PURPOSE Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry. PATIENTS AND METHODS A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR). RESULTS Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No dose-limiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%). CONCLUSIONS This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).

中文翻译：

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Ruxolitinib、来那度胺和类固醇治疗复发/难治性多发性骨髓瘤患者的 I 期研究。

目的 Ruxolitinib 与来那度胺和地塞米松在体外和体内显示出抗骨髓瘤作用。MUC1 导致多发性骨髓瘤细胞对来那度胺产生耐药性，而鲁索替尼可阻断其表达。因此，鲁索替尼可能会恢复对来那度胺的敏感性。因此，进行了一项 I 期试验，以确定鲁索替尼联合来那度胺和甲基强的松龙对接受来那度胺/类固醇和蛋白酶体抑制剂治疗并在研究开始时疾病进展的复发/难治性多发性骨髓瘤 (RRMM) 患者的安全性和有效性. 患者和方法 使用传统的 3+3 剂量递增设计在四个队列中招募受试者，计划总共招募 28 名患者。受试者每天接受两次鲁索替尼，在 28 天周期的第 1-21 天每天接受来那度胺，和甲基强的松龙每隔一天口服一次。主要终点是安全性、临床受益率（CBR）和总体反应率（ORR）。结果 共招募了 28 名患者。中位年龄为 67 岁，之前接受过中位数为 6 次的治疗，包括来那度胺和类固醇，其中 93% 为难治性。没有发生剂量限制性毒性。CBR 和 ORR 分别为 46% 和 38%。所有 12 名有反应的患者都对来那度胺难治。3 级或 4 级不良事件 (AE) 包括贫血 (18%)、血小板减少 (14%) 和淋巴细胞减少 (14%)。最常见的严重 AE 包括败血症 (11%) 和肺炎 (11%)。结论 该 I 期试验表明 JAK 抑制剂鲁索替尼可以克服 RRMM 患者对来那度胺和类固醇的难治性。