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

Jul 24, 2026 | Magazine: Blood

Carmen Gonzalez 1, Camila Guerrero 2, Marta Larrayoz 2, Aintzane Zabaleta 3, Junfei Zhao 4, Ioannis V Kostopoulos 5, Ourania Tsitsilonis 6, Evangelos Terpos 7, Norma C Gutierrez 8, Manuela Fernandez 9, Maria J José Calasanz 10, Paula Rodriguez-Otero 11, Felipe Prosper 12, Teresa Lozano 13, Juan J Lasarte 13, Benjamin L Ebert 14, Albert Oriol 15, Anna Sureda 16, María-Jesús Blanchard 17, Yolanda González-Montes 18, Joan Bargay 19, Sunil Lakhwani 20, Rafael Ríos-Tamayo 21, Laura Rosiñol 22, Joaquín Martínez-López 23, Juan-Jose Lahuerta 24, Joan Bladé 25, Maria-Victoria Mateos 26, Jesús San-Miguel 27, Maria-Teresa Cedena 9, Noemí Puig 28, Patrick Ryan Hagner 4, Maria Ortiz Estevez 29, Jose A Martínez-Climent 30, Bruno Paiva 31

Abstract

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 investigating if MRD interception with anti-BCMA CAR-T cells could improve outcomes. Infusion at MRD resistance prolonged mouse survival compared to identical treatment at relapse. Altogether, MRD dynamics is the strongest predictor of progression and may help tailoring treatment to prevent additional tumor and immune alterations prior to relapse.

CITA DEL ARTÍCULO Blood. 2026 Jul 24:blood.2026033878. doi: 10.1182/blood.2026033878. Online ahead of print.

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