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Nevertheless, the combination of melflufen (a peptide-drug conjugate pro-drug of melphalan) and dexamethasone was approved by the U.S. Food &amp; Drug Administration (FDA) for triple-class refractory (TCR) patients after \u2265\u20094 prior lines of therapy (LOT) following results of HORIZON clinical trial (NCT02963493). This combination was subsequently withdrawn as it was not associated with improved overall survival (OS) as compared to pomalidomide-dexamethasone (OCEAN clinical trial, NCT03151811). However, since a post-hoc analysis showed a benefit in OS for patients without prior ASCT or with a time to progression (TTP)\u2009&gt;\u200936 months after ASCT, the European Medicines Agency (EMA) has approved melflufen-dexamethasone for TCR patients after \u2265\u20093 LOT, including specification that TTP must be \u2265\u20093 years in patients with prior ASCT. In this paper, we report three cases of patients receiving the combination melflufen-dexamethasone in the aforementioned clinical trials in three hematologic centers across Europe and achieving exceptionally long responses as compared to the overall enrolled populations, with good tolerability. Further, we discuss the potential use of this chemotherapy-based regimen in the era of novel immunotherapies.<\/jats:p>","DOI":"10.1007\/s00432-025-06326-3","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T04:04:43Z","timestamp":1759982683000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exceptional long-term responses from OCEAN and HORIZON trials: melflufen-dexamethasone as an expansion of treatment options for relapsed\/refractory multiple myeloma in the era of new immunotherapies?"],"prefix":"10.1007","volume":"151","author":[{"given":"M.","family":"Talarico","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Barbato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Maisnar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Delimpasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Puppi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Rizzello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Pantani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Tacchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Martello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Vigliotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Terragna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Cavo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Zamagni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Mancuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"6326_CR1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2025015973","author":"BO Adegbite","year":"2025","unstructured":"Adegbite BO, Tan CR, Shekarkhand T et al (2025) Outcomes in frail patients receiving BCMA-directed bispecific antibodies for relapsed\/refractory multiple myeloma. 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