{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:00:01Z","timestamp":1790830801920,"version":"4.1.0"},"reference-count":108,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Multiple myeloma (MM) is increasingly understood as a spatially organized and dynamically evolving disease, in which malignant plasma-cell behavior is shaped by local immune, stromal, vascular, and metabolic contexts. Single-cell, spatial, and multi-omic technologies have resolved tumor-cell heterogeneity, bone marrow niche remodeling, immune dysfunction, and therapy-induced selection at unprecedented resolution, yet an integrated synthesis linking marrow architecture, extramedullary dissemination, circulating tumor cells, metabolic reprogramming, chimeric antigen receptor T (CAR-T) cell and T-cell-redirecting immunotherapy, and stem-cell transplantation remains lacking. Here, we review how malignant subclones occupy distinct marrow regions, focal lesions, and extramedullary sites with different transcriptional, antigenic, immune-interactive, and metabolic states. We discuss how spatial transcriptomics and multiplexed imaging reveal immune exclusion, stromal support, oxidative and glycolytic niches, and region-specific antigen heterogeneity. We further examine how circulating tumor cells serve as liquid readouts of tumor burden, high-risk genomics, and clonal evolution. Emphasis is placed on CAR T-cell and T-cell engager therapies, where response and resistance depend on antigen retention, effector-cell fitness, clonal T-cell expansion, myeloid suppression, and spatial accessibility. Finally, we consider autologous hematopoietic stem-cell transplantation as a clinical model of cytoreduction, lymphodepletion, and incomplete immune reconstitution. We propose that MM progression and relapse should be interpreted through an integrated spatial-temporal framework, in which therapeutic outcome reflects the interaction between malignant plasma-cell plasticity, immune competence, stromal persistence, metabolic adaptation, and residual disease localization.<\/jats:p>","DOI":"10.3390\/cancers18193158","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:33:12Z","timestamp":1790699592000},"page":"3158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-Cell and Multi-Omics Profiling of the Multiple Myeloma Immune Niche: From Bone Marrow Architecture and Metabolic Reprogramming to Immunotherapy Response"],"prefix":"10.3390","volume":"18","author":[{"given":"Katia","family":"Beider","sequence":"first","affiliation":[{"name":"Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel"},{"name":"Jerusalem Multidisciplinary College, Jerusalem 9101001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Ostrovsky","sequence":"additional","affiliation":[{"name":"Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0763-1265","authenticated-orcid":false,"given":"Arnon","family":"Nagler","sequence":"additional","affiliation":[{"name":"Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1002\/ajh.27422","article-title":"Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management","volume":"99","author":"Rajkumar","year":"2024","journal-title":"Am. 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