{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:10:05Z","timestamp":1760145005519,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T00:00:00Z","timestamp":1718064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Federal Ministry of Education","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Dutch Cancer Foundation, the German Federal Ministry of Education and Research","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Janssen-Cilag-Ortho Biotech","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Celgene, Janssen-Cilag, Chugai, and Binding Site","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Novartis","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Amgen","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Chugai","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]},{"name":"Roche","award":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"],"award-info":[{"award-number":["01ES1103","01ZX1309","SFB\/TRR79","GMMG-HD4","MMY3003","GMMG-MM5","P2004-0060"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65\/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin\/adriamycin\/dexamthasone)\/tandem-transplantation\/thalidomide-maintenance vs. PAD induction (bortezomib\/adriamycin\/dexamethasone)\/tandem transplantation\/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront \u201cnovel agents\u201d in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with \u201cconventional\u201d (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to \u201coutdated\u201d treatments, if resources do not permit state-of-the-art-treatment, normal renal function and\/or molecular profiling identifies patient subpopulations doing well without upfront \u201cnovel agents\u201d.<\/jats:p>","DOI":"10.3390\/ijms25126431","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T12:11:00Z","timestamp":1718107860000},"page":"6431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma\u2014Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2771-712X","authenticated-orcid":false,"given":"Anja","family":"Seckinger","sequence":"first","affiliation":[{"name":"Department of Hematology and Immunology, Myeloma Center Brussels & Labor f\u00fcr Myelomforschung, Vrije Universiteit Brussel (VUB), 1090 Jette, Belgium"},{"name":"Independent Myeloma Alliance, 8808 Pf\u00e4ffikon, SZ, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Salwender","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Asklepios Klinik Altona, 22763 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology\/Oncology, Goethe-University of Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6539-226X","authenticated-orcid":false,"given":"Christof","family":"Scheid","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, University of Cologne, 50923 K\u00f6ln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1277-310X","authenticated-orcid":false,"given":"Thomas","family":"Hielscher","sequence":"additional","affiliation":[{"name":"Abteilung f\u00fcr Biostatistik, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5584-3951","authenticated-orcid":false,"given":"Uta","family":"Bertsch","sequence":"additional","affiliation":[{"name":"Medizinische Klinik V, Universit\u00e4tsklinikum Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Hummel","sequence":"additional","affiliation":[{"name":"Abteilung f\u00fcr Biostatistik, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Jauch","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Humangenetik, Universit\u00e4t Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Knauf","sequence":"additional","affiliation":[{"name":"Onkologische Gemeinschaftspraxis, Agaplesion Bethanien Krankenhaus, 60389 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Emde-Rajaratnam","sequence":"additional","affiliation":[{"name":"Department of Hematology and Immunology, Myeloma Center Brussels & Labor f\u00fcr Myelomforschung, Vrije Universiteit Brussel (VUB), 1090 Jette, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Hematology and Immunology, Myeloma Center Brussels & Labor f\u00fcr Myelomforschung, Vrije Universiteit Brussel (VUB), 1090 Jette, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1311-8107","authenticated-orcid":false,"given":"Kai","family":"Neben","sequence":"additional","affiliation":[{"name":"Klinikum Mittelbaden, Medizinische Klinik 2, 76530 Baden-Baden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"D\u00fchrig","sequence":"additional","affiliation":[{"name":"Katholisches Krankenhaus Hagen, 58099 Hagen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Lindemann","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5655-0867","authenticated-orcid":false,"given":"Ingo G. H.","family":"Schmidt-Wolf","sequence":"additional","affiliation":[{"name":"Department of Integrated Oncology, CIO Bonn, University of Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias","family":"H\u00e4nel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Klinikum Chemnitz GmbH, 09113 Chemnitz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor W.","family":"Blau","sequence":"additional","affiliation":[{"name":"Medical Clinic III Hematology and Oncology, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katja","family":"Weisel","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Weinhold","sequence":"additional","affiliation":[{"name":"Medizinische Klinik V, Universit\u00e4tsklinikum Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc S.","family":"Raab","sequence":"additional","affiliation":[{"name":"Medizinische Klinik V, Universit\u00e4tsklinikum Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0961-0035","authenticated-orcid":false,"given":"Hartmut","family":"Goldschmidt","sequence":"additional","affiliation":[{"name":"Medizinische Klinik V, Universit\u00e4tsklinikum Heidelberg, 69120 Heidelberg, Germany"},{"name":"Nationales Centrum f\u00fcr Tumorerkrankungen, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mimi","family":"Choon-Quinones","sequence":"additional","affiliation":[{"name":"Independent Myeloma Alliance, 8808 Pf\u00e4ffikon, SZ, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Hose","sequence":"additional","affiliation":[{"name":"Department of Hematology and Immunology, Myeloma Center Brussels & Labor f\u00fcr Myelomforschung, Vrije Universiteit Brussel (VUB), 1090 Jette, Belgium"},{"name":"Independent Myeloma Alliance, 8808 Pf\u00e4ffikon, SZ, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1056\/NEJMra041875","article-title":"Multiple myeloma","volume":"351","author":"Kyle","year":"2004","journal-title":"N. 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