Exposure-response relationships of venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory t(11;14) multiple myeloma patients.

IF 3 3区 医学 Q2 ONCOLOGY Investigational New Drugs Pub Date : 2024-10-10 DOI:10.1007/s10637-024-01471-x
Mohamed Ali Badawi, Benjamin Engelhardt, Edyta Dobkowska, Rong Deng, Jonathan L Kaufman, Rajeev Menon, Ahmed Hamed Salem
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Abstract

Venetoclax is a first in class BCL-2 inhibitor, currently under investigation for the treatment of t(11;14) multiple myeloma (MM). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax when combined with carfilzomib and dexamethasone (VenKd) in t(11;14)-positive relapsed or refractory (R/R) MM patients from a phase 2 study. Fifty-seven patients receiving VenKd or Kd were included in the analysis. Efficacy endpoints included progression-free survival and clinical response rates of overall response, very good partial response or better and complete response or better. Grade ≥ 3 neutropenia, Grade ≥ 3 infections, Grade ≥ 3 treatment-emergent adverse events and any grade serious treatment-emergent adverse events were evaluated. The analysis demonstrated that adding venetoclax to Kd resulted in increased ORR, ≥VGPR and ≥ CR rates compared to the control arm. Within the venetoclax treatment arms (VenKd), no significant exposure-efficacy relationships were observed for ORR and ≥ VGPR rates. Higher ≥ CR rates trended with higher venetoclax exposures. While both 400 mg and 800 mg venetoclax in VenKd arms were generally tolerated, higher rates of Grade ≥ 3 neutropenia were observed with higher venetoclax exposures. Higher venetoclax exposures however were not associated with increased rates of Grade ≥ 3 treatment-emergent adverse events, Grade ≥ 3 infections, or serious treatment-emergent adverse events (any grade). These results confirm the benefit of adding venetoclax to carfilzomib and dexamethasone and support continued evaluation of venetoclax 400-800 mg once daily in this combination in t(11;14)-positive R/R MM patients. NCT02899052 registered April 18, 2017.

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Venetoclax与卡非佐米和地塞米松联合治疗复发/难治性t(11;14)多发性骨髓瘤患者的暴露-反应关系。
Venetoclax是首款BCL-2抑制剂,目前正在研究用于治疗t(11;14)多发性骨髓瘤(MM)。这项分析的目的是描述Venetoclax与卡非佐米和地塞米松(VenKd)联合治疗t(11;14)阳性复发或难治性(R/R)MM患者的暴露-疗效关系和暴露-安全性关系。57名接受VenKd或Kd治疗的患者被纳入分析。疗效终点包括无进展生存期和总体反应、很好的部分反应或更好的临床反应率以及完全反应或更好的临床反应率。对≥3级中性粒细胞减少、≥3级感染、≥3级治疗突发不良事件和任何级别的严重治疗突发不良事件进行了评估。分析表明,与对照组相比,在Kd中加入venetoclax可提高ORR、≥VGPR和≥CR率。在 Venetoclax 治疗组(VenKd)中,未观察到 ORR 和≥VGPR 率有显著的暴露-疗效关系。Venetoclax暴露量越高,≥CR率越高。虽然VenKd治疗组中400毫克和800毫克的venetoclax一般都能耐受,但venetoclax暴露量越高,≥3级中性粒细胞减少率越高。然而,较高的 Venetoclax 暴露与≥ 3 级治疗突发不良事件、≥ 3 级感染或严重治疗突发不良事件(任何级别)发生率的增加无关。这些结果证实了在卡非佐米和地塞米松基础上加用venetoclax的益处,并支持继续评估在t(11;14)阳性R/R MM患者中每日一次联合应用venetoclax 400-800毫克的效果。NCT02899052于2017年4月18日注册。
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来源期刊
CiteScore
7.60
自引率
0.00%
发文量
121
审稿时长
1 months
期刊介绍: The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist, toxicologist, pharmacist, pharmacologist, biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents.
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