{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:21Z","timestamp":1794047361022,"version":"4.8.0"},"reference-count":45,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"7","license":[{"start":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T00:00:00Z","timestamp":1591228800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P &lt; 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.<\/jats:p>","DOI":"10.3324\/haematol.2020.247130","type":"journal-article","created":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T15:05:30Z","timestamp":1591283130000},"page":"1957-1967","source":"Crossref","is-referenced-by-count":26,"title":["Lenalidomide before and after autologous stem cell transplantation for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial"],"prefix":"10.3324","volume":"106","author":[{"family":"Graham H. Jackson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Faith E. Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Charlotte Pawlyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"David A. Cairns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Alina Striha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Corinne Collett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Anna Waterhouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"John R. Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Bhuvan Kishore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Mamta Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Cathy D. Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Kamaraj Karunanithi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Jindriska Lindsay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"David Allotey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Salim Shafeek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Matthew W. Jenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Gordon Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Nigel H. Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Martin F. Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Mark T. Drayson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Roger G. Owen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Walter M. Gregory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Gareth J. Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"UK NCRI Haematological Oncology Clinical Studies Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,6,4]]},"reference":[{"key":"27333","doi-asserted-by":"crossref","unstructured":"Kumar SK, Rajkumar SV, Dispenzieri A. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111(5):2516-2520.","DOI":"10.1182\/blood-2007-10-116129"},{"key":"27334","doi-asserted-by":"crossref","unstructured":"Kristinsson SY, Anderson WF, Landgren O. Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia. 2014; 28(6):1346-1348.","DOI":"10.1038\/leu.2014.23"},{"key":"27335","doi-asserted-by":"crossref","unstructured":"Kumar SK, Dispenzieri A, Lacy MQ. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014; 28(5):1122-1128.","DOI":"10.1038\/leu.2013.313"},{"key":"27336","doi-asserted-by":"crossref","unstructured":"Child JA, Morgan GJ, Davies FE. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003; 348(19):1875-1883.","DOI":"10.1056\/NEJMoa022340"},{"key":"27337","doi-asserted-by":"crossref","unstructured":"Moreau P, Avet-Loiseau H, Facon T. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011; 118(22):5752-5758.","DOI":"10.1182\/blood-2011-05-355081"},{"key":"27338","doi-asserted-by":"crossref","unstructured":"Palumbo A, Cavallo F, Gay F. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014; 371(10):895-905.","DOI":"10.1056\/NEJMoa1402888"},{"key":"27339","doi-asserted-by":"crossref","unstructured":"Gay F, Oliva S, Petrucci MT. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015; 16(16):1617-1629.","DOI":"10.1016\/S1470-2045(15)00389-7"},{"key":"27340","doi-asserted-by":"crossref","unstructured":"Stadtmauer EA, Pasquini MC, Blackwell B. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol. 2019; 37(7):589-597.","DOI":"10.1200\/JCO.18.00685"},{"key":"27341","doi-asserted-by":"crossref","unstructured":"Attal M, Lauwers-Cances V, Hulin C. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017; 376(14):1311-1320.","DOI":"10.1056\/NEJMoa1611750"},{"key":"27342","doi-asserted-by":"crossref","unstructured":"Cavo M, Tacchetti P, Patriarca F. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010; 376(9758):2075-2085.","DOI":"10.1016\/S0140-6736(10)61424-9"},{"key":"27343","doi-asserted-by":"crossref","unstructured":"Davies FE, Wu P, Jenner M. The combination of cyclophosphamide, velcade and dexamethasone induces high response rates with comparable toxicity to velcade alone and velcade plus dexamethasone. Haematologica. 2007; 92(8):1149-1150.","DOI":"10.3324\/haematol.11228"},{"key":"27344","doi-asserted-by":"crossref","unstructured":"Lopez-Girona A, Mendy D, Ito T. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012; 26(11):2326-2335.","DOI":"10.1038\/leu.2012.119"},{"key":"27345","doi-asserted-by":"crossref","unstructured":"Gandhi AK, Kang J, Havens CG. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4. Br J Haematol. 2014; 164(6):811-821.","DOI":"10.1111\/bjh.12708"},{"key":"27346","doi-asserted-by":"crossref","unstructured":"Kronke J, Udeshi ND, Narla A. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014; 343(6168):301-305.","DOI":"10.1126\/science.1244851"},{"key":"27347","doi-asserted-by":"crossref","unstructured":"Bjorklund CC, Lu L, Kang J. Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. Blood Cancer J. 2015; 5:e354.","DOI":"10.1038\/bcj.2015.66"},{"key":"27348","doi-asserted-by":"crossref","unstructured":"Wu P, Davies FE, Horton C. The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide - vincristine - doxorubicin - methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis. Leuk Lymphoma. 2006; 47(11):2335-2338.","DOI":"10.1080\/10428190600821955"},{"key":"27349","doi-asserted-by":"crossref","unstructured":"Morgan GJ, Davies FE, Gregory WM. