Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial
Authors: Xia Zhongjun , Leng Yun , Fang Baijun , Liang Yang , Li Wei , Fu Chengcheng , Yang Linhua , Ke Xiaoyan , Jiang Hua , Weng Jianyu , Liu Li , Zhao Yaozhong , Zhang Xuejun , Huang Zhongxia , Liu Aichun , Shi Qingzhi , Gao Yuhuan , Chen Xiequn , Pan Ling , Cai Zhen , Wang Zhao , Wang Yafei , Fan Yaqun , Hou Ming , Ma Yigai , Hu Jianda , Liu Jing , Zhou Jianfeng , Zhang Xiaohong , Meng Haitao , Lu Xuzhang , Li Fei , Ren Hanyun , Huang Bintao , Shao Zonghong , Zhou Hebing , Hu Yu , Yang Shifang , Zheng Xiangjun , Wei Peng , Pang Hongyan , Yu Wei , Liu Yuzhang , Gao Sujun , Yan Lingzhi , Ma Yanping , Jing Hongmei , Du Juan , Ling Wei , Zhang Jingyi , Sui Weiwei , Wang Fuxu , Li Xin , Chen Wenming 
Published: October 2023

Abstract
Background
Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed.

Methods
Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR).

Results
A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49–0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55–0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors.

Conclusions
Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients.

Trial registration
The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.