{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:09:00Z","timestamp":1792271340668,"version":"4.4.0"},"reference-count":88,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T00:00:00Z","timestamp":1743292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>The therapeutic landscape for multiple myeloma has gradually expanded in recent decades, leading to unprecedented deep and sustained responses as well as remarkable improvements in patient survival. Nonetheless, changes in treatment algorithms have raised new demands for patients with relapsed\/refractory disease, as prior exposure and refractoriness to prior therapies impact the choice of subsequent treatments. In particular, refractoriness to lenalidomide\u2014an established backbone of treatment in both front-line and maintenance settings and a key component of many approved regimens used in relapsed disease\u2014is associated with suboptimal clinical outcomes. Therefore, identifying the most appropriate management in lenalidomide-refractory patients, and even more so in patients who are refractory to more than one agent, is critical. At present, treatment options for this growing subgroup of patients are still limited; however, recent data from clinical research are promising. Herein, we summarized the currently available treatment options and discuss future directions based on the latest results from ongoing clinical trials.<\/jats:p>","DOI":"10.3390\/cancers17071168","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T01:59:36Z","timestamp":1743386376000},"page":"1168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Forcing Ahead: Second-Line Treatment Options for Lenalidomide-Refractory Multiple Myeloma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1169-0129","authenticated-orcid":false,"given":"Katia","family":"Mancuso","sequence":"first","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \u201cSer\u00e0gnoli\u201d, 40138 Bologna, Italy"},{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7828-8230","authenticated-orcid":false,"given":"Simona","family":"Barbato","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \u201cSer\u00e0gnoli\u201d, 40138 Bologna, Italy"},{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Di Raimondo","sequence":"additional","affiliation":[{"name":"Divisione di Ematologia, Azienda Ospedaliero-Universitaria Policlinico di Catania, Scuola di Specializzazione in Ematologia dell\u2019universit\u00e0 di Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8619-412X","authenticated-orcid":false,"given":"Francesca","family":"Gay","sequence":"additional","affiliation":[{"name":"Divisione di Ematologia 1, AOU Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"},{"name":"Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Universit\u00e0 degli Studi di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3277-6594","authenticated-orcid":false,"given":"Pellegrino","family":"Musto","sequence":"additional","affiliation":[{"name":"Unit of Hematology and Stem Cell Transplantation, Department of Precision and Regenerative Medicine and Ionian Area, \u201cAldo Moro\u201d University School of Medicine, AOUC Policlinico, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2749-7347","authenticated-orcid":false,"given":"Massimo","family":"Offidani","sequence":"additional","affiliation":[{"name":"Clinica di Ematologia, Unit\u00e0 di Trapianto di Cellule Staminali e Terapia Cellulare dell\u2019AOU delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0688-4882","authenticated-orcid":false,"given":"Maria","family":"Petrucci","sequence":"additional","affiliation":[{"name":"Ematologia, Azienda Ospedaliera Universitaria Policlinico Umberto I, 00161 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1422-7305","authenticated-orcid":false,"given":"Elena","family":"Zamagni","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia \u201cSer\u00e0gnoli\u201d, 40138 Bologna, Italy"},{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8799-5324","authenticated-orcid":false,"given":"Renato","family":"Zambello","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Ematologia, Dipartimento di Medicina (DIMED), Universit\u00e0 di Padova, 65100 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4514-3227","authenticated-orcid":false,"given":"Michele","family":"Cavo","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4691","DOI":"10.1182\/blood-2010-10-299487","article-title":"Consensus recommendations for the uniform reporting of clinical trials: Report of the International Myeloma Workshop Consensus Panel 1","volume":"117","author":"Rajkumar","year":"2011","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e328","DOI":"10.1016\/S1470-2045(16)30206-6","article-title":"International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma","volume":"17","author":"Kumar","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1182\/blood.2020008734","article-title":"How I treat relapsed multiple 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