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012; 97(3):442-450.","DOI":"10.3324\/haematol.2011.043372"},{"key":"27350","doi-asserted-by":"crossref","unstructured":"Morgan GJ, Davies FE, Gregory WM. Long-term follow-up of MRC Myeloma IX Trial: survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013; 19(21):6030-6038.","DOI":"10.1158\/1078-0432.CCR-12-3211"},{"key":"27351","doi-asserted-by":"crossref","unstructured":"Attal M, Lauwers-Cances V, Marit G. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. 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Lancet Haematol. 2019; 6(12):e616-e629.","DOI":"10.1016\/S2352-3026(19)30167-X"},{"key":"27355","doi-asserted-by":"crossref","unstructured":"Jackson GH, Davies FE, Pawlyn C. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019; 20(1):57-73.","DOI":"10.1016\/S1470-2045(18)30687-9"},{"key":"27356","doi-asserted-by":"crossref","unstructured":"Morgan GJ, Davies FE, Gregory WM. Long-term follow-up of MRC Myeloma IX trial: survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013; 19(21):6030-6038.","DOI":"10.1158\/1078-0432.CCR-12-3211"},{"key":"27357","doi-asserted-by":"crossref","unstructured":"Kumar SK, Lacy MQ, Hayman SR. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol. 2011; 86(8):640-645.","DOI":"10.1002\/ajh.22053"},{"key":"27358","doi-asserted-by":"crossref","unstructured":"Morgan GJ, Schey SA, Wu P. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients. Br J Haematol. 2007; 137(3):268-269.","DOI":"10.1111\/j.1365-2141.2007.06538.x"},{"key":"27359","doi-asserted-by":"crossref","unstructured":"Gay F, Hayman SR, Lacy MQ. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood. 2010; 115(7):1343-1350.","DOI":"10.1182\/blood-2009-08-239046"},{"key":"27360","doi-asserted-by":"crossref","unstructured":"Luo J, Gagne JJ, Landon J. Comparative effectiveness and safety of thalidomide and lenalidomide in patients with multiple myeloma in the United States of America: a population-based cohort study. Eur J Cancer. 2017; 70:22-33.","DOI":"10.1016\/j.ejca.2016.10.018"},{"key":"27361","doi-asserted-by":"crossref","unstructured":"Zweegman S, van der Holt B, Mellqvist UH. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016; 127(9):1109-1116.","DOI":"10.1182\/blood-2015-11-679415"},{"key":"27362","doi-asserted-by":"crossref","unstructured":"Stewart AK, Jacobus S, Fonseca R. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015; 126(11):1294-1301.","DOI":"10.1182\/blood-2014-12-613927"},{"key":"27363","doi-asserted-by":"crossref","unstructured":"Sonneveld P, Schmidt-Wolf IG, van der Holt B. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65\/ GMMG-HD4 trial. 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Leukemia. 2015; 29(12):2429-2431.","DOI":"10.1038\/leu.2015.274"},{"key":"27367","doi-asserted-by":"crossref","unstructured":"Kumar S, Flinn I, Richardson PG. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012; 119(19):4375-4382.","DOI":"10.1182\/blood-2011-11-395749"},{"key":"27368","doi-asserted-by":"crossref","unstructured":"Moreau P, Attal M, Hulin C. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, openlabel, phase 3 study. Lancet. 2019; 394(10192):29-38.","DOI":"10.1016\/S0140-6736(19)31240-1"},{"key":"27369","doi-asserted-by":"crossref","unstructured":"McCarthy PL, Holstein SA, Petrucci MT. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a metaanalysis. J Clin Oncol. 2017; 35(29):3279-3289.","DOI":"10.1200\/JCO.2017.72.6679"},{"key":"27370","doi-asserted-by":"crossref","unstructured":"Holstein SA, Jung SH, Richardson PG. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017; 4(9):e431-e442.","DOI":"10.1016\/S2352-3026(17)30140-0"},{"key":"27371","doi-asserted-by":"crossref","unstructured":"Ozaki S, Harada T, Saitoh T. Survival of multiple myeloma patients aged 65-70 years in the era of novel agents and autologous stem cell transplantation. Acta Haematol. 2014; 132(2):211-219.","DOI":"10.1159\/000357394"},{"key":"27372","doi-asserted-by":"crossref","unstructured":"Minoia C, Pisapia G, Palazzo G. Impact of novel agents followed by autologous hematopoietic stem cell transplantation for multiple myeloma patients aged 65 years or older: a retrospective single Institutional analysis. Bone Marrow Transplant. 2015; 50(11):1486.","DOI":"10.1038\/bmt.2015.185"},{"key":"27373","doi-asserted-by":"crossref","unstructured":"Fonseca R, Bergsagel PL, Drach J. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23(12):2210-2221.","DOI":"10.1038\/leu.2009.174"},{"key":"27374","doi-asserted-by":"crossref","unstructured":"Avet-Loiseau H, Facon T. Front-line therapies for elderly patients with transplantineligible multiple myeloma and high-risk cytogenetics in the era of novel agents. Leukemia. 2018; 32(6):1267-1276.","DOI":"10.1038\/s41375-018-0098-9"},{"key":"27375","doi-asserted-by":"crossref","unstructured":"Palumbo A, Bringhen S, Kumar SK. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol. 2014; 15(3):333-342.","DOI":"10.1016\/S1470-2045(13)70609-0"},{"key":"27376","doi-asserted-by":"crossref","unstructured":"Jones JR, Cairns DA, Gregory WM. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer J. 2016; 6(12):e506.","DOI":"10.1038\/bcj.2016.114"},{"key":"27377","doi-asserted-by":"crossref","unstructured":"Abonour R, Wagner L, Durie BGM. Impact of post-transplantation maintenance therapy on health-related quality of life in patients with multiple myeloma: data from the Connect\u00ae MM Registry. Ann Hematol. 2018; 97(12):2425-2436.","DOI":"10.1007\/s00277-018-3446-y"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/9773\/70940","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9773\/70941","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9773\/70940","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T09:57:19Z","timestamp":1794045439000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/9773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,4]]},"references-count":45,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2020.247130","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2020,6,4]]}}}