Rapid and Sustained Reduction of Immunosuppressive T-Cells and Focusing of the T-Cell Repertoire in t(11;14) Relapsed/Refractory Multiple Myeloma Patients Treated with Venetoclax in Combination with Daratumumab and Dexamethasone
Authors: Bahlis Nizar J. , Kaufman Jonathan L. , Baz Rachid , Quach Hang , Ho Shir-Jing , Vangsted Annette J. , Plesner Torben , Moreau Philippe , Gibbs Simon D. , Medvedova Eva , Bueno Orlando F. , Luo Yan , Mantis Christine , Vishwamitra Deeksha , Ross Jeremy A. , Harrison Simon J 
Published: November 2021

Abstract

Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that is currently being evaluated as a targeted therapy for the treatment of t(11;14) relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown promising efficacy with a tolerable safety profile in the phase 1/2 study (NCT03314181). VenDd is hypothesized to have increased anti-myeloma activity based upon complementary mechanisms of pro-apoptotic effects on tumor cells as well as potentially enhanced T-cell activation and clonal expansion, which has been shown to be associated with achieving deep sustained response to D-based therapy in MM. Results presented herein describe the immunomodulatory effects observed upon VenDd treatment in t(11;14) RRMM patients, including effects on the T-cell repertoire.
Methods: Peripheral blood samples from t(11;14) RRMM patients (n=18) treated with VenDd (NCT03314181) were collected at day 1 of cycles 1-5 to characterize effects on B-, T-, and NK-cell populations by multicolor flow cytometry. TCRβ sequencing (ImmunoSEQ, Adaptive Biotechnologies) was also conducted on peripheral blood samples collected from t(11;14) RRMM patients (n=31) treated with VenDd at day 1 of cycles 1, 3, 5, and 9 to assess changes in T-cell clonality, defined as the extent of mono- or oligoclonal expansion by Simpson clonality index, and T-cell richness, defined as the number of clones with unique TCRβ rearrangements after computationally down-sampling to a common number of T-cells.
Results: Consistent with previous findings with Ven, rapid and sustained depletion of B-cells (CD19+/CD5-) was observed in patients treated with VenDd (median absolute count: 115 cells/ml at baseline vs 13 cells/ml at C2D1 (89% decrease), p&lt;0.0001; vs 4 cells/ml at C5D1 (97% decrease), p&lt;0.01). Significant reduction in NK cells (CD16+/CD56+) was also observed upon VenDd treatment (median absolute count: 179 cells/ml at baseline vs 30 cells/ml at C2D1 (83% decrease), p&lt;0.0001; vs 16 cells/ml at C5D1 (91% decrease), p&lt;0.01), which is consistent with previous results with D-containing regimens. Within the circulating T-cell population, a significant and sustained decrease in CD4+ T-cells (median absolute count: 421 cells/ml at baseline vs 251 cells/ml at C2D1 (40% reduction), p&lt;0.0001; vs 211 cells/ml at C5D1 (50% reduction), p&lt;0.01) was observed, with naïve and central memory CD4+ T-cells being more sensitive than effector memory T-cells (median absolute count: 61 cells/ml at baseline vs 34 cells/ml (45% reduction) at C3D1, p&lt;0.01; 162 cells/ml at baseline vs 79 cells/ml (51% reduction) at C3D1, p&lt;0.001; 151 cells/ml at baseline vs 120 cells/ml (21% reduction) at C3D1, p&lt;0.01; respectively). A rapid and sustained decrease in immunosuppressive regulatory T-cells (CD4+/CD25 hi/CD127 dim) was observed in VenDd treated patients (median absolute count: 42 cells/ml at baseline vs 18 cells/ml at C2D1 (56% reduction), p&lt;0.0001; vs 15 cells/ml at C5D1 (63% reduction), p&lt;0.01). In contrast to the CD4+ T-cell subsets, a transient decrease in CD8+ T-cells was observed at C2D1 (median absolute count: 333 cells/ml at baseline vs 259 cells/ml at C2D1 (22% reduction), p&lt;0.001) with levels returning to near-baseline by C3D1, including effector memory CD8+ T-cells. TCR-sequencing revealed a significant increase in T-cell clonality upon treatment with VenDd (Figure 1A). A significant decrease in T-cell richness was observed (Figure 1B), indicating a focusing of the T-cell repertoire. The observed increases in T-cell clonality upon VenDd treatment were due to expansion of both newly detected clones and clones that were present at baseline (Figure 1C). Finally, the immunomodulatory effects of VenDd described herein were consistent between the Ven dose cohorts (400 and 800mg).
Conclusions: Treatment of t(11;14) RRMM patients with VenDd resulted in selective depletion of B-cells, NK-cells, and immunosuppressive regulatory T-cells, but not CD8+ T-cell subsets. Increased T-cell clonality indicates focusing of the T-cell repertoire and generation of an adaptive anti-myeloma immune response upon treatment with VenDd. The study is continuing with a randomized, open-label expansion that will further evaluate the safety and efficacy of VenDd in patients with t(11;14) RRMM, including correlative studies between the observed immune modifications and patient outcome.
Figure 1 Figure 1.

Disclosures
Bahlis: Genentech: Consultancy; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman: Fortis Therapeutics: Research Funding; Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; BMS: Consultancy, Research Funding; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Amgen: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Baz: BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Merck: Research Funding; GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy. Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Genmab, Genentech, Roche: Research Funding; Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding. Moreau: Celgene BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Mantis: AbbVie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Harrison: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

OffLabel Disclosure:
Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that is being investigated as therapy for the treatment of relapsed/refractory multiple myeloma.