{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T19:19:47Z","timestamp":1787685587463,"version":"build-2784847793"},"posted":{"date-parts":[[2026,8,21]]},"group-title":"Cancer Biology","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["03LW0239K"],"award-info":[{"award-number":["03LW0239K"]}],"id":[{"id":"https:\/\/ror.org\/04pz7b180","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Multiple myeloma (MM) exhibits profound molecular heterogeneity, yet current risk stratification relies on cytogenetics or single-omics signatures that often fail to capture cross-layer regulatory complexity. We re-analyzed a multi-omics dataset integrating copy-number, transcriptomic, proteomic, and phosphoproteomic data to dissect how common genomic driver alterations propagate through the molecular cascade. Supervised classification demonstrated that downstream layers, particularly the proteome and phosphoproteome, classify genomic events more accurately than primary genomic or transcriptomic data. Intriguingly, trans-acting features alone were sufficient for classification, indicating that while direct dosage effects manifest at the RNA level, downstream network responses dominate the proteomic state.<\/jats:p>\n                <jats:p>Multi-omics factor analysis (MOFA2) identified a continuous latent axis predicting progression-free and overall survival independent of R-ISS. This factor captured a gain(1q)\/del(13q) axis modulated by immune infiltration and NSD2 expression, integrating variance across all four modalities. To enable clinical translation, we derived sparse, single-modality proxies using elastic net regression. An RNA proxy faithfully recapitulated the multi-omic factor and validated independently in published microarray and RNAseq cohorts, demonstrating robust prognostic utility across treatment eras. These findings reveal that multi-omics integration uncovers hidden prognostic axes obscured by single-omics analyses, and that sparse proxies can bridge the gap between complex discovery and clinical implementation.<\/jats:p>","DOI":"10.64898\/2026.08.21.746155","type":"posted-content","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T16:55:34Z","timestamp":1787331334000},"source":"Crossref","is-referenced-by-count":0,"title":["Translating multi-omics complexity into sparse prognostic biomarkers for multiple myeloma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9116-630X","authenticated-orcid":false,"given":"Benedikt","family":"Obermayer","sequence":"first","affiliation":[{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Center of Genomic Medicine, Translational Bioinformatics, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3067-2030","authenticated-orcid":false,"given":"Manuela","family":"Benary","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4649-0506","authenticated-orcid":false,"given":"Jan","family":"Kr\u00f6nke","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Cancer Immunology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"},{"name":"Department of Hematology, Oncology, Stem Cell Transplantation and Palliative Care, University Medicine Greifswald, Greifswald, Germany"},{"name":"German Cancer Consortium, Partner Site Berlin, a partnership between Deutsches Krebsforschungszentrum and Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-528X","authenticated-orcid":false,"given":"Philipp","family":"Mertins","sequence":"additional","affiliation":[{"name":"Proteomics Platform, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3284-0632","authenticated-orcid":false,"given":"Dieter","family":"Beule","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Center of Genomic Medicine, Translational Bioinformatics, Berlin, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany"},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026082512000648000_2026.08.21.746155v1.1","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1038\/s41588-025-02196-0","article-title":"Genomic landscape of multiple myeloma and its precursor conditions","volume":"57","year":"2025","journal-title":"Nat Genet"},{"key":"2026082512000648000_2026.08.21.746155v1.2","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1038\/s41467-024-46728-4","article-title":"Aberrant non-canonical NF-kappaB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026082512000648000_2026.08.21.746155v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02015-1"},{"key":"2026082512000648000_2026.08.21.746155v1.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.36.5726"},{"key":"2026082512000648000_2026.08.21.746155v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty199"},{"key":"2026082512000648000_2026.08.21.746155v1.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-01-0034"},{"key":"2026082512000648000_2026.08.21.746155v1.7","doi-asserted-by":"crossref","unstructured":"Bohra A , Dasari S , Zanwar S , Gonsalves WI , Kapoor P , Binder M , Dispenzieri A , Timm MM , Buadi F , Jevremovic D , Rajkumar SV and Kumar S (2026) Gene expression-based dissemination score predicts early spread and poor outcomes in multiple myeloma. 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