Background

Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).

Methods

KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1–21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.

Findings

Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5–10·9). Median progression-free survival was 5·6 months (95% CI 3·7–7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9–not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37–58) versus 60% (49–69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05–2·22; p=0·98). Median overall survival was not reached (95% CI 12·9–not reached) versus 15·2 months (12·7–not reached; HR 1·61; 95% CI 0·91–2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74–88) versus 90% (82–95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens–Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.

Interpretation

The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.

Funding

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

中文翻译：

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Pembrolizumab加上pomalidomide和地塞米松治疗复发或难治性多发性骨髓瘤（KEYNOTE-183）：一项随机，开放标签的3期临床试验。

背景

对于硼替佐米和来那度胺治疗失败的多发性骨髓瘤患者，波马利度胺和地塞米松是一种标准的治疗方法。KEYNOTE-183评估了帕马利度胺和地塞米松联合或不联合派姆单抗对复发或难治性多发性骨髓瘤患者的疗效和安全性。在这里，我们应美国食品和药物管理局（FDA）的要求，提出了一项计划外的临时性临时分析的结果。

方法

KEYNOTE-183是在11个国家（澳大利亚，加拿大，法国，德国，以色列，意大利，日本，新西兰，挪威，西班牙和美国）的97个医疗中心进行的一项随机，开放标签的3期临床试验。年龄至少18岁的多发性骨髓瘤，东部合作肿瘤小组（ECOG）的工作状态为0或1，先前接受了至少两线治疗（不包括pomalidomide）并且对最后一线无效的患者被随机分配为1：1。通过互动语音响应或集成网络响应系统将pembrolizumab加上pomalidomide和地塞米松组或pomalidomide和地塞米松组。患者在第1至21天每天口服口服pomalidomide 4 mg，在第28天的第1、8、15和22天接受口服小剂量地塞米松40 mg，每3周接受或不接受静脉注射pembrolizumab 200 mg。双重主要终点是无进展生存期和总生存期。评估所有随机分配的患者的疗效，并评估接受至少一剂研究治疗药物的患者的安全性。该试验已在ClinicalTrials.gov上进行了注册，编号为NCT02576977，目前尚未公开。

发现

在2016年1月18日至2017年6月7日之间，将249例患者随机分为pembrolizumab联合pomalidomide和地塞米松组（n = 125）或pomalidomide和dexamethasone组（n = 124）。2017年7月3日，FDA确认与三联组合相关的风险大于收益，并终止了该研究。中位随访时间为8·1个月（IQR 4·5-10·9）。pembrolizumab加上pomalidomide和地塞米松组的中位无进展生存期为5·6个月（95％CI 3·7-7·5），而pomalidomide和地塞米松组为8·4个月（5·9–未达到）。6个月时无进展生存率估计为48％（95％CI 37-58），而6个月时为60％（49-69）（危险比[HR] 1·53； 95％CI 1·05-2·22 ； p = 0·98）。未达到中位总生存期（95％CI 12·9 –未达到）与15·2个月（12·7–未达到； HR 1·61；未达到目标）。95％CI 0·91–2·85; p = 0·95）；在6个月时的总体生存估计为82％（95％CI 74-88），而90％（82-95）。pembrolizumab加pomalidomide和地塞米松组的120例患者中有75例（63％）发生严重不良事件，而pomalidomide和地塞米松组的121例患者中有56例（46％）。pembrolizumab加上pomalidomide和dexamethasone组发生了4例（3％）与治疗相关的死亡（原因不明，中性粒细胞减少症，心肌炎和Stevens-Johnson综合征各1例）。心肌炎和史蒂文斯-约翰逊综合征被认为与派姆单抗有关。在波马度胺和地塞米松组中未报告与治疗有关的死亡。pembrolizumab加pomalidomide和地塞米松组的120例患者中有75例（63％）发生严重不良事件，而pomalidomide和地塞米松组的121例患者中有56例（46％）。pembrolizumab加上pomalidomide和dexamethasone组发生了4例（3％）与治疗相关的死亡（原因不明，中性粒细胞减少症，心肌炎和Stevens-Johnson综合征各1例）。心肌炎和史蒂文斯-约翰逊综合征被认为与派姆单抗有关。在波马度胺和地塞米松组中未报告与治疗有关的死亡。pembrolizumab加pomalidomide和地塞米松组的120例患者中有75例（63％）发生严重不良事件，而pomalidomide和地塞米松组的121例患者中有56例（46％）。pembrolizumab加上pomalidomide和dexamethasone组发生了4例（3％）与治疗相关的死亡（原因不明，中性粒细胞减少症，心肌炎和Stevens-Johnson综合征各1例）。心肌炎和史蒂文斯-约翰逊综合征被认为与派姆单抗有关。在波马度胺和地塞米松组中未报告与治疗有关的死亡。心肌炎和史蒂文斯-约翰逊综合征）；心肌炎和史蒂文斯-约翰逊综合征被认为与派姆单抗有关。在波马度胺和地塞米松组中未报告与治疗有关的死亡。心肌炎和史蒂文斯-约翰逊综合征）；心肌炎和史蒂文斯-约翰逊综合征被认为与派姆单抗有关。在波马度胺和地塞米松组中未报告与治疗有关的死亡。

解释

这项未经计划的，FDA要求的中期分析的结果表明，对于复发或难治性多发性骨髓瘤患者，派姆单抗加普莫利度胺和地塞米松的获益风险曲线是不利的。

资金

默沙东（Merck＆Co）（美国新泽西州肯尼沃思）的子公司默沙东（Merck Sharp＆Dohme）。