Abstract 902: Examining the impact of chromosome 1q-located gamma secretase subunits in the resistance to BCMA-targeted therapies in multiple myeloma patients

Abstract Multiple Myeloma (MM) is an incurable hematological malignancy originating from abnormal plasma cells in the bone marrow. A common genetic abnormality in MM is the gain or amplification of chromosome arm 1q (chr1q), present in 30-40% of MM patients and typically associated with poor prognosis. Chr1q includes three subunits of the gamma-secretase (GS) enzyme- Nicastrin (NCSTN), Presenilin-2 (PS2), and Anterior Pharynx Defective 1 Homolog A (APH1A)—which catalyze the conversion of membrane-bound BCMA (mBCMA) to soluble BCMA (sBCMA). BCMA is a crucial target receptor for anti-BCMA therapies. Elevated sBCMA levels are linked to poor prognosis and reduced efficacy of BCMA-targeted therapies, apparently due to the sink effect. We hypothesize that chr1q amplification in MM leads to increased GS expression, resulting in reduced mBCMA and elevated sBCMA levels, which may drive resistance to BCMA-targeted therapies and contribute to adverse patient outcomes. To investigate this, we employed cloning and lentiviral transduction techniques to overexpress NCSTN, PS2, and APH1A individually, as well as in various combinations, in OPM2 myeloma cell lines, generating seven novel cell lines. Each subunit was fused with distinct tags to confirm successful transduction and overexpression. Using flow cytometry with BCMA-PE antibodies and sBCMA ELISA, we assessed mBCMA and sBCMA levels across these GS subunit-overexpressing cell lines compared to an empty vector control. Our results demonstrated that all seven GS subunit-overexpressing OPM2 cell lines exhibited decreased mBCMA levels. The triple-overexpressing cell line (NCSTN, PS2, and APH1A) showed a remarkable ten-fold reduction in mBCMA compared to the control. Additionally, differences in sBCMA levels were observed across the GS subunit-overexpressing cell lines relative to the control. These findings underscore the pivotal role of GS subunits encoded by chr1q in driving the poor prognosis associated with chr1q gain or amplification in MM. Ongoing analyses aim to elucidate the resistance mechanisms of these GS subunit-overexpressing OPM2 cell lines to anti-BCMA CAR-T therapies and T-cell engagers (TCEs). Citation Format: Sejal Chikhale, Mansour Poorebrahim, Holly Lee, Elham Hasheminasabgorji, Anja Barbour, David Jung, Paola Neri, Nizar J. Bahlis. Examining the impact of chromosome 1q-located gamma secretase subunits in the resistance to BCMA-targeted therapies in multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 902.