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However, the individual contribution of specific HR genetic abnormalities or their co-occurrence to poor outcomes, especially in the era of novel agents, remains unclear. This study evaluated the impact of multi-hit\n                    <jats:italic>TP53<\/jats:italic>\n                    (del(17p) and\n                    <jats:italic>TP53<\/jats:italic>\n                    mutation or\u2009\u2265\u20092\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations) compared with other HR abnormalities on progression-free survival (PFS), overall survival (OS) and blood signature in a real-world cohort of 204 patients with MM treated with novel agents (median follow-up 28\u00a0months). Patients with multi-hit\n                    <jats:italic>TP53<\/jats:italic>\n                    (10.4%) had the shortest PFS and OS compared with those with single HR abnormalities (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20090.011) or with co-occurrence of \u2265\u20092 other HR abnormalities (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20090.002), regardless of therapy line. The relative risk of early progression in patients with multi-hit\n                    <jats:italic>TP53<\/jats:italic>\n                    was almost three times higher than that of patients with other HR abnormalities. The prevalence of\n                    <jats:italic>TP53<\/jats:italic>\n                    alterations increased in later disease stages: multi-hit\n                    <jats:italic>TP53<\/jats:italic>\n                    was detected in 7.6% of patients with\u2009\u2264\u20091 prior therapy line and in 36.4% of patients with\u2009\u2265\u20092 prior lines. Patients with multi-hit\n                    <jats:italic>TP53<\/jats:italic>\n                    also differed in blood signature, particularly in counts of white blood cells, lymphocytes, serum creatinine and \u03b22-microglobulin levels compared with those with other HR abnormalities. In conclusion, multi-hit\n                    <jats:italic>TP53<\/jats:italic>\n                    is associated with the poorest survival among all HR subgroups in MM. Considering that\n                    <jats:italic>TP53<\/jats:italic>\n                    alterations accumulate during MM progression and are associated with drug resistance even in the context of novel therapies, our study further emphasizes the need for routine evaluation of both del(17p) and\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations. Patients with multi-hit\n                    <jats:italic>TP53<\/jats:italic>\n                    should be prioritized for inclusion in trials of novel therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1186\/s10020-025-01392-2","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T03:04:42Z","timestamp":1764385482000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multi-hit TP53 confers the poorest survival in multiple myeloma in the era of novel therapies"],"prefix":"10.1186","volume":"32","author":[{"given":"Romana","family":"Nesnadna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Petrackova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Minarik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vojtech","family":"Latal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jirina","family":"Manakova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Papajik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Kriegova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"1392_CR1","doi-asserted-by":"publisher","unstructured":"Abu Za\u2019nouneh FJ, Ababneh O, Schinke C, Thanendrarajan S, Zangari M, Shaughnessy JD, et al. 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The Ethics committee of University Hospital Olomouc and Palacky University Olomouc approved the study (ID60\/22).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All patients provided written informed consent for the publication of obtained data in the anonymous form, and personal data were handled in accordance with GDPR principles.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3"}}