Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma

Hitomi Hosoya, Mia Carleton, Kailee Tanaka, Brian Sworder, Shriya Syal, Bita Sahaf, Alisha M. Maltos, Oscar Silva, Henning Stehr, Vanna Hovanky, George Duran, Tian Zhang, Michaela Liedtke, Sally Arai, David Iberri, David Miklos, Michael S. Khodadoust, Surbhi Sidana () and David M. Kurtz ()
Additional contact information
Hitomi Hosoya: Stanford University
Mia Carleton: Stanford University
Kailee Tanaka: Stanford University
Brian Sworder: University of California
Shriya Syal: Stanford University
Bita Sahaf: Stanford University
Alisha M. Maltos: Stanford University
Oscar Silva: Stanford University
Henning Stehr: Stanford University
Vanna Hovanky: Stanford University
George Duran: Stanford University
Tian Zhang: Stanford University
Michaela Liedtke: Stanford University
Sally Arai: Stanford University
David Iberri: Stanford University
David Miklos: Stanford University
Michael S. Khodadoust: Stanford University
Surbhi Sidana: Stanford University
David M. Kurtz: Stanford University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Despite advances in treatments, multiple myeloma (MM) remains an incurable cancer where relapse is common. We developed a circulating tumor DNA (ctDNA) approach in order to characterize tumor genomics, monitor treatment response, and detect early relapse in MM. By sequencing 412 specimens from 64 patients with newly diagnosed or relapsed/refractory disease, we demonstrate the correlation between ctDNA and key clinical biomarkers, as well as patient outcomes. We further extend our approach to simultaneously track CAR-specific cell-free DNA (CAR-cfDNA) in patients undergoing anti-BCMA CAR T-cell (BCMA-CAR) therapy. We demonstrate that ctDNA levels following BCMA-CAR inversely correlate with relative time to progression (TTP), and that measurable residual disease (MRD) quantified by peripheral blood ctDNA (ctDNA-MRD) was concordant with clinical bone marrow MRD. Finally, we show that ctDNA-MRD can anticipate clinical relapse and identify the emergence of genomically-defined therapy-resistant clones. These findings suggest multiple clinical uses of ctDNA for MM in molecular characterization and disease surveillance.

Date: 2025
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DOI: 10.1038/s41467-025-56486-6

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