Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA.
J Clin Oncol. 2011 May 10;29(14):1916-23. doi: 10.1200/JCO.2010.34.0760. Epub 2011 Apr 11.
Despite tangible progress in recent years, substantial therapeutic challenges remain in multiple myeloma (MM), particularly for patients at high risk for early relapse or death and for those with advanced multi-drug resistant disease and refractoriness to currently available combination regimens. Addressing these challenges requires identification of novel classes of anti-MM agents, their incorporation into safe and more effective combination regimens, and development of efficient algorithms to select the most appropriate therapeutic options for the clinical and molecular features of individual patients at a given time during their disease. Ideally, these goals can be facilitated by preclinical identification of the "driver" molecular lesions on which different myeloma subtypes exquisitely depend, and by informative preclinical models simulating the clinical setting(s) in which trials will be conducted. Large prospective studies of patients treated uniformly with contemporary clinical regimens are essential, but there is also a major need for flexibility in studying new regimens in the future. Long-term patient follow-up and integrated annotation of clinical (safety and efficacy) and correlative (molecular, biochemical, etc) data are also critical. Novel molecular profiling techniques will likely identify more clinically and biologically discrete subsets of patients with recurrent, even if infrequent, lesions. This molecular heterogeneity, combined with the increasing numbers of candidate therapeutic targets and respective investigational agents, may pose formidable challenges for the development and implementation of personalized medicine in MM. This review discusses these challenges, as well as potential strategies to address them, with the aim of making significant improvement in the clinical outcome of patients with MM.
尽管近年来取得了明显的进展，但多发性骨髓瘤（MM）仍然存在重大的治疗挑战，特别是对于那些早期复发或死亡风险高、患有晚期多药耐药疾病和对现有联合治疗方案耐药的患者。为了应对这些挑战，需要确定新型抗 MM 药物，将其纳入安全且更有效的联合治疗方案，并制定有效的算法，根据患者疾病特定时间的临床和分子特征，为每位患者选择最合适的治疗方案。理想情况下，这些目标可以通过在不同骨髓瘤亚型高度依赖的“驱动”分子病变的临床前识别来实现，并通过模拟临床试验将进行的临床环境的信息性临床前模型来实现。对使用当代临床方案进行统一治疗的患者进行大型前瞻性研究至关重要，但未来研究新方案也需要灵活性。长期随访患者并对临床（安全性和疗效）和相关（分子、生化等）数据进行综合注释也至关重要。新的分子分析技术可能会识别出更多具有复发性、即使是罕见病变的临床和生物学上更为离散的患者亚群。这种分子异质性，加上越来越多的候选治疗靶点和相应的研究药物，可能会给 MM 中个性化医疗的发展和实施带来巨大挑战。本文讨论了这些挑战，以及解决这些挑战的潜在策略，以期显著改善 MM 患者的临床结局。
