Proteasome inhibitors (PIs), especially bortezomib (BTZ), have come to the forefront over the last years because of their unprecedented efficacy mainly against multiple myeloma (MM). Unfortunately, peripheral neuropathy (PN) secondary to treatment of MM with PIs has emerged as a clinically relevant complication, which negatively impacts the quality of life of MM survivors. Bortezomib‐induced peripheral neuropathy (BIPN) is a dose‐limiting toxicity, which develops in 30% to 60% of patients during treatment. Typically, BIPN is a length‐dependent sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution. BIPN mechanisms have not yet been fully elucidated. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity. A new generation of structurally distinct PIs has been developed, being increasingly used in clinical settings. Carfilzomib exhibits a much lower neurotoxicity profile, with a significantly lower incidence of PN compared to BTZ. Pre‐existing PN increases the risk of developing BIPN. Besides, BIPN is related to dose, schedule and mode of administration and modifications of these factors have lowered the incidence of PN. However, to date there is no cure for PIs‐induced PN (PIIPN), and a careful neurological monitoring and dose adjustment is a key strategy for preserving quality of life. This review critically looks at the pathogenesis, incidence, risk factors, both clinical and pharmacogenetics, clinical phenotype and management of PIIPN. We also make recommendations for further elucidating the whole clinical spectrum of PIIPN.

中文翻译：

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硼替佐米和其他蛋白体抑制剂引起的周围神经毒性：从发病到治疗。

蛋白酶体抑制剂（PIs），尤其是硼替佐米（BTZ），由于对多发性骨髓瘤（MM）的空前疗效，在过去几年中已走在前列。不幸的是，继发于PI治疗MM的周围神经病变（PN）已成为一种临床相关并发症，对MM生还者的生活质量产生了负面影响。硼替佐米诱发的周围神经病（BIPN）是一种剂量限制性毒性，在治疗期间会在30％至60％的患者中发展。通常，BIPN是一种长度依赖性的感觉轴突病，其特征是在储存和手套分配过程中出现麻木，刺痛和严重的神经性疼痛。BIPN机制尚未完全阐明。实验研究表明，聚集体形成，内质网应激，肌毒性，微管稳定，炎症反应和DNA损伤可能导致这种神经毒性。已经开发出了结构上不同的新一代PI，越来越多地用于临床环境。与BTZ相比，Carfilzomib表现出低得多的神经毒性，而PN的发生率则低得多。预先存在的PN会增加患BIPN的风险。此外，BIPN与剂量，给药时间表和给药方式有关，而这些因素的改变降低了PN的发生率。然而，迄今为止，尚无治愈PIs诱导的PN（PIIPN）的方法，而仔细的神经学监测和剂量调整是维持生活质量的关键策略。这篇综述主要研究了PIIPN的发病机制，发病率，危险因素，临床和药物遗传学，临床表型和管理。