Chung Clement
Lyndon Baines Johnson Hospital, Houston, Texas.
Pharmacotherapy. 2017 Jan;37(1):129-143. doi: 10.1002/phar.1871. Epub 2017 Jan 6.
Multiple myeloma (referred to henceforth as myeloma) is a B-cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor. Accordingly, a need exists for new therapeutic avenues that can overcome resistance to current therapies and improve survival outcomes. In addition, myeloma is associated with progressive immune dysregulation, with defects in T-cell immunity, natural killer cell function, and the antigen-presenting capacity of dendritic cells, resulting in a tumor microenvironment that promotes disease tolerance and progression. Together, the immunosuppressive microenvironment and oncogenic mutations activate signaling networks that promote myeloma cell survival. Immunotherapy incorporates novel treatment options (e.g., monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, bispecific antibodies, and tumor vaccines) either alone or in combination with existing lines of therapies (e.g., immunomodulatory agents, proteasome inhibitors, and histone deacetylase inhibitors) to enhance the host anti myeloma immunity within the bone marrow microenvironment and improve clinical response. Following the U.S. Food and Drug Administration approval of daratumumab and elotuzumab in 2015, more immunotherapeutic agents are expected to be become available as valuable treatment options in the near future. This review provides a basic understanding of the role of immunotherapy in modulating the bone marrow tumor microenvironment and its role in the treatment of myeloma. Clinical efficacy and safety of recently approved therapeutic monoclonal antibodies (daratumumab, elotuzumab) are discussed, along with the therapeutic potential of emerging immunotherapies (antibody-drug conjugates, chimeric antigen receptor T-cell therapy, tumor vaccines, and immune checkpoint inhibitors).
多发性骨髓瘤（以下简称骨髓瘤）是一种B细胞恶性肿瘤，其特征是骨髓中浆细胞不受控制地生长。在过去十年中，骨髓瘤的治疗模式发生了重大演变，这得益于对该疾病发病机制的深入了解以及靶向肿瘤细胞及其微环境的治疗药物的开发。尽管有这些治疗进展，但复发或难治性骨髓瘤患者的预后仍然很差。因此，需要新的治疗途径来克服对现有疗法的耐药性并改善生存结果。此外，骨髓瘤与进行性免疫失调有关，存在T细胞免疫、自然杀伤细胞功能和树突状细胞抗原呈递能力缺陷，导致促进疾病耐受和进展的肿瘤微环境。免疫抑制微环境和致癌突变共同激活促进骨髓瘤细胞存活的信号网络。免疫疗法采用新型治疗方案（例如单克隆抗体、抗体药物偶联物、嵌合抗原受体T细胞疗法、免疫检查点抑制剂、双特异性抗体和肿瘤疫苗）单独或与现有治疗方案（例如免疫调节剂、蛋白酶体抑制剂和组蛋白脱乙酰酶抑制剂）联合使用，以增强骨髓微环境中的宿主抗骨髓瘤免疫力并改善临床反应。继美国食品药品监督管理局于2015年批准达雷妥尤单抗和埃罗妥珠单抗之后，预计在不久的将来会有更多免疫治疗药物成为有价值的治疗选择。本综述提供了对免疫疗法在调节骨髓肿瘤微环境中的作用及其在骨髓瘤治疗中的作用的基本理解。讨论了最近批准的治疗性单克隆抗体（达雷妥尤单抗、埃罗妥珠单抗）的临床疗效和安全性，以及新兴免疫疗法（抗体药物偶联物、嵌合抗原受体T细胞疗法、肿瘤疫苗和免疫检查点抑制剂） 的治疗潜力。
