Gupta Vikas A, Ackley James, Kaufman Jonathan L, Boise Lawrence H
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA, USA.
Cancer Biology Graduate Program, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA, USA.
Blood Lymphat Cancer. 2021 Mar 12;11:11-24. doi: 10.2147/BLCTT.S245191. eCollection 2021.
Although much progress has been made in the treatment of multiple myeloma, the majority of patients fail to be cured and require numerous lines of therapy. Inhibitors of the BCL2 family represent an exciting new class of drugs with a novel mechanism of action that are likely to have activity as single agents and in combination with existing myeloma therapies. The BCL2 proteins are oncogenes that promote cell survival and are frequently upregulated in multiple myeloma, making them attractive targets. Venetoclax, a BCL2 specific inhibitor, is furthest along in development and has shown promising results in a subset of myeloma characterized by the t(11;14) translocation. Combining venetoclax with proteasome inhibitors and monoclonal antibodies has improved responses in a broader group of patients, but has come at the expense of a toxicity safety signal that requires additional follow-up. MCL1 inhibitors are likely to be effective in a broader range of patients and are currently in early clinical trials. This review will cover much of what is known about the biology of these drugs, biomarkers that predict response, mechanisms of resistance, and unanswered questions as they pertain to multiple myeloma.
尽管在多发性骨髓瘤的治疗方面已经取得了很大进展，但大多数患者仍无法治愈，需要接受多线治疗。BCL2家族抑制剂代表了一类令人兴奋的新型药物，其作用机制新颖，可能作为单一药物或与现有骨髓瘤疗法联合使用时具有活性。BCL2蛋白是促进细胞存活的癌基因，在多发性骨髓瘤中经常上调，使其成为有吸引力的靶点。维奈克拉是一种BCL2特异性抑制剂，在研发方面进展最为领先，并且在以t(11;14)易位为特征的一部分骨髓瘤患者中显示出了有前景的结果。将维奈克拉与蛋白酶体抑制剂和单克隆抗体联合使用，在更广泛的患者群体中改善了疗效，但代价是出现了毒性安全信号，这需要进一步随访。MCL1抑制剂可能在更广泛的患者群体中有效，目前正处于早期临床试验阶段。本综述将涵盖关于这些药物的生物学特性、预测反应的生物标志物、耐药机制以及与多发性骨髓瘤相关的未解决问题等诸多已知内容。
