MRD dynamics predicts progression and reveals a vulnerable state for immunotherapy interception in multiple myeloma
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.
Article Details
Authors (35)
Carmen González
Camila Guerrero
CIMA, Pamplona, Spain
Marta Larrayoz
Aintzane Zabaleta
Cancer Center Clinica Universidad de Navarra (CCUN), Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), CIBER-ONC number CB16/12/00369, Pamplona, Spain, Pamplona, Spain
Junfei Zhao
Ioannis V Kostopoulos
National and Kapodistrian University of Athens, ATHENS, Greece
Ourania Tsitsilonis
National and Kapodistrian University of Athens, Athens, Greece
Evangelos Terpos
Norma C. Gutierrez
Hospital Universitario de Salamanca. IBSAL. Centro de Investigación del Cáncer, Salamanca, Spain
Manuela Fernandez
Hospital Universitario 12 de Octubre, Madrid, Spain
Maria J José Calasanz
UNIVERSITY OF NAVARRA, Pamplona, Spain
Paula Rodriguez-Otero
Felipe Prosper
Teresa Lozano
Centro de Investigación Médica Aplicada, CIMA, Pamplona, Spain
Juan J Lasarte
Centro de Investigación Médica Aplicada, CIMA, Pamplona, Spain
Benjamin L Ebert
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Albert Oriol
Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona, Spain
Anna Sureda
Institut Català d'Oncologia, Barcelona, Spain
María-Jesús Blanchard
Hospital Ramon y Cajal, madrid, Spain
Yolanda González-Montes
Hospital Josep Trueta, Girona, Spain
Joan Bargay
Hospital Universitario Son LLatzer, Instituto de Investigación Sanitaria Illes Balears (IdISBa),, Palma de Mallorca, Spain
Sunil Lakhwani
Hospital Universitario de Canarias. Universidad de La Laguna., San Cristobal de La Laguna, Tenerife, Spain
Rafael Ríos-Tamayo
Hospital Universitario Virgen de las Nieves, Granada, Spain
Laura Rosiñol
Hospital Clínic de Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona
Joaquín Martínez-López
Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Complutense University of Madrid, Centro Nacional de Investigaciones Oncológicas, Madrid Institute of Cancer, Madrid
Juan-Jose Lahuerta
Instituto de Investigación.Hospital Universitario 12 de Octubre, Madrid, Spain
Joan Bladé
Hospital Clínic i Provincial, Institut de Investicacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
María-Victoria Mateos
Jesus San-Miguel
Maria-Teresa Cedena
Noemi Puig
Patrick Ryan Hagner
Bristol-Myers Squibb, Summit, New Jersey, United States
Maria Ortiz Estevez
Bristol Myers Squibb, Sevilla, Spain
Jose A Martínez-Climent
Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Bruno Paiva