Sensitivity to venetoclax: the B-side of myeloma?

In this issue of Blood, Gupta et al¹  demonstrated that venetoclax sensitivity in multiple myeloma (MM) is associated with B-cell gene expression. This study brings a new approach to improve identification of patients with MM most likely to respond to BCL2 targeted therapy.

The oral BH3 mimetic venetoclax induces apoptosis by displacing proapoptotic proteins from the antiapoptotic protein BCL2.²  Venetoclax is the first targeted therapy with clinical efficacy demonstrated in a specific cytogenetic subset of patients with MM. Preclinical studies demonstrated that sensitivity to venetoclax was restricted to MM cells harboring the t(11;14) translocation, a cytogenetic abnormality found in 15% to 20% of patients with MM.³  Phase 1 to 3 clinical trials in relapsed MM confirmed the efficacy of venetoclax in t(11;14) patients, whereas few patients from other cytogenetic subgroups obtain substantial benefit from the drug.^4-6  Biomarker analysis from these clinical trials also showed the prognostic value of high BCL2 expression, which is associated with higher response rate and longer progression-free survival.

To date, we still need to improve the identification of patients with MM most likely to respond to venetoclax. First, although most patients sensitive to BCL2 targeting harbor the t(11;14), only 40% to 60% of patients from this subgroup actually respond to this approach.^4,5  Moreover, BCL2 expression is not yet a standardized test and thus not available for routine use.

In the present study, Gupta et al demonstrate that MM cells sensitive to venetoclax are enriched for specific B-cell genes, including CD20 and CD79A. This partially reactivated B-cell program is related to a specific chromatin accessibility pattern leading to an increased binding of transcription factor involved in B-cell development (ie, basic leucine zipper ATF-like transcription factor [BATF]). This aberrant B-cell reprogramming may contribute to BCL2 dependence, which is normally downregulated during plasma cell differentiation (see figure). By using a flow cytometry score including B markers (ie, CD20, CD79A), the authors correctly predicted sensitivity to venetoclax in a series of MM cell lines and primary samples.

Previous flow cytometry and gene expression profile analysis revealed that CD20 expression in MM is mostly observed in patients with t(11;14).^7,8  However, in the study from Gupta et al, a subset of venetoclax-sensitive samples was identified by flow with positive B markers without t(11;14), including patients from the hyperdiploid molecular subgroup. CD20 expression was also shown in a subset of patients from the MAF subgroup.⁸ 

From a practical point of view, the use of flow cytometry using readily available reagents to predict sensitivity to venetoclax in patients with MM is very attractive. The mandatory next step will be to confirm the predictive value of B markers in a prospective study of patients treated with venetoclax. If confirmed, the determination of this B-cell phenotype using flow cytometry may help to identify patients that could benefit from venetoclax beyond the presence of t(11;14).