Dhillon Sohita
Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
Drugs. 2021 Jun;81(8):963-969. doi: 10.1007/s40265-021-01522-0.
Melphalan flufenamide (melflufen, Pepaxto) is a peptide conjugated alkylating drug developed by Oncopeptides for the treatment of multiple myeloma (MM) and amyloid light-chain amyloidosis. It is an ethyl ester of a lipophilic dipeptide consisting of melphalan and para-fluoro-L-phenylalanine. Due to its lipophilicity, melphalan flufenamide is rapidly transported across the cell membrane and almost immediately hydrolyzed by aminopeptidases in the cytoplasm to yield more hydrophilic alkylating molecules, such as melphalan and desethyl-melflufen. Like other nitrogen mustard drugs, melphalan flufenamide exerts antitumor activity through DNA crosslinking. In February 2021, melphalan flufenamide, in combination with dexamethasone, received its first approval in the USA for the treatment of adults with relapsed or refractory (r/r) MM who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent, and one CD38-directed monoclonal antibody. A multinational clinical study of melphalan flufenamide in amyloid light-chain amyloidosis is underway across several countries, and preclinical studies for various haematological and solid cancers are underway. This article summarizes the milestones in the development of melphalan flufenamide leading to this first approval.
美法仑氟芬酰胺（melflufen，Pepaxto）是Oncopeptides公司研发的一种肽偶联烷化剂药物，用于治疗多发性骨髓瘤（MM）和淀粉样轻链淀粉样变性。它是一种由美法仑和对氟-L-苯丙氨酸组成的亲脂性二肽的乙酯。由于其亲脂性，美法仑氟芬酰胺可迅速穿过细胞膜，并几乎立即被细胞质中的氨肽酶水解，生成更具亲水性的烷化分子，如美法仑和去乙基美法仑。与其他氮芥类药物一样，美法仑氟芬酰胺通过DNA交联发挥抗肿瘤活性。2021年2月，美法仑氟芬酰胺联合地塞米松在美国首次获批，用于治疗接受过至少四线先前治疗且疾病对至少一种蛋白酶体抑制剂（PI）、一种免疫调节剂和一种CD38定向单克隆抗体难治的复发或难治性（r/r）成年MM患者。一项关于美法仑氟芬酰胺治疗淀粉样轻链淀粉样变性的多国临床研究正在多个国家进行，针对各种血液系统和实体癌的临床前研究也正在开展。本文总结了美法仑氟芬酰胺研发过程中促成这一首次获批的里程碑事件。
