Unité de Génomique du Myélome, University of Toulouse, Toulouse, France.
Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
Clin Lymphoma Myeloma Leuk. 2020 Jan;20(1):e30-e37. doi: 10.1016/j.clml.2019.09.622. Epub 2019 Oct 9.
Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM).
We searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for "myeloma," "minimal residual disease," and "clinical trial." Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia. For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive.
Six randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy.
These results support the claim that MRD status can be used as a surrogate for PFS in NDMM.
多发性骨髓瘤患者的生存时间因治疗进展而大大延长，因此当使用生存结果作为主要终点时，需要进行越来越长的试验。能够更快速预测生存的替代终点可能会加速药物开发。我们进行了一项荟萃分析，以评估新发多发性骨髓瘤（NDMM）患者的微小残留病（MRD）状态是否为有效的无进展生存期（PFS）替代终点。
我们在 PubMed、美国血液学会和欧洲血液学会的摘要中搜索了“骨髓瘤”、“微小残留病”和“临床试验”。由于需要评估治疗对 MRD 反应的影响，仅纳入了针对 NDMM 受试者的随机研究。需要详细了解接受 MRD 检测的人群。荟萃分析按照 2013 年美国食品和药物管理局关于急性髓系白血病 MRD 的研讨会概述的原则进行。对于未进行 MRD 检测且在指定的 MRD 评估亚组内的样本，从具有已知 MRD 状态的样本中推断出其 MRD 状态。未计划进行 MRD 评估的患者被认为是 MRD 阳性。
六项随机研究，共 3283 名患者和 2208 份 MRD 样本，符合分析纳入标准。MRD 阴性率范围为 0.06 至 0.70。MRD 阴性反应的治疗效果与 PFS 的风险比呈强相关性，加权回归线的决定系数为 0.97。我们的荟萃分析表明，MRD 状态同时符合 PFS 替代终点的 Prentice 标准。
这些结果支持 MRD 状态可作为 NDMM 中 PFS 替代终点的说法。
