Department of Internal Medicine, Karl Landsteiner University of Health Sciences, University Hospital, Krems, Austria.
Karyopharm Therapeutics, Newton, MA, USA.
Expert Opin Pharmacother. 2020 Mar;21(4):399-408. doi: 10.1080/14656566.2019.1707184. Epub 2020 Jan 19.
: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.
尽管在多发性骨髓瘤(MM)的治疗方面取得了前所未有的进展,但几乎所有患者都会发展出对五种最常用和最有效的抗-MM 药物具有耐药性的疾病。这一患者群体的预后尤其差,因此需要额外的治疗选择。Exportin-1(XPO-1)是一种主要的核输出蛋白,可将大分子货物运出细胞核,在 MM 中经常过度表达。Selinexor 是一种首创的、口服的选择性核输出抑制剂(SINE)化合物,可阻碍 XPO-1。基于 STORM 试验的结果,Selinexor 联合地塞米松于 2019 年 7 月获得 FDA 加速批准,用于治疗五重难治性 MM 患者。本文总结了我们目前对 XPO-1 在 MM 中的病理生理作用的最新认识。此外,还回顾了 Selinexor 联合地塞米松和其他抗-MM 药物的最新临床数据,并讨论了其安全性特征、管理策略和潜在的未来发展。Selinexor 是一种具有创新作用机制的下一代新型药物,标志着对经过大量预处理的 MM 患者治疗的重大进展。正在进行的研究调查了其在早期治疗线中的治疗潜力。需要更多的数据来证实 Selinexor 和其他 SINE 化合物是我们当前治疗武器库的有价值的补充。