{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:53:05Z","timestamp":1788850385155,"version":"build-2803163510"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008413","name":"Instrumentariumin Tiedes\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008413","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Oncopeptides"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Hematol Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Patients with multiple myeloma bearing a deletion of chromosome 17p (del(17p)), mutation of\n                    <jats:italic>TP53<\/jats:italic>\n                    , or both have poorer prognosis compared to patients without these aberrations. We investigated the activity and mechanism of melflufen (melphalan flufenamide) in myeloma models with wild type\n                    <jats:italic>TP53<\/jats:italic>\n                    (\n                    <jats:italic>TP53<\/jats:italic>\n                    wt) and complete\n                    <jats:italic>TP53<\/jats:italic>\n                    deletion (\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) and assessed the efficacy of melflufen in patients with del(17p) and\/or\n                    <jats:italic>TP53<\/jats:italic>\n                    mutation. Ex vivo data from myeloma plasma cells (PC) showed comparable activity of melflufen in del(17p),\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    , and\n                    <jats:italic>TP53<\/jats:italic>\n                    wt samples. scRNAseq data demonstrated that melflufen sensitive PCs had lower expression of p53 target genes and higher expression of genes associated with DNA damage repair and cell cycle checkpoints. Irrespective of\n                    <jats:italic>TP53<\/jats:italic>\n                    status, melflufen induced apoptosis, DNA damage, and mitochondrial dysfunction, while only in\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells, it led to changes in expression of cell cycle checkpoint and apoptosis genes. Post-hoc analysis of the OCEAN trial melflufen-treated del(17p) patient population also demonstrated favorable progression free survival compared to pomalidomide-treated cohort. Our insights into the molecular mechanisms of melflufen activity in\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    myeloma support its clinical efficacy and application in the del(17p) and\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    patient population.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Trial registration<\/jats:italic>\n                    NCT03151811, registration 2017-05-09.\n                  <\/jats:p>","DOI":"10.1186\/s40164-025-00729-1","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T13:25:47Z","timestamp":1766496347000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Efficacy of melflufen in multiple myeloma with mutated or deleted TP53"],"prefix":"10.1186","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct03151811","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Klara","family":"Acs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juho J.","family":"Miettinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Sergeev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Heckel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Diao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Witt-Mulder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Thureson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Bischler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiju-Emilia","family":"Huppunen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Suvela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Oberm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umair","family":"Munawar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Slipicevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf C.","family":"Bargou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan Svensson","family":"Gelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Norin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Schjesvold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Sonneveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"St\u00fchmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline A.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"729_CR1","doi-asserted-by":"crossref","unstructured":"Ho T, Tan BX, Lane D. How the other half lives: what p53 does when it is not being a transcription factor. Int J Mol Sci. 2019;21(1).","DOI":"10.3390\/ijms21010013"},{"issue":"26","key":"729_CR2","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.1200\/JCO.2015.61.2267","volume":"33","author":"A Palumbo","year":"2015","unstructured":"Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: A report from international myeloma working group. J Clin Oncol. 2015;33(26):2863\u20139.","journal-title":"J Clin Oncol"},{"issue":"9","key":"729_CR3","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1182\/blood.2020008346","volume":"137","author":"J Corre","year":"2021","unstructured":"Corre J, Perrot A, Caillot D, et al. del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma. Blood. 2021;137(9):1192\u20135.","journal-title":"Blood"},{"key":"729_CR4","doi-asserted-by":"crossref","unstructured":"Flynt E, Bisht K, Sridharan V, Ortiz M, Towfic F, Thakurta A. Prognosis, biology, and targeting of TP53 dysregulation in multiple myeloma. Cells. 