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Approximately 3 to 5% of patients present with a variant form of the disease where there is no secretion of monoclonal proteins, characterizing the non-secretory MM picture. It exhibits a highly complex and heterogeneous genetic signature, allowing the disease to be classified into premalignant entities and symptomatic forms. In this context, an integrative narrative review was conducted, encompassing genomic, epigenomic, proteomic, metabolomic, and radiomic biomarkers described in the literature between 2018 and 2025. Emphasis was placed on their translational potential, current limitations in clinical practice, and gaps within recent recommendations. Several categories of biomarkers, particularly ctDNA methylome, single-cell multiomics, proteomics of surface antigens, functional ex vivo assays, and PET\/CT radiomics, demonstrate strong potential for enhancing risk stratification, detecting early progression, guiding therapy selection, and identifying novel therapeutic targets. These applications extend beyond existing guideline frameworks. Thus, integrating advanced biomarker platforms can overcome limitations of current diagnostic and therapeutic models and enhance precision strategies across plasma cell disorders.<\/jats:p>","DOI":"10.3390\/ph19020320","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T12:37:28Z","timestamp":1771245448000},"page":"320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Next-Generation Biomarkers in Multiple Myeloma: Advancing Diagnosis, Risk Stratification, and Precision Therapy Beyond Current Guidelines"],"prefix":"10.3390","volume":"19","author":[{"given":"Marta Marques de Carvalho","family":"Lopes","sequence":"first","affiliation":[{"name":"Postgraduate Program in Clinical and Toxicological Analysis, Department of Clinical and Toxicology Analysis, College of Pharmacy, Federal University of Minas Gerais, Prof. Moacir Gomes de Freitas Street-Pampulha, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura do Amaral","family":"Xavier","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Clinical and Toxicological Analysis, Department of Clinical and Toxicology Analysis, College of Pharmacy, Federal University of Minas Gerais, Prof. Moacir Gomes de Freitas Street-Pampulha, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Cristina Verde Mendes","family":"Nolasco","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Clinical and Toxicological Analysis, Department of Clinical and Toxicology Analysis, College of Pharmacy, Federal University of Minas Gerais, Prof. Moacir Gomes de Freitas Street-Pampulha, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone Rodrigues","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Clinical and Toxicological Analysis, Department of Clinical and Toxicology Analysis, College of Pharmacy, Federal University of Minas Gerais, Prof. Moacir Gomes de Freitas Street-Pampulha, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danila Felix","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Clinical and Toxicological Analysis, Department of Clinical and Toxicology Analysis, College of Pharmacy, Federal University of Minas Gerais, Prof. Moacir Gomes de Freitas Street-Pampulha, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8562-8689","authenticated-orcid":false,"given":"Adriano de Paula","family":"Sabino","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Clinical and Toxicological Analysis, Department of Clinical and Toxicology Analysis, College of Pharmacy, Federal University of Minas Gerais, Prof. Moacir Gomes de Freitas Street-Pampulha, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E538","DOI":"10.1016\/S1470-2045(14)70442-5","article-title":"International Myeloma Working Group Updated Criteria for the Diagnosis of Multiple Myeloma","volume":"15","author":"Rajkumar","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrc3257","article-title":"The Genetic Architecture of Multiple Myeloma","volume":"12","author":"Morgan","year":"2012","journal-title":"Nat. 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