Nuclear export proteins such as exportin-1 (XPO1) transport tumor-suppressor proteins and other growth-regulatory proteins from the nucleus to the cytoplasm. Overexpression of XPO1 has been observed in several cancers and correlates with shorter event-free and overall survival in multiple myeloma. Selinexor was developed as an oral first-in-class selective inhibitor of nuclear export (SINE) that inhibits XPO1. Preclinical studies in tumor cell lines and mouse models have demonstrated the efficacy of selinexor both as a single agent and in various combinations with known active antimyeloma agents. Results from the pivotal phase II STORM trial led to the US FDA approval of selinexor with dexamethasone in penta-refractory myeloma. Because of the feasibility of combining selinexor with other active antimyeloma agents, the multiarm STOMP trial was initiated and is ongoing, with impressive response rates reported in some of the combination arms thus far. The registrational phase III BOSTON trial demonstrated the superiority of selinexor in combination with bortezomib and dexamethasone as compared with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) who have received one to three prior anti-MM regimens. The toxicity profile of selinexor is well established and predictable and may be significant unless managed aggressively and preemptively. The most common side effects are thrombocytopenia, anemia, neutropenia, fatigue, nausea, anorexia, and weight loss. Hyponatremia and cataracts seem to be class effects. Other SINE compounds are now being studied in efforts to discover agents that will potentially be better tolerated. Eltanexor is an investigational SINE compound that has shown a more positive toxicity profile in preclinical studies, with reduced central nervous system penetration and gastrointestinal side effects, and is now undergoing clinical investigation. These and other trials will further clarify the role of these innovative agents in the therapeutic advancement of RRMM.

核输出蛋白如输出蛋白-1 (XPO1) 将肿瘤抑制蛋白和其他生长调节蛋白从细胞核转运到细胞质。已在几种癌症中观察到 XPO1 的过度表达，并且与多发性骨髓瘤中较短的无事件生存期和总生存期相关。Selinexor 被开发为一种口服一流的选择性核输出抑制剂 (SINE)，可抑制 XPO1。肿瘤细胞系和小鼠模型的临床前研究已经证明了 selinexor 作为单一药物和与已知活性抗骨髓瘤药物的各种组合的功效。关键的 II 期 STORM 试验的结果导致美国 FDA 批准 selinexor 与地塞米松一起治疗五难治性骨髓瘤。由于将 selinexor 与其他活性抗骨髓瘤药物联合使用的可行性，多组 STOMP 试验已启动并正在进行中，迄今为止，一些联合组的反应率令人印象深刻。注册 III 期 BOSTON 试验表明，与硼替佐米和地塞米松相比，selinexor 与硼替佐米和地塞米松联合用于已经接受过一到三个先前抗 MM 方案的复发难治性多发性骨髓瘤 (RRMM) 患者的优越性。selinexor 的毒性特征已经确立且可预测，除非积极和抢先管理，否则可能会很严重。最常见的副作用是血小板减少、贫血、中性粒细胞减少、疲劳、恶心、厌食和体重减轻。低钠血症和白内障似乎是阶级效应。目前正在研究其他 SINE 化合物，以发现可能具有更好耐受性的药物。Eltanexor 是一种研究性 SINE 化合物，在临床前研究中显示出更积极的毒性特征，减少中枢神经系统渗透和胃肠道副作用，目前正在进行临床研究。这些和其他试验将进一步阐明这些创新药物在 RRMM 治疗进展中的作用。