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Cited by 25Multiple Myeloma Research and TreatmentsBone Tumor Diagnosis and TreatmentsCancer Immunotherapy and Biomarkers

Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma

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Lutz, Raphael, Poos, Alexandra M., Solé-Boldo, Llorenç, John, Lukas, Wagner, Johanna, Prokoph, Nina, Baertsch, Marc A., Vonficht, Dominik +27 more·2025·Science Immunology
DOI 10.1126/sciimmunol.adp6667PMC PMC7619224
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Abstract

The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow–confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.

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  • Data from mice suggest that environmental factors clearly accelerate tumor expansion and development.

    “data from mice suggest that environmental factors clearly accelerate tumor expansion and development.94”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [94]

    The Introduction (page unavailable) says preclinical models support a critical role for the tumor microenvironment in myeloma’s extramedullary spread, and the Discussion says the bone marrow microenvironment is pivotal in myeloma development and progression. These passages support an environmental role, but they do not identify the models as mice or show that environmental factors accelerate tumor expansion. (LLM, conf=0.83)

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References 78 · Cited by 25

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Authors
Lutz, R., Poos, A. M., Solé-Boldo, L., John, L., Wagner, J., Prokoph, N., Baertsch, M. A., Vonficht, D., Palit, S., Brobeil, A., Mechtersheimer, G., Hildenbrand, N., Hemmer, S., Steiger, S., Horn, S., Pepke, W., Spranz, D. M., Rehnitz, C., Sant, P., Mallm, J.-P., Friedrich, M. J., Reichert, P., Huhn, S., Trumpp, A., Rippe, K., Haghverdi, L., Fröhling, S., Müller-Tidow, C., Hübschmann, D., Goldschmidt, H., Willimsky, G., Sauer, S., Raab, M. S., Haas, S., & Weinhold, N.
Affiliations
  • German Cancer Research Center (DE)
  • Berlin Institute of Health (BIH) at Charité Universitätsmedizin Berlin, Berlin, Germany.
  • Max Delbrück Center (DE)
  • Heidelberg University (DE)
  • Humboldt-Universität zu Berlin (DE)
  • National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • Queen Mary University of London (GB)
Corresponding author
  • Lutz, Raphael
  • Poos, Alexandra M.
  • John, Lukas
  • Haas, Simon
  • Weinhold, Niels
ORCID
Venue
Science Immunology
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-02-28
Volume
10
Issue
104
Pages
eadp6667-eadp6667
ISSN
2470-9468 (ISSN-L)
DOI
10.1126/sciimmunol.adp6667
PMC
PMC7619224
OpenAlex
W4407263638
Cited by
25
References
78
Citations by year
2026: 11 · 2025: 14
FWCI
18.36
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
multiple myeloma, bone marrow microenvironment, tumor-immune cell interactions, natural killer cells, macrophages, T cell clones, tumor genomic evolution, cortical bone, tumor microenvironment
MeSH terms
Animals, Bone Marrow, Humans, Killer Cells, Natural, Macrophages, Multiple Myeloma, Plasma Cells, Single-Cell Analysis, Tumor Microenvironment

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