Abstract
Multiple myeloma (MM) is associated with skewed T cell activation and function which is present in asymptomatic myeloma precursor conditions, but underlying mechanisms of progression remain undefined. Here, we assemble a large single-cell RNA sequencing dataset of the bone marrow and blood from patients with MM, precursor conditions, and non-cancer controls. We demonstrate that, unlike solid cancers, MM is not characterized by T cell exhaustion, but by antigen-driven terminal memory differentiation. This is influenced by tumour-intrinsic features including tumour burden and expression of antigen-presentation genes. Expanded TCR clones accumulating in MM are not enriched with viral specificities but accumulate in effector states in highly-infiltrated marrows. Additionally, we identify a role for T cell dynamics in patients treated with autologous stem cell transplantation and demonstrate T cell features predict progression from precursor to symptomatic MM. Together, these results suggest that anti-tumour immunity drives a distinctive form of cancer-associated T cell differentiation in MM.
Data availability
The unprocessed sequencing data have been deposited in the Sequence Read Archive under the accession PRJNA1401834. The processed single-cell RNA and TCR data (CellRanger outputs) have been deposited in the Zenodo repository under the accession 13171648. The full integrated single-cell RNA and TCR datasets and cohort information have been deposited in the Zenodo repository under the accession 17418275. All data are included in the Supplementary Information or available from the authors, as are unique reagents used in this Article. The raw numbers for charts and graphs are available in the Source Data file whenever possible. Source data are provided with this paper.
Code availability
The code to reproduce the analysis has been deposited on GitHub under the accession kanefos/myeloma-singlecell.
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Acknowledgements
This research was funded by Cancer Research UK Early Detection and Diagnosis Programme award No. C9203/A28770). E.M.B is supported by the Wellcome Trust, A.L is supported by Myeloma UK. This work was funded in part by the University College London/UCL Hospitals Biomedical Research Centre. We thank members of the CARDAMON, COSMOS and RADAR teams, the UCL Cancer Trials Centre, the Leeds Clinical Trials Research Unit, and all patients who participated in these studies. We thank the Multiple Myeloma Research Foundation (MMRF), the Perelman Family Foundation, and the International Myeloma Society.
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Conceptualisation: B.C., S.A.Q., and K.L.Y. Methodology: E.R., L.A., A.L., E.M.B., L.L., G.W., D.G.F., E.F., A.M., E.J.L., D.J., J.R., M.T., D.M., C.G.K., I.U., G.B., Y.H., C.Z., I.W., and M.C. Investigation: K.A.F. Funding acquisition: L.L., K.R., B.C., S.A.Q., and K.L.Y. Project administration: B.C., S.A.Q., and K.L.Y. Supervision: E.M.B., J.L.R., J.H., B.C., S.A.Q., and K.L.Y. Writing—original draft: K.A.F. Writing—review and editing: K.A.F., E.R., L.A., A.L., E.M.B., L.L., B.C., S.A.Q., and K.L.Y.
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Nature Communications thanks P. Leif Bergsagel, Arun Wiita, who co-reviewed with Bonell Patiño-Escobar, and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Foster, K.A., Rees, E., Ainley, L. et al. Tumour-intrinsic features shape T cell differentiation through precursor to symptomatic multiple myeloma. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68718-4
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DOI: https://doi.org/10.1038/s41467-026-68718-4
