SWIFT-seq enables comprehensive single-cell transcriptomic profiling of circulating tumor cells in multiple myeloma and its precursors

Elizabeth D Lightbody^#^{1

2

3}, Romanos Sklavenitis-Pistofidis^#^{1

2

3}, Ting Wu³, Junko Tsuji³, Danielle T Firer³, Michael P Agius^{1

2

3}, Ankit K Dutta^{1

2

3}, Hadley Barr^{1

2}, Sungjae Kim³, Jean-Baptiste Alberge^{1

2

3}, Sarah Nersesian⁴, Tim Coorens³, Nicholas J Haradhvala³, Nang Kham Su^{1

2

3}, Cody J Boehner^{1

2

3}, Michelle P Aranha^{1

2

3}, Mahshid Rahmat^{1

2

3}, Yoshinobu Konishi^{1

2

3}, Laura Hevenor^{1

2}, Katherine Towle^{1

2}, Erica Horowitz^{1

2}, Jacqueline Perry^{1

2}, Maya Davis^{1

2}, Kelly A Walsh⁵, Christian J Cea-Curry^{1

2}, Grace Fleming^{1

2}, Michael E Vinyard³, Daniel Heilpern-Mallory^{1

2

3}, Habib El-Khoury^{1

2

3}, Annie Cowan^{1

2}, John E Ready^{2

5}, Catherine R Marinac^{1

2

6}, Gad Getz^{7

8

9}, Irene M Ghobrial^{10

11

12

13}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
⁴ Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵ Department of Orthopaedic Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Center for Early Detection and Interception of Blood Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Harvard Medical School, Boston, MA, USA. gadgetz@broadinstitute.org.
⁸ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. gadgetz@broadinstitute.org.
⁹ Krantz Family Center for Cancer Research and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. gadgetz@broadinstitute.org.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹¹ Harvard Medical School, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹² Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹³ Center for Early Detection and Interception of Blood Cancers, Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.

^# Contributed equally.

PMID: 40781193
DOI: 10.1038/s43018-025-01006-0

SWIFT-seq enables comprehensive single-cell transcriptomic profiling of circulating tumor cells in multiple myeloma and its precursors

Elizabeth D Lightbody et al. Nat Cancer. 2025.

. 2025 Aug 8.

doi: 10.1038/s43018-025-01006-0. Online ahead of print.

Authors

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
⁴ Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵ Department of Orthopaedic Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Center for Early Detection and Interception of Blood Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Harvard Medical School, Boston, MA, USA. gadgetz@broadinstitute.org.
⁸ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. gadgetz@broadinstitute.org.
⁹ Krantz Family Center for Cancer Research and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. gadgetz@broadinstitute.org.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹¹ Harvard Medical School, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹² Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹³ Center for Early Detection and Interception of Blood Cancers, Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.

^# Contributed equally.

PMID: 40781193
DOI: 10.1038/s43018-025-01006-0

Abstract

Multiple myeloma is a bone marrow (BM) plasma cell malignancy preceded by precursor conditions. BM biopsies are conducted infrequently and can yield inconclusive results due to technical limitations. Profiling circulating tumor cells (CTCs) may enable noninvasive routine clinical assessments but remains challenging. Here, to address this, we describe a single-cell sequencing workflow to interrogate few tumor cells (SWIFT-seq), and employ single-cell RNA sequencing and B cell receptor sequencing on paired BM and CTCs from 101 patients and healthy donors. We establish a sequencing-based CTC enumeration strategy and develop a CTC classifier to infer cytogenetic abnormalities. Additionally, we leverage expression profiling to measure tumor proliferative index in CTCs, and demonstrate that clonal dynamics can be captured in CTCs. Last, we propose a circulatory dynamics model whereby tumor burden, proliferation, cytogenetics and a circulatory capacity signature influence CTC burden. Overall, SWIFT-seq may advance blood-based myeloma diagnostics, surveillance and prognostication, and reveal biological mechanisms of tumor dissemination.

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Conflict of interest statement

Competing interests: J.T., D.T.F., T.W., M.P. Agius, A.K.D., H.B., S.K., J.-B.A., T.C., S.N., N.K.S., C.J.B., M.P. Aranha, M.R., Y.K., L.H., K.T., E.H., J.P., M.D., K.A.W., C.J.C.-C., G.F., M.E.V., D.H.-M., H.E.-K., A.C., J.E.R. and C.R.M. declare no competing interests. R.S.-P. is a co-founder, equity holder and consultant for PreDICTA Biosciences, a precision oncology company integrating multiomics and liquid biopsies to develop diagnostic and therapeutic products. N.J.H. is a consultant for Constellation Pharmaceuticals. G.G. is an inventor on patent applications filed by the Broad Institute related to MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, MSIDetect and MinumuMM-seq. G.G. receives research funds from IBM, Pharmacyclics and Ultima Genomics, and is a founder of, consultant for and holds privately held equity in Scorpion Therapeutics; he is also a founder of and holds privately held equity in PreDICTA Biosciences. I.M.G. has a consulting or advisory role with AbbVie, Adaptive, Amgen, Aptitude Health, Bristol Myers Squibb, GlaxoSmithKline, Huron Consulting, Janssen, Menarini Silicon Biosystems, Oncopeptides, Pfizer, Sanofi, Sognef, Takeda, The Binding Site and Window Therapeutics; has received speaker fees from Vor Biopharma and Veeva Systems, Inc.; is a co-founder, equity holder and consultant for PreDICTA Biosciences; and her spouse is the CMO and equity holder of Disc Medicine. E.D.L., R.S.-P., G.G. and I.M.G. have submitted a patent application related to this work.

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SWIFT-seq enables comprehensive single-cell transcriptomic profiling of circulating tumor cells in multiple myeloma and its precursors

Affiliations

SWIFT-seq enables comprehensive single-cell transcriptomic profiling of circulating tumor cells in multiple myeloma and its precursors

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Abstract

Conflict of interest statement

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