Nadeem Omar, Aranha Michelle P, Redd Robert, Timonian Michael, Magidson Sophie, Lightbody Elizabeth D, Alberge Jean-Baptiste, Bertamini Luca, Dutta Ankit K, El-Khoury Habib, Bustoros Mark, Laubach Jacob P, Bianchi Giada, O'Donnell Elizabeth, Wu Ting, Tsuji Junko, Anderson Kenneth C, Getz Gad, Trippa Lorenzo, Richardson Paul G, Sklavenitis-Pistofidis Romanos, Ghobrial Irene M
Center for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Nat Commun. 2025 Jan 3;16(1):358. doi: 10.1038/s41467-024-55308-5.
Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7-NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9-NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p = 0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+ T cells within clonally expanded CD8+ T cells associated with suboptimal outcomes.
早期对高危冒烟型多发性骨髓瘤（HR-SMM）进行治疗干预已显示出益处，然而，尚无研究评估生化进展或缓解深度是否能预测长期预后。单臂I-PRISM II期试验（NCT02916771）对55例HR-SMM患者使用了伊沙佐米、来那度胺和地塞米松进行评估。主要终点，即无进展生存期（PFS）的中位数未达到（NR）（95%CI：57.7 - NR，中位随访50个月）。次要终点，即生化无进展生存期为48.6个月（95%CI：39.9 - NR），并且在8例患者中与SLiM-CRAB同时出现或先于其出现。对于其他次要目标，总体缓解率为93%，其中31%达到完全缓解（CR），45%达到非常好的部分缓解（VGPR）或更好。CR与无SLiM-CRAB和生化进展密切相关。微小残留病阴性（灵敏度为10）预测5年生化无进展生存期在微小残留病阳性患者中为100%，而在微小残留病阳性患者中为40%（p = 0.051），表明深度缓解显著改善疾病进展时间。探索性单细胞RNA测序将肿瘤MHC I类表达与蛋白酶体抑制剂反应联系起来，并且在克隆性扩增的CD8 + T细胞中较低比例的GZMB + T细胞与欠佳的预后相关。
