Purple Squirrel Economics, a Cytel Company, Montreal, Canada.
Pfizer Inc., Groton, Connecticut, United States of America.
PLoS One. 2022 May 12;17(5):e0267979. doi: 10.1371/journal.pone.0267979. eCollection 2022.
Progression-free survival (PFS) is a common primary endpoint in newly diagnosed multiple myeloma (NDMM). Patients with NDMM typically have longer PFS and are more likely to achieve minimal residual disease (MRD) or complete response (CR) compared to patients with relapsed or refractory multiple myeloma. Response-based surrogate endpoints may hold value given the longer follow-up time required to evaluate PFS in NDMM. In this work, systematic literature reviews of Medline, Embase, and Cochrane databases (2010-06/2020) and relevant congresses (2018-2020) were performed to identify randomized clinical trials (RCTs) and real-world studies in NDMM reporting median PFS and objective response. Associations between PFS and each response endpoint were evaluated using Pearson's product-moment correlation weighted by sample size in each RCT arm. Unadjusted and adjusted weighted linear regression models were applied to estimate the gain in median PFS associated with each response endpoint. Statistically significant correlations were identified for median PFS with overall response rate (ORR; Pearson r = 0.59), CR (r = 0.48), stringent CR (sCR; r = 0.68), and MRD (r = 0.69). The unadjusted models estimated 0.50 (95% CI: 0.36, 0.64; p<0.001), 0.42 (95% CI: 0.25, 0.58; p<0.001), 1.05 (95% CI: 0.58, 1.52; p<0.001), and 0.35 (95% CI: 0.12, 0.58; p = 0.006) months of median PFS gained per point of ORR, CR, sCR, and MRD, respectively. Associations for median PFS remained statistically significant in models adjusted for age and treatment type with ORR (0.35, 95% CI: 0.21, 0.49; p<0.001), and adjusted for age and International Staging System risk stage with CR (0.29, 95% CI: 0.16, 0.41; p<0.001). Due to small sample size, adjusted models could not be constructed for sCR or MRD. Nevertheless, evidence of significant survival benefit (p<0.05) associated with MRD negativity and sCR was identified across real-world studies. These findings provide support for the use of response outcomes as surrogate endpoints to estimate PFS benefit in NDMM.
无进展生存期（PFS）是新诊断多发性骨髓瘤（NDMM）的常见主要终点。与复发或难治性多发性骨髓瘤患者相比，NDMM 患者的 PFS 通常更长，并且更有可能达到微小残留疾病（MRD）或完全缓解（CR）。鉴于需要更长的随访时间来评估 NDMM 中的 PFS，基于反应的替代终点可能具有价值。在这项工作中，对 Medline、Embase 和 Cochrane 数据库（2010-06/2020）以及相关会议（2018-2020 年）进行了系统的文献综述，以确定报告中位数 PFS 和客观反应的 NDMM 中的随机临床试验（RCT）和真实世界研究。使用每个 RCT 臂中的样本量对 PFS 和每个反应终点之间的相关性进行了 Pearson 积矩相关加权评估。应用未调整和调整后的加权线性回归模型来估计与每个反应终点相关的中位 PFS 获益。无进展生存期与总缓解率（ORR；Pearson r = 0.59）、CR（r = 0.48）、严格 CR（sCR；r = 0.68）和 MRD（r = 0.69）之间存在统计学显著相关性。未调整模型估计 ORR、CR、sCR 和 MRD 每增加 1 分，中位 PFS 分别增加 0.50（95%CI：0.36，0.64；p<0.001）、0.42（95%CI：0.25，0.58；p<0.001）、1.05（95%CI：0.58，1.52；p<0.001）和 0.35（95%CI：0.12，0.58；p = 0.006）个月。在调整年龄和治疗类型后的模型中，与 ORR（0.35，95%CI：0.21，0.49；p<0.001）和调整年龄和国际分期系统风险分期后的 CR（0.29，95%CI：0.16，0.41；p<0.001）的模型中，相关性仍然具有统计学意义。由于样本量小，无法为 sCR 或 MRD 构建调整后的模型。尽管如此，在真实世界研究中，仍发现 MRD 阴性和 sCR 与显著生存获益（p<0.05）相关的证据。这些发现为使用反应结果作为替代终点来估计 NDMM 中的 PFS 获益提供了支持。
