Translocation t(11;14) and BCL2-inhibition in multiple myeloma

Multiple myeloma is an increasingly treatable disease with improved survival, although characterized by multiple subclones that drive heterogeneity and variable clinical outcomes between patients. A biomarker-driven approach can help to tailor treatment and improve patient outcomes. Translocation t(11;14), a primary cytogenetic abnormality present in 15-20% of myeloma patients at diagnosis, is currently the most prominent targetable lesion in myeloma. In the era of induction with proteasome inhibitors and/or immunomodulatory drugs, t(11;14) has been associated with poorer outcomes compared to other standard-risk subgroups, with shorter progression-free and overall survival. The presence of t(11;14) in myeloma cells confers increased dependence on the pro-survival BCL2 protein, thus driving its ability to evade apoptosis, and is the main biomarker predicting response to BCL2-inhibitors. This review examines the pathogenesis and prognostic significance of t(11;14) in myeloma and the impact of concurrent high-risk cytogenetics, the mechanism of action of BCL2-inhibitors, cumulative evidence supporting their use, and proposed mechanisms of resistance. The review also presents potential future directions regarding BCL2-inhibitor-based regimens and how best to position these drugs to optimize patient outcomes.