Celmod-Dexamethasone Combination Overcomes Primary Resistance to T Cell Engagers Caused By High Tumor Burden in a Human CRBN+ Preclinical Model of Multiple Myeloma

Introduction/Background: Bispecific T cell engagers (TCE) targeting BCMA and CD3 induce deep hematologic responses in approximately 60% of heavily pre-treated multiple myeloma (MM) patients. There is an unmet need to overcome primary resistance, as this off-the-shelf therapy is readily available to patients with aggressive disease relapse and has the potential to be delivered in the community. We and others found that high tumor burden leads to primary resistance to TCE ^1,2,3,4 and that combination with immunomodulatory drugs (IMiDs) transiently improves responses yet exacerbates T cell exhaustion². Here, we present preclinical strategies to overcome primary resistance which are tolerable and provide more durable responses specifically for the high tumor burden setting.

Methods: We evaluated response and survival to a murine surrogate BCMA/CD3 TCE in the Vk*MYC immunocompetent mouse model of MM expressing human CRBN to investigate tumor burden as a mechanism underpinning primary resistance. We evaluated dosing methods and combination strategies with IMiDs or novel CELMoDs, checkpoint inhibitors, and dexamethasone to improve response rates while maintaining a manageable safety profile.

Results: We investigated primary resistance in an expanded panel of Vk*MYC models reflecting differing genomic heterogeneity and confirmed that a threshold of tumor burden limits T cell activation and correlates with resistance to TCE. BCMA is cleaved from the tumor cell surface by gamma-secretase and thus, high density of shed BCMA may act as a sponge to BCMA TCE. However, we found that administration of gamma-secretase inhibitors, while stabilizing BCMA expression on MM cells, is not sufficient to overcome high tumor burden-driven resistance to TCE. We previously reported the combinatorial activity of BCMA TCE with IMiDs and revealed a role for tumor-extrinsic effects of IMiDs in allowing mice with a high tumor burden to transiently respond to BCMA-TCE before T cell exhaustion prevailed². To build on that combination strategy, we first hypothesized that the addition of a PD1 checkpoint inhibitor could reduce T cell exhaustion that occurs in response the BCMA-TCE in the resistant setting. We found that this triple combination provides more persistent activation and expansion of cytolytic T cells and sustains remission but leads to toxic cytokine release syndrome and early mortality in half of the cohort. Next, to address the acute toxicity from the hyperactivated T cell response and reduce tumor burden, we combined the triple combination with dexamethasone (Dex). To our surprise, concurrent Dex, even in the absence of IMiDs/CELMoDs, boosts responses to TCE. We observe that Dex moderates T cell proliferation in response to the TCE and leads to a moderate sustained cytokine production (IFN-γ, TNF, and IL-2R) systemically and in the bone marrow compared with a high transient burst seen with TCE alone or the concurrent treatment with IMiD + PD1 blockade. We determined that incremental step-up TCE dosing allows the combination of IMiDs or CELMoDs (iberdomide or mezigdomide) with Dex to be completely tolerated. To investigate whether delivering IMiD or CELMoDs before or during TCE administration altered efficacy, we tested pre-treatment with IMiDs/CELMoDs + Dex compared with concurrent dosing and found pre-treatment led to superior durable responses. Pre-treatment with iberdomide + Dex followed by step-up dosed TCE generated 100% response rate and the highest overall survival in subjects bearing a high tumor burden. This was accompanied by a more favorable T cell profiling over time, with limited expansion of regulatory T cells and reduced accumulation of exhausted T cells.

Conclusion: Modelling the dosing and combination strategies of a BCMA-TCE in our immunocompetent system has allowed us to understand the dynamic changes in T cell fitness that are required for effective, tolerable, and durable TCE therapy for MM. We illustrate how improvements to TCE therapy mitigate T cell exhaustion and overcome primary resistance, and importantly, suggest a strong immunotherapeutic strategy for MM patients with challenging-to-treat actively progressing disease.

1. Lee et al., Nat Med 29, 2295–2306 (2023)

2. Meermeier et al. Blood Cancer Discov. 2021 Jul;2(4):354-369.

3. Rees et al. Blood Cancer J. 2024 Jul 23;14(1):122.

4. Girgis et al. Blood Adv. 2023 Feb 28;7(4):644-648