Multiple myeloma with amplification of chromosome 1q is highly sensitive to MCL-1 targeting

Introduction
Pro-survival BCL-2 family proteins are potent inhibitors of apoptosis and are often overexpressed in lymphoid malignancies. In multiple myeloma (MM), BCL-2 inhibitor Venetoclax induces cell death, particularly in presence of t(11;14) and high BCL-2 expression. The most prominent BCL-2 family member in MM is MCL-1, whose expression contributes to survival of malignant plasma cells and overexpression correlates with poor prognosis. Amplification of 1q21, the chromosome region that contains the MCL1 locus, occurs in approximately 40% of newly diagnosed MM, and 70% at relapse. This chromosomal abnormality is associated with poor disease prognosis. In this study, we investigate whether sensitivity to the novel MCL-1-inhibitor S63845 can be predicted using cytogenetics, thereby focusing on amplification of 1q21. In addition, we study the relation of MCL-1 inhibitor sensitivity with other diagnostic characteristics, and with BCL-2 family protein expression.

Methods
In 31 human myeloma cell lines and in bone marrow aspirates from 47 newly diagnosed MM patients, we measured the effect of S63845 alone, or combined with BCL-2 inhibitor ABT-199 (Venetoclax), and BCL-XL inhibitors A-1155463 or A-1331852, on cell viability.

Results
We demonstrate for the first time that MM patients with 1q21 amplification are significantly more sensitive to inhibition of MCL-1 in vitro. We propose that this increased sensitivity results from increased MCL1 expression due to amplification of 1q21. Additionally, and independent from 1q21 status, increased serum β2m level and presence of renal insufficiency correlated with increased sensitivity to MCL-1 inhibitor treatment. Using both 1q21 status and serum β2m level, we identified a MM subset with very strong dependence on MCL-1. Combining S63845 with other BH3-mimetics synergistically increased apoptosis compared to single inhibitors, and sensitivity to inhibitor combinations was found in a large proportion of MCL-1-independent MM.

Conclusion
Collectively, our data indicate that amplification of 1q21 identifies a poor prognosis MM subset that is highly sensitive to MCL-1 inhibitor treatment.