Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, immunology, Biological Processes
Methods: We identified 15 RRMM patients who had progressed on a T cell directed therapy, either anti-BCMA CAR-T (n=10) or BiAbs (n=5) and then received another BiAb as a subsequent line of therapy. 70% of patients who progressed on anti-BCMA CAR-T (7/10) and 20% who progressed on BiAbs had interim therapies before receiving subsequent BiAbs therapy. The median time between the first T cell directed therapy and subsequent therapy was 5 months (range 0- 26 months). We profiled immune cell activation in peripheral blood (PB) by high dimensional flow cytometry and Olink Proteomics. Clinical data such as patient demographics, disease characteristics and post-clinical trial outcomes were collected retrospectively until July of 2022. Data and sample collection for this study was approved by the institutional review board (IRB) and follows the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice (IRB: GCO#: 11-1433 & GCO #: 18-00456).
Results: We compared baseline immune cell populations of 15 RRMM patients in the PB post relapse on T cell mediated therapy and during subsequent BiAb treatment (Figure 1a). 93% of patients (14/15) received BiAbs therapy with a different target than their first T cell directed regimen. 73% of patients (11/15) received sequential BiAbs therapy in combination with an anti-CD38 monoclonal antibody. Patients had a median age of 63 years (range 43-89) at time of progression after the first T cell directed therapy. MM patients were heavily pre-treated with a median of 6 prior lines of therapy (range 3-16). All patients were triple-class refractory while 66% were penta-drug refractory.
Immune profiling at time of progression on the first T cell directed therapy, was associated with increased expression of exhaustion markers on CD4+ and CD8+ T cells. Treatment with a second BiAb was associated with significant re-activation of endogenous T cells. Specifically, CD8+ T cells demonstrated increased expression of hallmark surface activation markers such as HLA-DR and CD69+ (p<0.05, Figure 1b), and this increase was consistent in CD4+ T cells as well (p<0.01, Figure 1b). Alongside T cell engagement we saw an increase in surface activation markers CD69+ and HLA-DR on NK and DC populations respectively (p<0.01). This indicates that the application of the second T cell directed therapy not only reactivates T cell compartment but potentiates widespread immune cell activation. Plasma cytokine analysis from these patients revealed elevated CXCL10, CXCL9, and TNFa during bispecific therapy; reinforcing the activation state of the patients during treatment. Although the CD4:CD8 ratios remain conserved, we observed a significant differentiation of CD8+ T cells through sequential therapy, with a reduction of naïve CD8+ T cells (p=0.022) and increase of effector memory CD8+ T cells (p<0.01).
Conclusion: Our data suggests that patients who progressed on T cell directed therapy and went on to receive T cell mediated BiAbs, not only respond clinically, but also have hallmark expression of activation markers. T cells can be reactivated post relapse from T cell mediated therapies, indicating that T cell targeted treatments can be applied successfully in sequential order with favorable patient outcomes. We are currently performing immune profiling on more PB and bone marrow samples to further confirm these findings in a larger patient population.
Disclosures: Rossi: janssen: Consultancy; BMS: Consultancy; adaptive: Consultancy; sanofi: Consultancy; gsk: Consultancy. Richter: Takeda: Consultancy; Oncopeptides: Consultancy, Honoraria; Secura Bio: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cho: BMS/Celgene: Other: Receive laboratory research support from the above companies. Salary value is less than $10,000 per company., Research Funding; Takeda: Other: Receive laboratory research support from the above companies. Salary value is less than $10,000 per company., Research Funding. Rodriguez: Janssen, BMS, Takeda, AbbVie, karyopharm, Artiva: Consultancy, Speakers Bureau. Chari: Novartis Pharmaceuticals: Research Funding; Glaxo Smith Klein: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy; Oncoceutics: Research Funding. Jagannath: BMS: Consultancy; Legend Biotech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy.
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