38 improves patient survival. To further explore this therapeutic approach, we investigated the safety and activity of MOR202, a novel monoclonal antibody targeting CD38, in patients with multiple myeloma. METHODS This is a multicentre, open-label, phase 1-2a trial done at ten hospitals in Germany and Austria. Enrolled patients were aged 18 years or older with relapsed or refractory multiple myeloma and Karnofsky performance status of 60% or higher. Patients were assigned to the different treatment regimens with MOR202 ranging between 0·01 mg/kg and 16 mg/kg in a 3 + 3 design. Dose-escalation and expansion was done either with MOR202 intravenous infusions alone (MOR202 q2w [twice a week] and q1w [weekly] groups) or in combination with dexamethasone (MOR202 with dexamethasone group), with dexamethasone plus pomalidomide (MOR202 with dexamethasone plus pomalidomide group) or plus lenalidomide (MOR202 with dexamethasone plus lenalidomide group). Primary endpoints were safety, MOR202 maximum tolerated dose (or recommended dose) and regimen, and immunogenicity. The primary analysis was assessed in the safety population, which included patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, NCT01421186. FINDINGS Between Aug 24, 2011, and Aug 1, 2017, 91 patients were treated, 35 with MOR202 monotherapy, and 56 with MOR202 combination regimens (18 in the MOR202 with dexamethasone group, 21 in the MOR202 with dexamethasone plus pomalidomide group, and 17 in the MOR202 with dexamethasone plus lenalidomide group). MOR202 intravenous infusions were safely administered within 30 min. Infusion-related reactions occurred in 14 (40%) of 35 patients receiving MOR202 monotherapy without steroids, and in four (7%) of 56 patients receiving MOR202 combination treatment. MOR202 maximum tolerated dose was not reached and the recommended regimens were MOR202 administered as an intravenous infusion for 30 min at doses up to 16 mg/kg with dexamethasone (40 mg), or in combination with dexamethasone plus lenalidomide (25 mg) or pomalidomide (4 mg). 35 (38%) of 91 patients developed lymphopenia, 30 (33%) developed neutropenia, and 27 (30%) developed leukopenia; these were the most common grade 3 or higher treatment-emergent adverse events. Serious adverse events were reported in 51 (56%) of 91 patients. None of the deaths were associated with MOR202. One pomalidomide-associated death occurred in the MOR202 with dexamethasone plus pomalidomide group. No anti-MOR202 antibodies were detected in patients. INTERPRETATION MOR202 is safe and its clinical activity in patients with relapsed or refractory multiple myeloma is promising. Further clinical investigations of combinations with an immunomodulatory drug and dexamethasone are recommended. FUNDING MorphoSys AG.

中文翻译：

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MOR202，一种新型抗CD38单克隆抗体，用于患有复发性或难治性多发性骨髓瘤的患者：一项在人类中的首次，多中心，1-2a期试验。

背景技术多发性骨髓瘤的治疗不是治愈性的，但是靶向CD38改善了患者的存活率。为了进一步探索这种治疗方法，我们研究了多发性骨髓瘤患者MOR202（一种靶向CD38的新型单克隆抗体）的安全性和活性。方法这是在德国和奥地利的十家医院进行的多中心，开放标签的1-2a期试验。入组患者年龄在18岁或以上，复发或难治性多发性骨髓瘤，Karnofsky表现状态为60％或更高。按照3 + 3设计，将患者分配为0至01 mg / kg至16 mg / kg的MOR202不同治疗方案。剂量递增和扩展可以单独使用MOR202静脉输注（MOR202 q2w [每周两次]和q1w [每周]组），也可以与地塞米松（MOR202与地塞米松组联合），地塞米松+泊马度胺（MOR202与地塞米松+ pomalidomide）一起进行组）或加来那度胺（MOR202与地塞米松加来那度胺组）。主要终点指标是安全性，MOR202最大耐受剂量（或推荐剂量）和方案以及免疫原性。在安全人群中评估了主要分析，其中包括接受至少一剂任何研究药物的患者。该试验已在ClinicalTrials.gov（NCT01421186）上注册。在2011年8月24日至2017年8月1日之间，共治疗了91例患者，其中35例接受了MOR202单药治疗，和56种使用MOR202联合疗法的方案（在地塞米松组中的MOR202中为18种，在地塞米松加泊马利度组中在MOR202中为21种，在地塞米松联合来那度胺组中在MOR202中为17种）。在30分钟内安全施用MOR202静脉输液。接受MOR202单药非甾体治疗的35例患者中有14例（40％）发生了输注相关反应，接受MOR202联合治疗的56例患者中有4例（7％）发生。未达到MOR202的最大耐受剂量，建议的治疗方案为MOR202以30 mg的剂量静脉滴注地塞米松（40 mg），或与地塞米松加来那度胺（25 mg）或pomalidomide（ 4毫克）。91名患者中有35名（38％）出现了淋巴细胞减少，30名（33％）出现了中性粒细胞减少和27名（30％）出现了白细胞减少。这些是最常见的3级或更高级别的紧急治疗不良事件。91例患者中有51例（56％）报告严重不良事件。没有死亡与MOR202有关。在MOR202中，地塞米松加波马利米德组发生1例与波马利米德相关的死亡。患者中未检测到抗MOR202抗体。解释MOR202是安全的，其在复发或难治性多发性骨髓瘤患者中的临床活动前景广阔。建议与免疫调节药物和地塞米松联合使用的进一步临床研究。融资MorphoSys AG。在MOR202中，地塞米松加波马利米德组发生1例与波马利米德相关的死亡。患者中未检测到抗MOR202抗体。解释MOR202是安全的，其在复发或难治性多发性骨髓瘤患者中的临床活动前景广阔。建议与免疫调节药物和地塞米松联用的进一步临床研究。融资MorphoSys AG。在MOR202中，地塞米松加波马利米德组发生1例与波马利米德相关的死亡。患者中未检测到抗MOR202抗体。解释MOR202是安全的，其在复发或难治性多发性骨髓瘤患者中的临床活动前景广阔。建议与免疫调节药物和地塞米松联合使用的进一步临床研究。融资MorphoSys AG。