Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma
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 f...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56486-6 |
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| author | 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 David M. Kurtz |
| author_facet | 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 David M. Kurtz |
| author_sort | Hitomi Hosoya |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-be35e91ab7aa4c96bd05e00d032968c4 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-be35e91ab7aa4c96bd05e00d032968c42025-08-20T02:15:08ZengNature PortfolioNature Communications2041-17232025-02-0116111310.1038/s41467-025-56486-6Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myelomaHitomi Hosoya0Mia Carleton1Kailee Tanaka2Brian Sworder3Shriya Syal4Bita Sahaf5Alisha M. Maltos6Oscar Silva7Henning Stehr8Vanna Hovanky9George Duran10Tian Zhang11Michaela Liedtke12Sally Arai13David Iberri14David Miklos15Michael S. Khodadoust16Surbhi Sidana17David M. Kurtz18Division of Blood and Marrow Transplant and Cell Therapy, Department of Medicine, Stanford UniversityDivision of Oncology, Department of Medicine, Stanford UniversityDivision of Oncology, Department of Medicine, Stanford UniversityDivision of Hematology/Oncology, Department of Medicine, University of CaliforniaCenter for Cell Therapy, Stanford Cancer Institute, Stanford UniversityCenter for Cell Therapy, Stanford Cancer Institute, Stanford UniversityDepartment of Pathology, Stanford UniversityDepartment of Pathology, Stanford UniversityDepartment of Pathology, Stanford UniversityDivision of Blood and Marrow Transplant and Cell Therapy, Department of Medicine, Stanford UniversityDivision of Oncology, Department of Medicine, Stanford UniversityDivision of Hematology, Department of Medicine, Stanford UniversityDivision of Hematology, Department of Medicine, Stanford UniversityDivision of Blood and Marrow Transplant and Cell Therapy, Department of Medicine, Stanford UniversityDivision of Hematology, Department of Medicine, Stanford UniversityDivision of Blood and Marrow Transplant and Cell Therapy, Department of Medicine, Stanford UniversityDivision of Oncology, Department of Medicine, Stanford UniversityDivision of Blood and Marrow Transplant and Cell Therapy, Department of Medicine, Stanford UniversityDivision of Oncology, Department of Medicine, Stanford UniversityAbstract 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.https://doi.org/10.1038/s41467-025-56486-6 |
| spellingShingle | 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 David M. Kurtz Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma Nature Communications |
| title | Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma |
| title_full | Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma |
| title_fullStr | Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma |
| title_full_unstemmed | Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma |
| title_short | Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma |
| title_sort | deciphering response dynamics and treatment resistance from circulating tumor dna after car t cells in multiple myeloma |
| url | https://doi.org/10.1038/s41467-025-56486-6 |
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