Department of Neurology, Division of Neuromuscular Medicine, The University of Michigan Health System, Ann Arbor, Michigan, USA.
Department of Internal Medicine, Division of Hematology-Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Eur J Neurol. 2024 Mar;31(3):e16164. doi: 10.1111/ene.16164. Epub 2023 Nov 28.
Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy.
This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD.
Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12.
Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate.
Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.
抗髓鞘相关糖蛋白（MAG）神经病是一种使人衰弱的脱髓鞘性多发性神经病，目前尚无批准的治疗方法。我们的主要目的是确定来那度胺在抗 MAG 神经病中的安全性和最大耐受剂量（MTD）。
这是一项 2019 年至 2022 年进行的 1b 期、开放性、单臂、剂量探索试验。最初的设计包括剂量递增/扩展阶段和剂量扩展阶段。评估了三种来那度胺剂量：10、15 和 25mg。主要结果是 MTD。
11 名患者入组（10 名男性），平均年龄 67.6 岁（SD=6.18，范围 58-77 岁），平均病程 8.5 年（SD=10.9，范围 1-40 年）。由于静脉血栓栓塞症（VTE）事件的发生率高于预期的非剂量限制毒性，该研究提前终止。计算出的 MTD 为 25mg（毒性概率后验均值为 0.01，95%可信区间为 0.00，0.06），但建议的 2 期剂量为 15mg。对于次要探索性结局，只有 EQ-5D（-0.95，95%CI-1.81 至-0.09）和总 IgM（-162mg/dL，95%CI-298 至-26）在 12 个月时显示出改善的迹象。
尽管计算出的 MTD 为 25mg，但来那度胺在抗 MAG 神经病患者中与高于预期的 VTE 事件相关。建议采用 2 期 15mg 剂量。在 12 个月时，来那度胺并没有改善残疾或损伤，尽管这项研究没有显示出疗效。对于抗 MAG 神经病患者，长期使用来那度胺的风险可能大于获益。任何未来的疗效研究都应解决 VTE 风险，因为目前的骨髓瘤指南似乎不够充分。
来那度胺治疗抗 MAG 神经病的 1b 期研究，ClinicalTrials.gov 标识符：NCT03701711，https://clinicaltrials.gov/ct2/show/NCT03701711。首次提交于 2018 年 10 月 10 日。首位患者于 2019 年 1 月入组。
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