Scheid Christof, Reece Donna, Beksac Meral, Spencer Andrew, Callander Natalie, Sonneveld Pieter, Kalimi Ghulam, Cai Can, Shi Michael, Scott Jeffrey W, Stewart A Keith
University Hospital of Cologne, Cologne, Germany.
Princess Margaret Cancer Centre, Toronto, ON, Canada.
Eur J Haematol. 2015 Oct;95(4):316-24. doi: 10.1111/ejh.12491. Epub 2015 Jan 22.
Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation.
Adult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2-stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5-days-on/2-days-off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non-responding patients, treatment could continue with the addition of low-dose dexamethasone.
In total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non-interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)-positive group and 3.7 weeks in the t(4;14)-negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)-positive group and 34.6% in the t(4;14)-negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%).
Dovitinib showed no single-agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)-positive patients.
约15%的多发性骨髓瘤（MM）患者存在t(4;14)易位，这通常导致受体酪氨酸激酶（RTK）成纤维细胞生长因子受体3（FGFR3）的组成性激活。本研究评估了多韦替尼（一种对FGFR具有体外抑制活性的RTK抑制剂）在伴有或不伴有t(4;14)易位的复发或难治性MM患者中的疗效和安全性。
入组本多中心、2期、2阶段试验的为接受过≥2种既往治疗方案的复发或难治性MM成年患者。患者根据其t(4;14)状态分组。多韦替尼（口服500 mg/天）采用5天用药/2天停药的给药方案。主要终点为经当地研究者评估的总缓解率（按照国际骨髓瘤工作组标准）。对于无反应的患者，可加用低剂量地塞米松继续治疗。
共入组43例患者（中位年龄63岁）（13例t(4;14)阳性，26例t(4;14)阴性，4例t(4;14)状态无法判读）。患者既往接受治疗方案的中位数为5种。t(4;14)阳性组的中位治疗持续时间为8.7周，t(4;14)阴性组为3.7周。接受多韦替尼治疗的患者均无客观缓解。t(4;14)阳性组的疾病稳定率为61.5%，t(4;14)阴性组为34.6%。总体而言，39例患者（90.7%）发生了疑似与研究药物相关的不良事件，最常见的是腹泻（60.5%）、恶心（58.1%）、呕吐（46.5%）和疲劳（32.6%）。
多韦替尼在复发或难治性MM中未显示出单药活性，但可能使部分t(4;14)阳性患者的病情稳定。
