{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:15:00Z","timestamp":1789146900728,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,7]]},"group-title":"Oncology","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Philanthropic funding from Pentecost Family Myeloma Research Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Translocation t(11;14) defines a biologically distinct subset of multiple myeloma (MM) enriched for BCL2 dependency. Treatment with venetoclax, selective BCL2 inhibitor, has shown varied responses in clinical trials and retrospective cohorts. Efficacy of venetoclax-based combination therapies and optimal timing of treatment in t(11;14) MM patients remain incompletely characterized.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We have compared the overall survival of t(11;14) MM patients who received Venetoclax (N = 97) at any moment in time, to those who never did (N =284), in the largest retrospective cohort (N = 381) reported to date. We used longitudinal fluorescence in situ hybridization (FISH) to assess cytogenetic evolution and genomic complexity. We performed transcriptomic profiling of CD138-enriched tumors using RNA sequencing in a subset of samples and gene-expression signatures (UAMS\/HALLMARKS) were used to define molecular subtypes. Ex vivo drug sensitivity assays integrated with paired RNA sequencing were used to identify subtype-specific therapeutic vulnerabilities and rational venetoclax-based combination strategies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Venetoclax exposure was associated with an improvement of median overall survival by nearly four years compared to non\u2013VEN-exposed patients (p = 0.0003). Longitudinal cytogenetic analysis demonstrated stability of the primary t(11;14) translocation over time, while secondary abnormalities tend to accumulate, including those harboring high-risk secondary cytogenetic abnormalities such as del13q, amp\/gain1q21, del17p, and del1p, resulting in increasing genomic complexity with disease progression. Transcriptomic analyses identified selective enrichment of CD1\/CD2 signature (associated with t(11;14) NDMM) by single-sample gene set enrichment analysis as a marker of prolonged progression-free survival. However, patients with more than five prior lines of therapy were enriched for transcriptionally complex biology characterized by CD1\/CD2 with either proliferative\/hypermetabolic or inflammatory transcriptional programming which were associated with inferior outcomes with VEN-based treatment. Ex vivo drug sensitivity profiling revealed subtype-specific vulnerabilities, identifying daratumumab, lenalidomide, ixazomib, and panobinostat as rational partners for venetoclax depending on transcriptional context.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Venetoclax-based therapy significantly improved overall survival in t(11;14) MM. Clinical benefit, defined by improved progression free survival, was greatest when venetoclax was administered earlier, preceding the emergence of transcriptomic reprogramming that reduces BCL2 dependency. These findings support transcriptomic biomarker-guided, subtype-specific venetoclax-based treatment strategies to optimize outcomes in patients with t(11;14) MM.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.02.26361956","type":"posted-content","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:45:22Z","timestamp":1788839122000},"source":"Crossref","is-referenced-by-count":0,"title":["Venetoclax-based Therapy Improves Outcomes across the Evolving Biology of t(11;14) Multiple Myeloma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1283-9332","authenticated-orcid":false,"given":"Praneeth Reddy","family":"Sudalagunta","sequence":"first","affiliation":[{"name":"Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Ionescu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mon Health Cancer Center, Morgantown, WV, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8722-8512","authenticated-orcid":false,"given":"Rafael Renatino","family":"Canevarolo","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Coelho Siqueira","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"DeAvila","sequence":"additional","affiliation":[{"name":"Collaborative Data Services Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark B.","family":"Meads","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Drekolias","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxandra","family":"Irimia","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, H. 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