Abstract CT122: BCL2 expression is a potential predictive biomarker of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma
Authors: Ross Jeremy , Chyla Brenda , Goswami Rasna , Roberts-Rapp Lisa , Sun Yan , Jiang Yanwen , Punnoose Elizabeth , Verdugo Maria , Bhathena Anahita , Maciag Paulo 
Published: July 2017

The anti-apoptotic proteins BCL-2 and MCL-1 have been shown to promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, and orally bioavailable small-molecule inhibitor of BCL-2. Bortezomib (BTZ) is a proteasome inhibitor that can inhibit MCL-1 activity by increasing the MCL-1 antagonist, NOXA. Results presented herein describe correlative biomarker analyses in the ongoing phase 1b study of VEN in combination with BTZ and dexamethasone in patients with relapsed/refractory (R/R) MM (NCT01794507). As of 19 Aug 2016, 66 patients were enrolled on study. Baseline bone marrow aspirate samples were available from 52 patients, of which 45 were evaluable for BCL-2 family gene expression by droplet digital PCR in CD138-selected tumor cells. Correlation between BCL2 (BCL-2), BCL2L1 (BCL-XL) and MCL1 (MCL-1) mRNA expression (log2-transformed copies/ul normalized to housekeeping gene) and preliminary efficacy [overall response rate (ORR), time to disease progression (TTP) and duration of response (DoR)] were examined by Log-rank and Wilcoxon tests for binary biomarkers, and by risk ratio from Cox proportional hazard model for continuous biomarkers. The ORR was 68% (44/65) for all evaluable patients and 89% (31/35) in patients who had 1-3 prior therapies (31/35). A broad range of BCL2, BCL2L1 and MCL1 expression was observed, however higher BCL2 levels were detected in patients who achieved a partial response (PR) or better (median: 3.01 vs 0.87, p&lt;0.01). Additionally, higher BCL2 levels were observed in patients who had 1-3 prior lines of therapy compared to 4 or more lines of therapy (median: 3.03 vs 0.94, p&lt;0.01). In contrast, no association was observed between BCL2L1 or MCL1 gene expression and response or number of prior therapies. Bootstrapping and aggregating thresholds from trees was used to estimate a threshold value for BCL2 expression that would provide optimum selection of patients likely to have a response. Overall, seventeen of 18 patients with high BCL2 expression (≥3.0) achieved at least a PR (ORR 94%), with 12 patients (66%) achieving VGPR or better. Sixteen of 27 patients with low BCL2 expression achieved at least a PR (ORR 59%), with 6 patients (22%) achieving a VGPR or better. Median TTP (11.6 vs 5.7 months) and DoR (10.2 vs 7 months) were longer for patients with high versus low BCL2 expression. Responses in high BCL2 expressors were independent of cytogenetic status as determined by interphase FISH analysis, including t(11;14), t(4;14), del(13q) and del(17p). Targeting BCL-2 and MCL-1 with the combination of VEN, BTZ and dexamethasone provides a unique approach for MM treatment. Efficacy results in tumors expressing high BCL2 levels, including 94% ORR, provide supportive evidence for the evaluation of this combination regimen in the ongoing phase 3 study (NCT02755597) in R/R MM.

Citation Format: Jeremy Ross, Brenda Chyla, Rasna Goswami, Lisa Roberts-Rapp, Yan Sun, Yanwen Jiang, Elizabeth Punnoose, Maria Verdugo, Anahita Bhathena, Paulo Maciag. BCL2 expression is a potential predictive biomarker of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT122. doi:10.1158/1538-7445.AM2017-CT122