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Preprint WatchModerateSeptember 8th, 2026

Venetoclax-based Therapy Improves Outcomes across the Evolving Biology of t(11;14) Multiple Myeloma

Sudalagunta, P. R.; Ionescu, F.; Canevarolo, R. R.; Silva, M. C. S.; DeAvila, D.; Meads, M. B.; Zhao, X.; Perez, A.; Drekolias, D.; Irimia, R.; Thapa, S.; Patel, P.; Baz, R.; Shain, K. H.; Silva, A. S.; Grajales-Cruz, A.

t(11;14) multiple myeloma is enriched for BCL2 dependency, and venetoclax exposure in that cytogenetically defined subset was associated with substantially longer overall survival in a retrospective cohort.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that in a retrospective cohort of 381 patients with t(11;14) multiple myeloma, the 97 who received venetoclax had median overall survival roughly four years longer than the 284 who did not, p equals 0.0003, with the t(11;14) translocation stable over time while secondary high-risk abnormalities accumulated. The Claidex graph holds two BCL2 failures, both venetoclax in acute myeloid leukaemia and both in populations not selected for BCL2 dependency. In venetoclax-azacitidine-bcl2-aml-post-transplant-maintenance-phase3-strategic-termination the Phase 3 post-transplant maintenance study ended by sponsor reprioritisation, and in venetoclax-flag-clag-bcl2-secondary-aml-frontline-induction-phase2-interim-termination the Phase 2 addition of venetoclax to FLAG or CLAG induction in secondary AML ended at interim for efficacy. The preprint does not contradict those results so much as sharpen the boundary around them, since it locates benefit in a cytogenetically defined subset with an explicit BCL2 dependency rather than in unselected disease. The flag is raised because the same target now carries two recorded failures and the claim rests on a retrospective, non-randomised comparison in which treatment assignment was not controlled, so the survival difference is subject to confounding by indication and by era of treatment. Readers extending this to a prospective design should carry the biomarker selection forward explicitly rather than assuming the effect generalises to BCL2-unselected populations.

Abstract excerpt

Background: 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. Methods: 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. Results: Venetoclax exposure was associated with an improvement of median overall survival by nearly four years compared to non VEN 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 co

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.