P-086: Quantitative seroproteomics analysis of Multiple Myeloma patients treated with Tagraxofusp, a novel CD123-directed targeted therapy, identifies novel cytokine-mediated mechanism of action

Background We previously described a tumor-promoting and immunosuppressive role of plasmacytoid dendritic cells (pDCs; CD123/IL-3R+) in multiple myeloma (MM) pathogenesis (Chauhan et al. Cancer Cell, 2009; Ray et al, Leukemia, 2018). Tagraxofusp, an FDA-approved (for patients with blastic plasmacytoid dendritic cell neoplasm [BPDCN]) novel targeted therapy directed against CD123, can trigger anti-MM activity by decreasing the viability of MM-promoting pDCs. These observations led to a recently completed phase 1/2 clinical trial of tagraxofusp and pomalidomide/dexamethasone in relapsed/refractory MM patients (NCT02661022). The treatment regimen demonstrated preliminary safety and efficacy, with 5 of 9 heavily pretreated patients achieving durable partial response (PR) (ASH 2019). Here, we report the early results of our translational correlative studies using bone marrow (BM), peripheral blood (PB), and serum from the study cohort. Methods Tagraxofusp is a bioengineered targeted therapy directed to CD123 developed by fusing human IL-3 to a truncated diphtheria toxin (DT) payload (Stemline Therapeutics, NY). pDCs and patient MM cells were purified from BM/PB samples after informed consent, and quantified using FACS, as described (Ray et al, Leukemia, 2018). A novel high throughput seroproteomics platform SOMAscan was used to analyze 1,310 protein analytes in serum samples from MM patients (n = 9). SOMAscan data were subjected to meta-analysis to generate heatmaps, followed by hierarchical cluster analysis. SOMAscan results were validated with ELISA using supernatants from MM patient pDCs cultured with or without tagraxofusp. Results Analysis of BM/PB samples from MM patients receiving tagraxofusp therapy showed a distinct reduction in the frequency of viable pDCs [average 2% at screening vs 0.75% post-tagraxofusp; n = 6; p = 0.036]. Of note, pDCs isolated from tagraxofusp-treated patients showed decreased ability to trigger MM cell growth. SOMAscan analysis of patient serum before and after tagraxofusp therapy showed alterations in the levels of 100 proteins [Median Fold Change in expression: 0.39 to 4.5; n = 6; 3 each; p Conclusions Our correlative science studies validate the target specificity of tagraxofusp against MM pDCs in relapsed and refractory MM patients enrolled in a phase 1/2 clinical trial. Our study favors further evaluation for this novel therapeutic to improve the clinical outcome of patients with MM. Further combination studies are planned.