Tao Yali, Zhou Hui, Niu Ting
Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, China.
Front Pharmacol. 2021 Dec 3;12:758992. doi: 10.3389/fphar.2021.758992. eCollection 2021.
Selinexor (SEL) is an orally bioavailable, highly-selective, and slowly-reversible small molecule that inhibits Exportin 1. Preclinical studies showed that SEL had synergistic antimyeloma activity with glucocorticoids, proteasome inhibitors (PIs) and immunomodulators. The combination of selinexor and dexamethasone (DEX) has been approved in the United States for patients with penta-refractory multiple myeloma in July 2019. This meta-analysis aimed to investigate the safety and efficacy of selinexor based treatment in Multiple myeloma. We systematically searched the Medline (PubMed), Embase, Web of Science, Cochrane Central Register of Controlled Trials Library databases and ClinicalTrials.gov. Outcome measures of efficacy included overall response rate (ORR), clinical benefit rate (CBR), stringent complete response rate (sCR), complete response rate (CR), very good partial response (VGPR), partial response rate (PR), minimal response (MR), rate of stable disease (SDR), rate of progressive disease (PDR) and median progression-free survival (mPFS). Safety was evaluated by the incidences of all grade adverse events and Grade≥3 adverse events. The subgroup analysis was conducted to analyze the difference in different combination treatment regimens (SEL + DEX + PIs vs SEL + DEX). We included six studies with 477 patients. The pooled ORR, CBR, sCR, CR, VGPR, PR, MR, SDR, and PDR were 43% (18-67%), 55% (32-78%), 5% (-2-13%), 7% (4-11%), 14% (5-24%), 23% (15-31%), 11% (8-14%), 26% (14-38%) and 14% (4-23%), respectively. SEL + DEX + PIs treatment had higher ORR (54 vs 24%, = 0.01), CBR (66 vs 37%, = 0.01), sCR (10 vs 2%, = 0.0008), and VGPR (23 vs 5%, < 0.00001) compared to SEL + DEX treatment, and lower PDR (4 vs 23%, < 0.00001) and SDR (17 vs 37%, = 0.0006). The pooled incidences of any grade and grade≥3 were 45 and 30% in hematological AEs, and in non-hematological AEs were 40 and 30%, respectively. The most common all grade (68%) and grade≥3 (54%) hematological AE were both thrombocytopenia. Fatigue was the most common all grade (62%) and grade≥3 (16%) non-hematological AE. Compared to SEL + DEX treatment, SEL + DEX + PIs treatment had lower incidences of hyponatremia (39 vs 12%, < 0.00001), nausea (72 vs 52%, < 0.00001), vomiting (41 vs 23%, < 0.0001), and weight loss (42 vs 17%, = 0.03) in all grade AEs. Meanwhile, SEL + DEX + PIs treatment had lower incidences of anemia (36 vs 16%, = 0.02), fatigue (20 vs 13%, = 0.04), hyponatremia (22 vs 5%, < 0.0001) than SEL + DEX treatment in grade≥3 AEs. Our meta-analysis revealed that selinexor-based regimens could offer reasonable efficacy and tolerable adverse events in patients with multiple myeloma. SEL + DEX + PIs treatments had higher efficacy and lower toxicities than SEL + DEX.
塞利尼索（SEL）是一种口服生物可利用、高度选择性且可逆性缓慢的小分子，可抑制核输出蛋白1。临床前研究表明，SEL与糖皮质激素、蛋白酶体抑制剂（PIs）和免疫调节剂具有协同抗骨髓瘤活性。塞利尼索与地塞米松（DEX）的联合用药于2019年7月在美国被批准用于五重难治性多发性骨髓瘤患者。这项荟萃分析旨在研究基于塞利尼索的治疗在多发性骨髓瘤中的安全性和疗效。我们系统检索了Medline（PubMed）、Embase、科学网、Cochrane对照试验中央注册库数据库和ClinicalTrials.gov。疗效的观察指标包括总缓解率（ORR）、临床获益率（CBR）、严格完全缓解率（sCR）、完全缓解率（CR）、非常好的部分缓解（VGPR）、部分缓解率（PR）、最小缓解（MR）、疾病稳定率（SDR）、疾病进展率（PDR）和中位无进展生存期（mPFS）。通过所有级别不良事件和≥3级不良事件的发生率评估安全性。进行亚组分析以分析不同联合治疗方案（SEL + DEX + PIs与SEL + DEX）之间的差异。我们纳入了6项研究，共477例患者。汇总的ORR、CBR、sCR、CR、VGPR、PR、MR、SDR和PDR分别为43%（18 - 67%）、55%（32 - 78%）、5%（-2 - 13%）、7%（4 - 11%）、14%（5 - 24%）、23%（15 - 31%）、11%（8 - 14%）、26%（14 - 38%）和14%（4 - 23%）。与SEL + DEX治疗相比，SEL + DEX + PIs治疗的ORR更高（54%对24%，P = 0.01）、CBR更高（66%对37%，P = 0.01）、sCR更高（10%对2%，P = 0.0008）和VGPR更高（23%对5%，P < 0.00001），且PDR更低（4%对23%，P < 0.00001）和SDR更低（17%对37%，P = 0.0006）。血液学不良事件中任何级别和≥3级的汇总发生率分别为45%和30%，非血液学不良事件中分别为40%和30%。最常见的所有级别（68%）和≥3级（54%）血液学不良事件均为血小板减少症。疲劳是最常见的所有级别（62%）和≥3级（16%）非血液学不良事件。与SEL + DEX治疗相比，SEL + DEX + PIs治疗在所有级别不良事件中低钠血症（39%对12%，P < 0.00001）、恶心（72%对52%，P < 0.00001）、呕吐（41%对23%，P < 0.0001）和体重减轻（42%对17%，P = 0.03）的发生率更低。同时，在≥3级不良事件中，SEL + DEX + PIs治疗的贫血（36%对16%，P = 0.02）、疲劳（20%对13%，P = 0.04）、低钠血症（22%对5%，P < 0.0001）的发生率低于SEL + DEX治疗。我们的荟萃分析表明，基于塞利尼索的方案可为多发性骨髓瘤患者提供合理的疗效和可耐受的不良事件。SEL + DEX + PIs治疗比SEL + DEX具有更高的疗效和更低的毒性。
