评估idecabtagene vicleucel在三重暴露的复发/难治性多发性骨髓瘤患者中的细胞扩增情况及其与临床疗效和安全性的关联。

Characterizing Cellular Expansion of Idecabtagene Vicleucel and Association with Clinical Efficacy and Safety in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.

作者信息

Wu Fan, Zheng Xirong, Burnett Joseph, Masilamani Madhan, Zhang Wanying, Zhong Xiaobo, Caia Andrea, Cook Mark, Piasecki Julia, Kondic Anna, Lamba Manisha, Zhou Jian

机构信息

Translational Medical and Clinical Pharmacology, Bristol Myers Squibb, Princeton, NJ, USA.

Global Biometric Sciences, Bristol Myers Squibb, Princeton, NJ, USA.

出版信息

J Clin Pharmacol. 2025 Jul 10. doi: 10.1002/jcph.70075.

Abstract

Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen-directed, chimeric antigen receptor (CAR) T-cell therapy, which has demonstrated significantly improved progression-free survival (PFS) and overall response rate (ORR) in patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE RRMM). Here, we characterize cellular expansion of ide-cel in vivo and further evaluate associations between cellular expansion and clinical efficacy and safety endpoints. The exposure parameters of ide-cel were evaluated through non-compartmental analysis methods using the time course data of CAR transgene copy numbers collected from the ide-cel arm of Study KarMMa-3 (NCT03651128). Multivariable regression analyses were conducted between the exposure parameters and clinical responses to characterize relationships between cellular expansion in vivo and clinical outcomes and to evaluate potential effects of covariates on the exposure-response (E-R) relationships. There appears to be lack of a strong association between actual ide-cel dose and cellular expansion at the dose range evaluated in Study KarMMa-3. The multivariable E-R regression models suggest positive relationships between cellular expansion and clinical efficacy and safety endpoints, with higher exposure associated with longer PFS, higher ORR, and higher rates of cytokine release syndrome requiring tocilizumab or corticosteroids. The current analyses do not identify any clinically relevant covariate effects on the E-R relationships. The positive exposure-response relationships were found to be overall similar between KarMMa-3 and a previous study KarMMa. The modeling analyses, paired with clinical data, support extending the dose range from previously approved 300-460 × 10 CAR+ T cells to 300-510 × 10 CAR+ T cells for TCE RRMM patients.

摘要

伊德凯达基因自体嵌合抗原受体T细胞疗法(ide-cel,ABECMA)是一种自体、靶向B细胞成熟抗原的嵌合抗原受体(CAR)T细胞疗法,已在三重暴露复发/难治性多发性骨髓瘤(TCE RRMM)患者中显示出无进展生存期(PFS)和总缓解率(ORR)显著改善。在此,我们对ide-cel在体内的细胞扩增进行表征,并进一步评估细胞扩增与临床疗效和安全性终点之间的关联。通过非房室分析方法,利用从KarMMa-3研究(NCT03651128)的ide-cel组收集的CAR转基因拷贝数的时间进程数据,评估ide-cel的暴露参数。在暴露参数与临床反应之间进行多变量回归分析,以表征体内细胞扩增与临床结果之间的关系,并评估协变量对暴露-反应(E-R)关系的潜在影响。在KarMMa-3研究评估的剂量范围内,实际的ide-cel剂量与细胞扩增之间似乎缺乏强关联。多变量E-R回归模型表明细胞扩增与临床疗效和安全性终点之间呈正相关,暴露越高,PFS越长,ORR越高,需要托珠单抗或皮质类固醇治疗的细胞因子释放综合征发生率越高。目前的分析未发现任何对E-R关系有临床意义的协变量效应。发现KarMMa-3与先前的KarMMa研究之间的阳性暴露-反应关系总体相似。建模分析与临床数据相结合,支持将TCE RRMM患者的剂量范围从先前批准的300 - 460×10个CAR+ T细胞扩展至300 - 510×10个CAR+ T细胞。

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