Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety

IF 3.3 4区医学 Q2 HEMATOLOGY Hematological Oncology Pub Date : 2023-09-23 DOI:10.1002/hon.3222

Mohamed Badawi, Sheryl Coppola, Doerthe Eckert, Sathej Gopalakrishnan, Benjamin Engelhardt, Eva Doelger, Weize Huang, Edyta Dobkowska, Shaji Kumar, Rajeev M. Menon, Ahmed Hamed Salem

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Abstract

Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure–response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUC_avg) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

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Venetoclax生物标志物选择的多发性骨髓瘤患者：暴露对临床疗效和安全性的影响。

Venetoclax是一种强效的BCL-2抑制剂，目前正在开发用于治疗t（11；14）多发性骨髓瘤（MM）的药物。本研究的目的是调查venetoclax的暴露-反应关系，用于1/2期研究，评估Venetoclaz单药治疗或与地塞米松联合治疗复发或难治性MM。共有117名接受300、600、800、900或1200 mg Venetoclay治疗的患者被纳入分析。评估了venetoclax暴露对疗效（客观有效率[ORR]、无进展生存期[PFS]和总生存期[OS]）以及安全性（中性粒细胞减少症、感染和任何级别的严重治疗引发的不良反应的治疗引发不良反应（≥3级））的影响。在t（11；14）阳性亚群中，与PFS和OS的venetoclax暴露关系表明，PFS和OS越长，暴露量越高。此外，临床反应（ORR和≥VGPR率）的逻辑回归分析显示，具有统计学意义（p平均值）且≥3级感染、≥3级中性粒细胞减少症、≥3级别治疗突发不良事件或任何级别的严重治疗突发不良事件。这些发现支持在t（11；14）阳性患者群体中进一步研究每天一次服用800 mg venetoclax与地塞米松的联合用药，观察到疗效增加，但安全性事件没有增加。临床试验：NCT01794520于2013年2月20日注册。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Hematological Oncology 医学-血液学

CiteScore

4.20

自引率

6.10%

发文量

147

审稿时长

>12 weeks

期刊介绍： Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.