Abstract CT121: Correlative biomarkers of response to venetoclax monotherapy in patients with relapsed/refractory multiple myeloma

Abstract

Abstract Selective BCL-2 targeting with venetoclax (VEN) has shown potent anti-tumor activity in human multiple myeloma (MM) cell lines and primary MM cells harboring the t(11;14) translocation, which is present in approximately 15-20% of patients (pts) with MM. Preclinical studies also indicated that VEN single-agent activity correlated with higher expression levels of BCL-2 relative to BCL-XL and MCL-1. The results presented herein describe correlative biomarker analyses in the ongoing phase 1 study of VEN monotherapy in pts with relapsed/refractory (R/R) MM (NCT01794520). As of 19 Aug 2016, 66 pts were enrolled on study, including 30 pts with t(11;14) MM as determined by interphase FISH analysis on CD138-selected bone marrow plasma cells. The overall response rate (ORR) in pts with t(11;14) MM was 40%, compared to 6% in the non-t(11;14) group (n=36). Responses in t(11;14) pts were durable, with a median duration of response (DoR) of 9.7 months and a median time to progression (TTP) of 6.6 months. In contrast, the median TTP was 1.9 months for non-t(11;14) pts. VEN activity was independent of refractory status to prior therapies and clinical responses were observed in t(11;14) pts with concurrent high-risk cytogenetics, including chromosome 17p deletion. In addition to cytogenetic analyses, baseline bone marrow aspirate samples from 44 pts were evaluable for BCL2 (BCL-2), BCL2L1 (BCL-XL) and MCL1 (MCL-1) mRNA expression by droplet digital PCR. Gene expression analysis revealed that the ratios of BCL2:BCL2L1 (log2 median: 2.75 vs 0.56, p<0.01, Wilcoxon) and BCL2:MCL1 (log2 median: -3.15 vs -5.01, p<0.05, Wilcoxon) were significantly higher in pts who achieved a partial response or better to VEN monotherapy. The rank order of expression profiles that best correlated with response to VEN was identified as high BCL2:BCL2L1 > low BCL2L1 > high BCL2:MCL1 > high BCL2 > low MCL1. On the basis of these results, bootstrapping and aggregating thresholds from trees was used to estimate a threshold value for BCL2:BCL2L1 that would provide optimum selection of pts likely to have a response. A high BCL2:BCL2L1 expression ratio (≥5.0) was observed in 10/44 (23%) pts, and was enriched in the t(11;14) subgroup [9/24 (38%) vs 1/20 (5%) in the non-t(11;14) subgroup]. Within the t(11;14) group, 8/9 pts with a high BCL2:BCL2L1 expression ratio achieved a partial response or better (ORR 88%), with a median DoR of 9.7 months and median TTP of 11.5 months. Median TTP for t(11;14) pts (n=15) with a low BCL2:BCL2L1 ratio was 5.3 months. Commensurate with preclinical findings, VEN has promising single-agent activity in pts with R/R t(11;14) MM. Additionally, BCL-2 family expression profiling can further define clinical activity within t(11;14) pts, including 88% ORR in high BCL2:BCL2L1 expressors, thus providing further supportive evidence for VEN monotherapy as a unique biomarker-driven approach for MM treatment. Citation Format: Jeremy Ross, Brenda Chyla, Rasna Goswami, Lisa Roberts-Rapp, Yan Sun, Yanwen Jiang, Elizabeth Punnoose, Maria Verdugo, Anahita Bhathena, Paulo Maciag. Correlative biomarkers of response to venetoclax monotherapy 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 CT121. doi:10.1158/1538-7445.AM2017-CT121