MRD dynamics predicts progression and reveals a vulnerable state for immunotherapy interception in multiple myeloma

作者：Carmen González, Camila Guerrero, Marta Larráyoz, Aintzane Zabaleta, Junfei Zhao, Ioannis V. Kostopoulos, O Tsitsilonis, Evangelos Terpos, Norma C. Gutiérrez, Manuela Fernández, Marı́a José Calasanz, Paula Rodríguez‐Otero, Felipe Prósper, Teresa Lozano, Juan José Lasarte, Benjamin L. Ebert, Albert Oriol, Anna Sureda, María-Jesús Blanchard, Yolanda González‐Montes, Joan Bargay, Sunil Lakhwani, Rafael Ríos, Laura Rosiñol, Joaquín Martínez‐López, Juan José Lahuerta, Joan Bladé, María‐Victoria Mateos, Jesús F. San Miguel, María‐Teresa Cedena, Noemí Puig, Patrick R. Hagner, María Ortiz Estévez, José A. Martinez‐Climent, Bruno Paiva · 发表于：Blood · 年份：2026 · DOI：10.1182/blood.2026033878 · 研究领域：Multiple Myeloma Research and Treatments、Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research

The clinical significance of one or two measurable residual disease (MRD) assessments is established in multiple myeloma (MM). However, how to stratify patients according to ≥3 MRD assessments remains unknown. The traits of MRD resistance and if treatment of persistent MRD vs relapse could improve outcomes also remains unknown. MRD dynamics were computed using next-generation flow cytometry and Connector in 539 newly-diagnosed MM patients with ≥3 assessments in the GEM2012MENOS65/GEM2014MAIN and GEM2017FIT trials. Molecular and immune profiling were performed in matched diagnostic and MRD samples. The survival impact of treating persistent MRD vs relapse was investigated with anti-BCMA CAR T cells in MIcγ1huCRBN mice. Computed MRD dynamics based on 3,610 MRD assessments identified five subgroups with different survival. Patients with late-sustained MRD response had excellent outcomes, similar to those with early-sustained MRD response. Patients with volatile results and those with primarily and resurgent MRD resistance had dismal survival. MRD dynamics outperformed transplant-eligibility and the R-ISS. These results were validated in 249 MM patients treated in routine practice. Multiomics characterization of MRD dynamics in patients and mouse models of MRD resistance revealed genomic evolution, transcriptional adaption and a pro-inflammatory tumor-immune microenvironment. Increasing clonality and exhaustion of endogenous T cells throughout disease progression urged investigat...