The Role of NOXA in Venetoclax Treatment Response in Multiple Myeloma

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.4635-4635
• Main Authors: Shivaram, Suganti, Yan, Huihuang, Tang, Hongwei, Anderson, Hans M., Kaddoura, Marcella, Wiedmeier-Nutor, J Erin, Tian, Shulan, Howe, Michael D, Bolarinwa, Abiola, Zepeda Mendoza, Cinthya, Gupta, Vikas A, Lehman, Stacey, Mitsiades, Constantine S, Bergsagel, P. Leif, Braggio, Esteban, Boise, Lawrence H., Fonseca, Rafael, Maura, Francesco, Kumar, Shaji, Baughn, Linda B.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-205385

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy with several recurrent primary cytogenetic abnormalities including t(11,14)(q13;q32), resulting in increased expression of CCND1. Although 40% of patients with t(11;14) MM respond favorably to the BCL-2 inhibitor venetoclax (ven), 60% fail to achieve an objective response. Previous studies have suggested upregulation of PMAIP1, encoding the pro-apoptotic NOXA protein, in association with ven sensitivity (Leblay, Blood, 2024). Here we sought to evaluate the role for NOXA in ven response in t(11;14) MM. Methods: We analyzed whole exome, whole genome and RNA sequencing data of CD138+ tumor cells from 1,359 patients with MM in the CoMMpass and Mayo Clinic cohorts. The histone mark H3K27ac was assessed in t(11;14)+ KMS12PE and U266B1 human myeloma cell lines using ChIP-seq. Gene expression and protein levels of PMAIP1 (NOXA) were also detected by qRT-PCR and Western blot, respectively. Live cell detection was evaluated by Annexin V and PI using flow cytometry and by YoYo3 dye using IncuCyte following treatment with ven. Results: The t(11;14) MM subtype was associated with a 1.6-5.5-fold increased expression of PMAIP1 compared to non-t(11,14) MM in the CoMMpass and Mayo Clinic cohorts (p