Background

Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit–risk of the combination at the request of the US Food and Drug Administration (FDA).

Methods

KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1–21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual.

Findings

Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4–9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2–88·1) versus 85·0% (76·8–90·5; hazard ratio [HR] 1·22; 95% CI 0·67–2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure).

Interpretation

The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing.

Funding

Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).

中文翻译：

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派姆单抗加来那度胺和地塞米松治疗未治疗的多发性骨髓瘤（KEYNOTE-185）：一项随机，开放标签的3期试验

背景

来那度胺和地塞米松已成为新诊断为多发性骨髓瘤的不适合移植的患者的治疗标准。向该组合中添加第三种药物可能会改善治疗效果。KEYNOTE-185评估了来那度胺和地塞米松联合或不联合派姆单抗治疗先前未治疗的多发性骨髓瘤的疗效和安全性。在这里，我们应美国食品和药物管理局（FDA）的要求，提供了一项计划外中期分析的结果，以评估该组合的收益风险。

方法

KEYNOTE-185是在15个国家（澳大利亚，加拿大，法国，德国，爱尔兰，以色列，意大利，日本，新西兰，挪威，俄罗斯，南非，西班牙， ，英国和美国）。入选18岁及以上，初诊多发性骨髓瘤，东部合作肿瘤小组表现为0或1且未接受过治疗的不适合移植的患者，并随机分配1：1接受pembrolizumab联合来那度胺和地塞米松或来那度胺治疗和地塞米松单独使用互动语音或集成的网络响应系统。患者在重复的28天周期中的第1-21天接受来那度胺25 mg口服治疗，并在第1、8、15和22天接受地塞米松40 mg口服治疗，每3周接受或不接受静脉注射pembrolizumab 200 mg。主要终点是无进展生存期，这是由于试验的早期终止而由​​研究者评估的。对所有随机分配的患者的疗效进行了分析，并对接受至少一种剂量研究药物的所有患者的安全性进行了分析。该试验已在ClinicalTrials.gov上进行了注册，编号为NCT02579863，目前尚未公开。

发现

在2016年1月7日至2017年6月9日之间，将301例患者随机分为派姆单抗加来那度胺和地塞米松组（n = 151）或来那度胺和地塞米松组（n = 150）。2017年7月3日，由于各组之间死亡比例的不平衡，FDA决定中止该研究。在数据库终止时（2017年6月2日），中位随访6·6个月（IQR 3·4-9·6），派姆单抗加来那度胺和地塞米松组为149例患者，来那度胺和地塞米松组为145例已收到分配给他们的研究药物。两组均未达到中位无进展生存期。在6个月时无进展生存率估计为82·0％（95％CI 73·2–88·1）与85·0％（76·8–90·5；危险比[HR] 1·22; 95 ％CI 0·67-2·22； p = 0·75）。pembrolizumab联合来那度胺和地塞米松组中有81名（54％）患者发生严重不良事件，而来那度胺和地塞米松组中有57名（39％）患者；派姆单抗加来那度胺和地塞米松组最常见的严重不良事件是肺炎（9 [6％]）和发热（7 [5％]）和发热（8 [6％]）和败血症（2 [1％]）在来那度胺和地塞米松组中。pembrolizumab联合来那度胺和地塞米松组发生六例（4％）与治疗有关的死亡（心脏骤停，心力衰竭，心肌炎，大肠穿孔，肺炎和肺栓塞），来那度胺和地塞米松组中发生两例（1％）（上消化道出血和呼吸衰竭）。

解释

这项未经计划，FDA要求的中期分析的结果表明，对于新诊断，先前未治疗的多发性骨髓瘤患者，派姆单抗加来那度胺和地塞米松的获益风险曲线是不利的。正在进行长期的安全和生存随访。

资金

默克夏普（Merck Sharp＆Dohme），默克公司（Merck＆Co，Inc）（美国，新泽西州，肯尼沃思）的子公司。