{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:37:21Z","timestamp":1768520241176,"version":"3.49.0"},"reference-count":34,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013119","name":"PharmaMar","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013119","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed\/refractory multiple myeloma (r\/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells. This phase I trial evaluated plitidepsin (3\u2010h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4\u2009weeks in 36 r\/r MM patients. Twenty\u2010two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose\u2010limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0\u00a0mg\/m<jats:sup>2<\/jats:sup>, BTZ 1.3\u00a0mg\/m<jats:sup>2<\/jats:sup>, DXM 40.0\u00a0mg) was the RD for phase II studies. Results shown herein are focused on this RD. Two patients had DLTs (grade 3 diarrhea, and grade 3 nausea\/vomiting refractory to antiemetic therapy). Grade\u2009\u2265\u20093 hematological toxicity (thrombocytopenia 46%, anemia 33%, and neutropenia 17%) was manageable and did not result in treatment discontinuation. Transient and manageable grade 3 ALT increase (26%) was the most common biochemical abnormality. At the RD cohort, overall response rate was 22.2% (95%CI, 6.4%\u201347.6%), including one stringent complete response, one very good partial response, and two partial responses in r\/r patients to BTZ and\/or lenalidomide. The clinical benefit rate was 77.8% (95%CI, 52.4\u201393.6%). No major pharmacokinetic drug\u2013drug interaction was found. In conclusion, the triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r\/r MM.<\/jats:p>","DOI":"10.1002\/cam4.5250","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T04:40:09Z","timestamp":1663735209000},"page":"3999-4009","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed\/refractory multiple myeloma"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-1218","authenticated-orcid":false,"given":"Mar\u00eda Victoria","family":"Mateos","sequence":"first","affiliation":[{"name":"Hospital Universitario de Salamanca  Salamanca Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-8790","authenticated-orcid":false,"given":"Felipe","family":"Prosper","sequence":"additional","affiliation":[{"name":"Cl\u00ednica Universidad de Navarra  Pamplona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4250-4824","authenticated-orcid":false,"given":"Jes\u00fas","family":"Martin S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Hospital Universitario Virgen del Rocio  Sevilla Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique M.","family":"Ocio","sequence":"additional","affiliation":[{"name":"Hospital Universitario de Salamanca  Salamanca Spain"},{"name":"Hospital Universitario Marqu\u00e9s de Valdecilla (IDIVAL) Universidad de Cantabria  Santander Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Oriol","sequence":"additional","affiliation":[{"name":"Institut Catal\u00e0 d'Oncologia Hospital Germans Trias i Pujol  Badalona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Motll\u00f3","sequence":"additional","affiliation":[{"name":"Institut Catal\u00e0 d'Oncologia Hospital Germans Trias i Pujol  Badalona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3482-3331","authenticated-orcid":false,"given":"Jean\u2010Marie","family":"Michot","sequence":"additional","affiliation":[{"name":"Institut Gustave Roussy  Villejuif France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isidro","family":"Jarque","sequence":"additional","affiliation":[{"name":"Hospital Universitario La Fe  Valencia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebeca","family":"Iglesias","sequence":"additional","affiliation":[{"name":"M.D. Anderson Cancer Center  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Sol\u00e9","sequence":"additional","affiliation":[{"name":"Hospital Universitario Virgen del Rocio  Sevilla Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"PharmaMar  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Kahatt","sequence":"additional","affiliation":[{"name":"PharmaMar  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvador","family":"Fudio","sequence":"additional","affiliation":[{"name":"PharmaMar  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gema","family":"Corral","sequence":"additional","affiliation":[{"name":"PharmaMar  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Zeaiter","sequence":"additional","affiliation":[{"name":"PharmaMar  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lola","family":"Montilla","sequence":"additional","affiliation":[{"name":"PharmaMar  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Ribrag","sequence":"additional","affiliation":[{"name":"Institut Gustave Roussy  Villejuif France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.293"},{"key":"e_1_2_10_3_1","unstructured":"National Cancer Institute Surveillance.Epidemiology and End Results Program. SEER stat fact sheets: myeloma;2022.http:\/\/seer.cancer.gov\/statfacts\/html\/mulmy.html"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14213"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-017-0841-y"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1903455"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30788-0"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024850"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.0638"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12198"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.21740"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-08-036947"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-07-517276"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.173"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-09-665018"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-01-694604"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1606038"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5725"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep35100"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-019-03739-2"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1358\/dot.2020.56.5.3135886"},{"key":"e_1_2_10_22_1","article-title":"Phase I clinical and pharmacokinetic study of the marine compound Aplidin (APL) administered as a 3 hour infusion every 2\u2009weeks","volume":"21","author":"Ciruelos EM","year":"2002","journal-title":"Proc Am Soc Clin Oncol"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2004.05188.x"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-299487"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.34.15_suppl.8006"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.13285"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0469"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa030288"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.cco.0000245320.34658.bd"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa070594"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa070596"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-09-452375"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13227"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-481325"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-788323"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.5250","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.5250","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.5250","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T16:58:00Z","timestamp":1747673880000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.5250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,20]]},"references-count":34,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1002\/cam4.5250"],"URL":"https:\/\/doi.org\/10.1002\/cam4.5250","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,20]]},"assertion":[{"value":"2022-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}