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In this study, we investigated the frequency and disease characteristics of ER during the first 18 months after treatment initiation (ER18), in a series of 1215 newly\u2010diagnosed MM patients enrolled in four PETHEMA\/GEM clinical trials for the transplant\u2010eligible and transplant\u2010ineligible populations. ER18 was observed in 266 of the 1215 patients (22%) and resulted in a median OS of 19 versus 114 months in cases without ER18. When compared to the ISS and the presence of \u22652 high\u2010risk cytogenetic abnormalities, a modified version of the new high\u2010risk definition from the International Myeloma Society (mHR\u2010IMS) showed the most balanced negative and positive predictive values of ER18 (83.5% and 40%, respectively). In addition to the mHR\u2010IMS, an ECOG\u2009=\u20092, ISS 3, and calcium levels \u2265\u200911\u2009mg\/dL were independently associated with ER18. These variables were modeled into a predictive score in which the rates of ER18 were 2%, 24.5%, and 59% in patients with low\u2010, intermediate\u2010, and high\u2010risk score. The risk of ER18 and OS were modulated by the VGPR status at 6\u20139 months after treatment initiation. In conclusion, we present a risk model that predicts ER18 and can be readily applied in clinical trials and routine practice to identify treatment strategies empowered to prevent ER18 and improve survival outcomes of newly\u2010diagnosed patients with functional high\u2010risk MM.<\/jats:p>","DOI":"10.1002\/hem3.70127","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T09:28:25Z","timestamp":1745486905000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High\u2010risk features of early relapse in newly\u2010diagnosed multiple myeloma: The impact of cytogenetics and response to initial therapy"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4541-6339","authenticated-orcid":false,"given":"Andrea","family":"Manubens","sequence":"first","affiliation":[{"name":"Cancer Center Cl\u00ednica Universidad de Navarra, CIMA, IDISNA, CIBERONC Pamplona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Paiva","sequence":"additional","affiliation":[{"name":"Cancer Center Cl\u00ednica Universidad de Navarra, CIMA, IDISNA, CIBERONC Pamplona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norma C.","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Department of Hematology University Hospital of Salamanca, IBSAL, Cancer Research Center\u2010IBMCC (USAL\u2010CSIC), CIBERONC Salamanca Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria\u2010Jos\u00e9","family":"Calasanz","sequence":"additional","affiliation":[{"name":"Cancer Center Cl\u00ednica Universidad de Navarra, CIMA, IDISNA, CIBERONC Pamplona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Rosi\u00f1ol","sequence":"additional","affiliation":[{"name":"Hospital Clinic i Provincial de Barcelona, IDIBAPS Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Oriol","sequence":"additional","affiliation":[{"name":"Hospital Universitari Germans Trias i Pujol Badalona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma Jes\u00fas","family":"Blanchard","sequence":"additional","affiliation":[{"name":"Hospital Ram\u00f3n y Cajal Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estrella","family":"Carrillo","sequence":"additional","affiliation":[{"name":"Complejo Hospitalario Regional Virgen Del Roc\u00edo Sevilla Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celina","family":"Benavente","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico San Carlos Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Mart\u00ednez\u2010L\u00f3pez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan","family":"Bargay","sequence":"additional","affiliation":[{"name":"Hospital Universitario Son Ll\u00e0tzer Palma de Mallorca Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel Teodoro","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Hospital Universitario De Canarias La Laguna Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"de la Rubia","sequence":"additional","affiliation":[{"name":"Hospital Universitario la Fe, Instituto de Investigaci\u00f3n Sanitaria La Fe, School of Medicine and Dentistry Catholic University of Valencia Valencia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yolanda","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Hospital Universitari Dr. Josep Trueta de Girona Girona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Paricio","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico Universitario Lozano Blesa Zaragoza Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4451-1318","authenticated-orcid":false,"given":"Felipe","family":"de Arriba","sequence":"additional","affiliation":[{"name":"Hospital General Universitario Morales Meseguer, IMIB\u2010Pascual Parrilla. 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