Diamantidis Michael D, Papadaki Sofia, Hatjiharissi Evdoxia
Thalassemia and Sickle Cell Disease Unit, Department of Hematology, General Hospital of Larissa, Larissa, Greece.
Division of Hematology, First Department of Internal Medicine, AHEPA General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Front Oncol. 2022 Aug 2;12:934008. doi: 10.3389/fonc.2022.934008. eCollection 2022.
Multiple myeloma (MM) is a genetically complex disease. The key myeloma-initiating genetic events are hyperdiploidy and translocations involving the immunoglobulin heavy chain (IgH) enhancer on chromosome 14, which leads to the activation of oncogenes (e.g., CCND1, CCND3, MAF, and MMSET). The t(11;14) translocation is the most common in MM (15%-20%) and results in cyclin D1 (CCND1) upregulation, which leads to kinase activation and tumor cell proliferation. Notably, t(11;14) occurs at a higher rate in patients with plasma cell leukemia (40%) and light chain amyloidosis (50%). Patients with myeloma who harbor the t(11;14) translocation have high levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2). Multiple studies demonstrated that the presence of t(11;14) was predictive of BCL2 dependency, suggesting that BCL2 could be a target in this subtype of myeloma. Venetoclax, an oral BCL2 inhibitor, has shown remarkable activity in treating relapsed/refractory MM patients with t(11;14) and BCL2 overexpression, either as monotherapy or in combination with other anti-myeloma agents. In this review, we describe the molecular defects associated with the t(11;14), bring into question the standard cytogenetic risk of myeloma patients harboring t(11;14), summarize current efficacy and safety data of targeted venetoclax-based therapies, and discuss the future of individualized or precision medicine for this unique myeloma subgroup, which will guide optimal treatment.
多发性骨髓瘤（MM）是一种基因复杂的疾病。关键的骨髓瘤起始基因事件是超二倍体和涉及14号染色体上免疫球蛋白重链（IgH）增强子的易位，这会导致癌基因（如CCND1、CCND3、MAF和MMSET）的激活。t(11;14)易位在MM中最为常见（15%-20%），会导致细胞周期蛋白D1（CCND1）上调，进而导致激酶激活和肿瘤细胞增殖。值得注意的是，t(11;14)在浆细胞白血病患者（40%）和轻链淀粉样变性患者（50%）中发生率更高。携带t(11;14)易位的骨髓瘤患者抗凋亡蛋白B细胞淋巴瘤2（BCL2）水平较高。多项研究表明，t(11;14)的存在预示着对BCL2的依赖性，这表明BCL2可能是这种骨髓瘤亚型的一个靶点。维奈克拉是一种口服BCL2抑制剂，无论是作为单一疗法还是与其他抗骨髓瘤药物联合使用，在治疗复发/难治性且伴有t(11;14)和BCL2过表达的MM患者方面均显示出显著活性。在本综述中，我们描述了与t(11;14)相关的分子缺陷，对携带t(11;14)的骨髓瘤患者的标准细胞遗传学风险提出质疑，总结基于维奈克拉的靶向治疗的当前疗效和安全性数据，并讨论针对这一独特骨髓瘤亚组的个体化或精准医学的未来发展，这将指导优化治疗。
