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These factors contribute to treatment resistance, disease progression, and significant variability in clinical outcomes among patients. This review explores the mechanisms underlying MM progression, including the genetic and epigenetic changes that drive clonal evolution, the role of the bone marrow microenvironment in supporting tumor growth and immune evasion, and the impact of genomic instability. We highlight the critical insights gained from single-cell technologies, such as single-cell transcriptomics, genomics, and multiomics, which have enabled a detailed understanding of MM heterogeneity at the cellular level, facilitating the identification of rare cell populations and mechanisms of drug resistance. Despite the promise of advanced technologies, MM remains an incurable disease and challenges remain in their clinical application, including high costs, data complexity, and the need for standardized bioinformatics and ethical considerations. This review emphasizes the importance of continued research and collaboration to address these challenges, ultimately aiming to enhance personalized treatment strategies and improve patient outcomes in MM.<\/jats:p>","DOI":"10.3390\/cancers17040653","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T11:14:41Z","timestamp":1739531681000},"page":"653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multiple Myeloma Insights from Single-Cell Analysis: Clonal Evolution, the Microenvironment, Therapy Evasion, and Clinical Implications"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9395-9952","authenticated-orcid":false,"given":"Sihong","family":"Li","sequence":"first","affiliation":[{"name":"Indiana Bioscience Research Institute, Indianapolis, IN 46202, USA"},{"name":"Richard M. 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Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA"},{"name":"School of Medicine, Indiana University, Indianapolis, IN 46202, USA"},{"name":"Regenstrief Institute, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Lazaro","sequence":"additional","affiliation":[{"name":"Indiana Bioscience Research Institute, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean D.","family":"McCabe","sequence":"additional","affiliation":[{"name":"School of Medicine, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2183-8398","authenticated-orcid":false,"given":"Xiaoqing","family":"Huang","sequence":"additional","affiliation":[{"name":"Richard M. 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