Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax

Abstract

Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. Results suggest that venetoclax is only active in a small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in 4 of the 5 cell lines tested. The most striking results were seen with dexamethasone. Co-treatment of human myeloma cell lines and primary patient samples, with dexamethasone and venetoclax significantly increased cell death over venetoclax alone in 4 of the 5 cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of dexamethasone. This results in alterations in Bim binding to anti-apoptotic proteins. Dexamethasone shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with dexamethasone could be an effective therapy for a broader range of patients than would be predicted by single agent activity.

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma

“…26,27 Dexamethasone also increases BCL-2 dependency of myeloma cells by upregulating the expression of the proapoptotic molecule BIM and shifting its binding toward BCL-2, resulting in increased sensitivity to venetoclax. 28 Accordingly, an ongoing phase 1b study of venetoclax in combination with bortezomib and dexamethasone (NCT01794507) has shown high response rates in patients with relapsed/refractory MM irrespective of t (11;14) status. 29 In the present study, the addition of dexamethasone at the time of progression did not appear to add any clinical benefit for patients on venetoclax monotherapy.…”

Peptide vaccination against multiple myeloma using peptides derived from anti-apoptotic proteins: a phase I trial

“…Due to its immunosuppressive effects dexamethasone is generally thought to be difficult to combine with therapeutic vaccination; however, interestingly, dexamethasone seems to increase Bcl-2 dependence in MM resulting in increased sensitivity to the Bcl-2-inhibitor venetoclax in vitro (14). Furthermore, a recent paper reported the efficacy of a peptide vaccine combined with low-dose dexamethasone in prostate cancer (15).…”

Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM

“…20,21 Dexamethasone, a steroid commonly used in MM treatment, can upregulate the expression of the proapoptotic molecule BIM and increase its binding to BCL-2, which also results in increased sensitivity to venetoclax. 22 Thus, targeting BCL-2 and MCL-1 function to induce apoptosis through the combination of venetoclax, bortezomib, and dexamethasone is a compelling approach to treat MM.…”