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    Myeloma Novel Drug Targets and agents

    Category: Myeloma Novel Drug Targets and agents

    Ex vivo evaluation of BCL-2 family member dependencies in multiple myeloma: synergistic combinations and biomarkers of sensitivity and resistance

    (PA-316) Ex vivo Evaluation of BCL-2 Family Member Dependencies in Multiple Myeloma: Synergistic Combinations and Biomarkers of Sensitivity and Resistance

    Wednesday, September 17, 2025
    Introduction: Multiple myeloma (MM) is a malignancy of plasma cells, with patients commonly developing resistance to multiple therapies. MM cell fate is controlled by a balance of BCL-2 family members, including BCL-2, BCL-XL, and MCL-1. In this study, we evaluated the cytotoxic activity of BCL-2 family inhibitors, both as single agents, in combination, and with standard MM therapies. We also aimed to identify predictive biomarkers and mechanisms of sensitivity or resistance to this class of agents.

    Methods: Ex vivo chemosensitivity assays were performed in a unique organotypic platform using 98 fresh primary MM samples, spanning smoldering MM to relapsed/refractory stages. Cytotoxic responses to single agents and combinations were quantified using area under the curve and LD50 metrics. Synergy and antagonism were assessed using the BLISS synergy model. Ex vivo data were integrated with molecular (WES, RNA-Seq) and clinical data using Fisher’s Exact Test (mutations), enrichment analysis (transcriptional data), and adapted univariate Cox models to identify features associated with increased synergy or sensitivity ex vivo.

    Results: ABBV-467, an MCL-1 inhibitor, was the most potent single agent, with LD50 values in the nanomolar range. It showed particular efficacy against samples with t(14;16), gain1q21, mutations in PTPN11 and HUWE1, "MF" and "PR" transcriptional subtypes, and those overexpressing BAK1. The BCL-2 inhibitor venetoclax was highly effective in MM with t(11;14), gain18q, trisomy 13, mutations in ARID2, XBP1, CYLD and HUWE1, "CD1" and "CD2" subtypes, and those overexpressing BCL2. In contrast, BCL-XL inhibition with A-1331852 showed limited single-agent activity. Among combinations, MCL1 + BCL-XL inhibition showed the strongest synergy, including in high-risk (HR) MM (hypodiploidy, t(14;16), del17p) and the "LB" subtype. BCL-2 + BCL-XL inhibition was also highly synergistic, especially in t(11;14) samples. MCL-1 + BCL-2 and BCL-2 + BCL-XL inhibition targeted complementary subgroups within the “PR” subtype (linked to poor prognosis). Interestingly, MCL-1 inhibition + Pom demonstrated increased activity in t(14;16) samples, and consistent with preclinical data, BCL-2 inhibition synergized with panobinostat. Molecular features associated with sensitivity to other combinations will be presented.

    Conclusions: BCL-2 and MCL-1 are the dominant anti-apoptotic BCL-2 family effectors in MM. While MCL-1 inhibition may effectively target specific HR MM subtypes, its activity is enhanced when combined with BCL-XL inhibition. These data also indicate that BCL-XL is a primary resistance factor, becoming relevant in the context of MCL-1 or BCL-2 inhibition, where significant synergy is observed. This underscores the pivotal role of BCL-2 family members in MM cell survival, including potential strategies that could exploit these vulnerabilities in certain high-risk subtypes.