2020;9(2).","DOI":"10.3390\/cells9020287"},{"issue":"1","key":"729_CR5","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41375-018-0196-8","volume":"33","author":"BA Walker","year":"2019","unstructured":"Walker BA, Mavrommatis K, Wardell CP, et al. A high-risk, double-hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;33(1):159\u201370.","journal-title":"Leukemia"},{"issue":"2","key":"729_CR6","doi-asserted-by":"publisher","first-page":"e98","DOI":"10.1016\/S2352-3026(21)00381-1","volume":"9","author":"FH Schjesvold","year":"2022","unstructured":"Schjesvold FH, Dimopoulos MA, Delimpasi S, et al. Melflufen or Pomalidomide plus dexamethasone for patients with multiple myeloma refractory to Lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol. 2022;9(2):e98\u2013110.","journal-title":"Lancet Haematol"},{"issue":"11","key":"729_CR7","doi-asserted-by":"publisher","first-page":"631","DOI":"10.2217\/fon-2020-0024","volume":"16","author":"F Schjesvold","year":"2020","unstructured":"Schjesvold F, Robak P, Pour L, Aschan J, Sonneveld P. OCEAN: a randomized phase III study of melflufen\u2009+\u2009dexamethasone to treat relapsed refractory multiple myeloma. Future Oncol. 2020;16(11):631\u201341.","journal-title":"Future Oncol"},{"issue":"9","key":"729_CR8","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.clml.2023.05.004","volume":"23","author":"P Sonneveld","year":"2023","unstructured":"Sonneveld P, Richardson PG, Ludwig H, et al. Benefit versus risk assessment of Melflufen and dexamethasone in relapsed\/refractory multiple myeloma: analyses from longer follow-up of the OCEAN and HORIZON studies. Clin Lymphoma Myeloma Leuk. 2023;23(9):687\u201396.","journal-title":"Clin Lymphoma Myeloma Leuk"},{"issue":"1","key":"729_CR9","doi-asserted-by":"publisher","first-page":"18062","DOI":"10.1038\/s41598-019-54407-4","volume":"9","author":"U Munawar","year":"2019","unstructured":"Munawar U, Roth M, Barrio S, et al. Assessment of TP53 lesions for p53 system functionality and drug resistance in multiple myeloma using an isogenic cell line model. Sci Rep. 2019;9(1):18062.","journal-title":"Sci Rep"},{"issue":"10","key":"729_CR10","doi-asserted-by":"publisher","first-page":"3609","DOI":"10.1182\/blood-2005-04-1489","volume":"106","author":"T St\u00fchmer","year":"2005","unstructured":"St\u00fchmer T, Chatterjee M, Hildebrandt M, et al. Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood. 2005;106(10):3609\u201317.","journal-title":"Blood"},{"issue":"11","key":"729_CR11","doi-asserted-by":"publisher","first-page":"3019","DOI":"10.1158\/1078-0432.CCR-12-3752","volume":"19","author":"D Chauhan","year":"2013","unstructured":"Chauhan D, Ray A, Viktorsson K, et al. In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clin Cancer Res. 2013;19(11):3019\u201331.","journal-title":"Clin Cancer Res"},{"issue":"3","key":"729_CR12","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1111\/bjh.14065","volume":"174","author":"A Ray","year":"2016","unstructured":"Ray A, Ravillah D, Das DS, et al. A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol. 2016;174(3):397\u2013409.","journal-title":"Br J Haematol"}],"container-title":["Experimental Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00729-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40164-025-00729-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00729-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T13:25:49Z","timestamp":1766496349000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s40164-025-00729-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":12,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["729"],"URL":"https:\/\/doi.org\/10.1186\/s40164-025-00729-1","relation":{},"ISSN":["2162-3619"],"issn-type":[{"value":"2162-3619","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]},"assertion":[{"value":"11 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Bone marrow (BM) aspirates were collected from multiple myeloma (MM) patients after informed consent using protocols approved by the ethical committee of Helsinki University Hospital (Ethical Committee Statement 303\/13\/03\/01\/201, latest amendment 7 dated 15 June 2016; latest HUS study permit HUS\/395\/2018 dated 13 February 2018; Permit numbers 239\/13\/03\/00\/2010, 303\/13\/03\/01\/2011) and in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"K.A., Y.D., K.W.M., J.O., S.S.G. are employees of and receives stock or stock options from Oncopeptides. S.N. is an employee of, has participated on a data safety monitoring board or advisory board for, and receives stock or stock options from Oncopeptides. M.T. is a consultant of and receives stock or stock options from Oncopeptides. A.S., F.L., are former employees of and receive stock or stock options from Oncopeptides. F.S. has received grants or contracts from Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Targovax, and Sanofi; payment or honoraria for lectures or speakers\u2019 bureau participation from AbbVie, Amgen, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Pfizer, Sanofi, SkyliteDX, and Takeda; serving on a data safety monitoring or advisory board for AbbVie, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Takeda; and stock or stock options from Nordic Nanovector. P.So. has received grants or contracts from Amgen, Celgene, Janssen, Takeda, and SkylineDx. C.A.H. has received research funding from Oncopeptides related to this work, and from IMI2 projects HARMONY and HARMONY PLUS, WntResearch, Orion, Kronos Bio, Novartis, Celgene, Zentalis Pharmaceuticals for unrelated work, plus honoraria or personal fees from Amgen and Autolus. The remaining authors declare no competing financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"138"}}