{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T08:42:04Z","timestamp":1794559324904,"version":"4.9.1"},"reference-count":71,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,11,14]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor, even in the era of novel immunotherapies. Here, we applied spatial transcriptomics (RNA tomography for spatially resolved transcriptomics [tomo-seq] [n\u00a0=\u00a02] and 10x Visium [n\u00a0=\u00a012]) and single-cell RNA sequencing (n\u00a0=\u00a03) to a set of 14 EMD biopsies to dissect the 3-dimensional architecture of tumor cells and their microenvironment. Overall, infiltrating immune and stromal cells showed both intrapatient and interpatient variations, with no uniform distribution over the lesion. We observed substantial heterogeneity at the copy number level within plasma cells, including the emergence of new subclones in circumscribed areas of the tumor, which is consistent with genomic instability. We further identified the spatial expression differences between GPRC5D and TNFRSF17, 2 important antigens for bispecific antibody therapy. EMD masses were infiltrated by various immune cells, including T cells. Notably, exhausted TIM3+\/PD-1+ T cells diffusely colocalized with MM cells, whereas functional and activated CD8+ T cells showed a focal infiltration pattern along with M1 macrophages in tumor-free regions. This segregation of fit and exhausted T cells was resolved in the case of response to T-cell\u2013engaging bispecific antibodies. MM and microenvironment cells were embedded in a complex network that influenced immune activation and angiogenesis, and oxidative phosphorylation represented the major metabolic program within EMD lesions. In summary, spatial transcriptomics has revealed a multicellular ecosystem in EMD with checkpoint inhibition and dual targeting as potential new therapeutic avenues.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024024590","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T18:22:48Z","timestamp":1724350968000},"page":"2121-2135","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":75,"title":["Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma"],"prefix":"10.1182","volume":"144","author":[{"given":"Mara","family":"John","sequence":"first","affiliation":[{"name":"1Mildred Scheel Early Career Center, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9561-1669","authenticated-orcid":false,"given":"Moutaz","family":"Helal","sequence":"additional","affiliation":[{"name":"1Mildred Scheel Early Career Center, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Duell","sequence":"additional","affiliation":[{"name":"2Department of Internal Medicine II, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2208-7017","authenticated-orcid":false,"given":"Greta","family":"Mattavelli","sequence":"additional","affiliation":[{"name":"1Mildred Scheel Early Career Center, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Stanojkovska","sequence":"additional","affiliation":[{"name":"1Mildred Scheel Early Career Center, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazia","family":"Afrin","sequence":"additional","affiliation":[{"name":"1Mildred Scheel Early Career Center, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-3276","authenticated-orcid":false,"given":"Alexander M.","family":"Leipold","sequence":"additional","affiliation":[{"name":"3Helmholtz Institute for RNA-based Infection Research, Helmholtz-Center for Infection Research, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian J.","family":"Steinhardt","sequence":"additional","affiliation":[{"name":"2Department of Internal Medicine II, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"2Department of Internal Medicine II, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"\u017dihala","sequence":"additional","affiliation":[{"name":"4Department of Hematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic"},{"name":"5Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjana","family":"Anilkumar Sithara","sequence":"additional","affiliation":[{"name":"4Department of Hematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic"},{"name":"5Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marietta","family":"Truger","sequence":"additional","affiliation":[{"name":"6Munich Leukemia Laboratory, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf A.","family":"Werner","sequence":"additional","affiliation":[{"name":"7Department of Nuclear Medicine, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"8Department of Nuclear Medicine, Clinic for Radiology and Nuclear Medicine, University Hospital, Goethe University Frankfurt, Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Haferlach","sequence":"additional","affiliation":[{"name":"6Munich Leukemia Laboratory, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Einsele","sequence":"additional","affiliation":[{"name":"2Department of Internal Medicine II, University Hospital W\u00fcrzburg, W\u00fcrzburg, 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