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Although progression is partly shaped by intrinsic genetic and epigenetic changes within the plasma cell clone, increasing evidence indicates that the bone marrow microenvironment plays a decisive role in determining whether the clone remains clinically silent or evolves toward symptomatic disease. This review examines how the marrow niche changes across the MGUS\u2013SMM\u2013MM continuum. In early MGUS, the microenvironment may already be permissive, but it remains partly restrained: immune control is not fully lost, stromal activation is incomplete, vascular remodeling is limited, and the bone\u2010remodeling compartment has not yet become overtly tumor\u2010supportive. Progression appears to occur when these initially modest stromal, vascular, skeletal, immune, and extracellular matrix alterations become functionally connected. Once linked, these changes form reinforcing circuits that enhance plasma cell retention and survival, weaken immune containment, remodel the vascular and skeletal niche, and promote resistance to therapy. In this view, MGUS\u2010to\u2010MM progression is not simply a plasma cell\u2013autonomous process, but a gradual ecological shift in which the marrow niche becomes increasingly aligned with the needs of the malignant clone. Understanding this coordinated microenvironmental remodeling may improve risk stratification and support therapeutic strategies that target both the plasma cell clone and its supportive niche.<\/jats:p>","DOI":"10.1002\/hon.70240","type":"journal-article","created":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T03:31:48Z","timestamp":1786851108000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Transformation of the Microenvironment: From Observer to Coordinator in Monoclonal Gammopathy of Undetermined Significance (MGUS) to Myeloma Development"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5481-5617","authenticated-orcid":false,"given":"Amr Ali Mohamed","family":"Abdelgawwad El\u2010Sehrawy","sequence":"first","affiliation":[{"name":"Internal Medicine, Diabetes, Endocrinology and Metabolism Mansoura University  Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer Jabra","family":"Shnoudeh","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics &amp; Clinical Phamacy, Faculty of Pharmacy Al\u2010 Ahliyya Amman University Hourani Center for Applied Scientific Research  Amman Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilkhom","family":"Yuldashev","sequence":"additional","affiliation":[{"name":"Department of Allergology, Clinical Immunology, Microbiology Tashkent State Medical University  Tashkent Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dildora","family":"Jalilova","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy Samarkand State Medical University  Samarkand Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zebiniso","family":"Alimova","sequence":"additional","affiliation":[{"name":"Department of Medical Fundamental Sciences Termez University of Economics and Service  Termez Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajashree","family":"Panigrahi","sequence":"additional","affiliation":[{"name":"Department of Microbiology IMS and SUM Hospital Siksha 'O' Anusandhan  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rswl Mahmoud","family":"Hashem","sequence":"additional","affiliation":[{"name":"Department of Tqnyat Altkhdyr College Altqnyat Altbyh The Islamic University  Najaf Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Bainsal","sequence":"additional","affiliation":[{"name":"University Institute of Pharma Sciences Chandigarh University  Mohali India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,15]]},"reference":[{"key":"e_1_2_19_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.60"},{"key":"e_1_2_19_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation\u20102013.1.478"},{"key":"e_1_2_19_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.203"},{"key":"e_1_2_19_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010020\u201001051\u2010x"},{"key":"e_1_2_19_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102008\u201012\u2010194241"},{"key":"e_1_2_19_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.1568"},{"issue":"7","key":"e_1_2_19_8_1","first-page":"578","article-title":"Management of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM)","volume":"25","author":"Kyle R. 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