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

Abstract

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. 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. 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 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. 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.