Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Institut Català d'Oncologia and Josep Carreras Research Institute, Hospital Germans Trias i Pujol, Badalona, Spain.
J Clin Oncol. 2021 Mar 1;39(7):757-767. doi: 10.1200/JCO.20.02259. Epub 2020 Dec 9.
Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.
Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.
Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.
Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.
美法仑氟苯酰胺（melflufen）是一种首创的肽药物偶联物，靶向氨肽酶，并迅速且选择性地将烷化剂释放到肿瘤细胞中。在复发和难治性多发性骨髓瘤（RRMM）中评估了 melflufen 联合地塞米松的疗效，RRMM 是一种具有重要未满足医疗需求的人群。
对泊马度胺和/或抗 CD38 单克隆抗体耐药的 RRMM 患者接受静脉注射 melflufen 40mg，每 28 天周期的第 1 天，每周一次口服地塞米松 40mg（75 岁以上患者为 20mg）。主要终点是由研究者评估和独立审查确认的总体缓解率（部分缓解或更好）。次要终点包括缓解持续时间、无进展生存期、总生存期和安全性。主要分析已经完成，正在进行长期随访。
在入组和治疗的 157 例患者（中位年龄 65 岁；中位既往治疗线 5 线）中，119 例（76%）为三药耐药疾病，55 例（35%）有髓外疾病，92 例（59%）对既往烷化剂治疗耐药。在所有治疗人群中，总体缓解率为 29%，三药耐药人群中为 26%。在所有治疗人群中，中位缓解持续时间为 5.5 个月，中位无进展生存期为 4.2 个月，中位总生存期为 11.6 个月，中位随访时间为 14 个月。96%的患者发生≥3 级治疗相关不良事件，最常见的是中性粒细胞减少症（79%）、血小板减少症（76%）和贫血（43%）。肺炎（10%）是最常见的 3/4 级非血液学事件。4 例患者同时发生血小板减少症和出血（均为 3/4 级，但完全可逆）。在 97 例患者（62%）中报告了胃肠道事件，主要为 1/2 级（93%）；无 4 级事件。
melflufen 联合地塞米松在既往治疗过多的 RRMM 患者中显示出有临床意义的疗效和可管理的安全性，包括三药耐药和髓外疾病患者。
