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

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.

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Publication Details

Journal
Blood
Published
2026-07-24
DOI
https://doi.org/10.1182/blood.2026033878
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
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article

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

José A. Martínez-Climent, Yolanda González‐Montes, Marta Larráyoz, Laura Rosiñol et al.
Blood
Multiple Myeloma Research and Treatments
article

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

José A. Martínez-Climent, Yolanda González‐Montes, Marta Larráyoz, Laura Rosiñol, Felipe Prósper, Patrick R. Hagner, Juan José Lahuerta, Jesús F. San Miguel, Junfei Zhao, María‐Victoria Mateos, Joaquín Martínez‐López, Ioannis V. Kostopoulos, Joan Bargay, Evangelos Terpos, Sunil Lakhwani, María‐Teresa Cedena, Noemí Puig, Norma C. Gutiérrez, Albert Oriol, Teresa Lozano, Bruno Paiva, María Ortiz Estévez, Benjamin L. Ebert, Anna Sureda, Juan José Lasarte, Paula Rodríguez‐Otero, Aintzane Zabaleta, Marı́a José Calasanz, Rafael Ríos, Carmen González, Manuela Fernández, O Tsitsilonis, Camila Guerrero, Joan Bladé, María-Jesús Blanchard
article en

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.

Blood
Universidad de La Laguna (ES), Universidad de Salamanca (ES), National and Kapodistrian University of Athens (GR), Hospital Universitario de Canarias (ES), Research Institute Hospital 12 de Octubre (ES), Hospital Son Llatzer (ES), Bristol-Myers Squibb (United States) (US), Hospital Universitario 12 De Octubre (ES), Institut Català d'Oncologia (ES), Navarre Institute of Health Research (ES), Hospital Clínic de Barcelona (ES), Hospital Universitario Virgen de las Nieves (ES), Dana-Farber Cancer Institute (US), Health Research Institute of the Balearic Islands (ES), Instituto de Investigación Biomédica de Salamanca (ES), Clinica Universidad de Navarra (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Centro de Investigación del Cáncer (ES), Hospital Universitari de Girona Doctor Josep Trueta (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Hospital Universitario Ramón y Cajal (ES), Universidad de Navarra (ES), Chartered Institute of Management Accountants (GB)
Openalex Percentile: Top 9%
Multiple Myeloma Research and Treatments
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