NCI Serological Sciences Network Capacity Building Centers

We have received funding from the NCI Serological Sciences Networks for COVID-19 (SeroNet) to implement a clinical trial in which we monitor immune responses in patients with Multiple Myeloma. This clinical trial will allow us to use patient samples to test the humoral and cellular immune responses in our MM patient population directly in response to SARS-CoV-2 vaccinations to elucidate underlying mechanisms that are involved in the variability of responses. Together, these findings are expected to aid in advising proper guidelines for patients with MM regarding continued precautions and booster applications in the context of viral infections.

Goal: Filling these fundamental gaps in our current knowledge will not only help us understand why some immunocompromised patients have absent or low immune responses to SARS-CoV2 vaccination but also point to what mechanisms drive highly efficient antibody responses. This will be especially important in the future waves of the pandemic with emerging variants (e.g., Omicron BA.4, BA.5) and the development of broad-spectrum monoclonal antibody therapeutics as well as variant-proof SARS-CoV-2 vaccines.

Targeting SOX11 in Mantle Cell Lymphoma

Goal: To a) define the mechanism by which SOX11 increases BCR signaling in MCL, b) to determine efficacy of molecular probes inhibiting SOX11-DNA binding in vitro and in vivo models of BTKi or BCL2i resistant MCL, and c) to determine the mechanism by which SOX11 cooperates with CCND1 in vitro and in vivo to drive MCL.

Development of a multi-omic clinical decision platform to guide personalized therapy

Goal: In this application Icahn School of Medicine at Mount Sinai will partner with Cancer Genetics, Inc. to develop a multi-omics clinical decision assay that will improve long-term outcomes for patients with advanced myeloma and generate valuable insights and tools that can be broadly leveraged for other disease indications.

Developing a SOX11 inhibitor for Mantle Cell Lymphoma

Goal: The overall objective is to generate data for IND filing of a SOX11 small-molecule inhibitor demonstrating 1) on- target pharmacology 2) safety & selectivity in vivo and 3) establish a starting dose for first-in-human studies.

Clinical-Grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies

Goal: The major goals of this project are the development and application of genetic biomarkers and improved therapeutic outcomes in multiple myeloma.

MRD Consortium – Mount Sinai CC220 Correlatives

Goal: We propose a translational collaboration to study primary samples from ongoing clinical trials incorporating novel Celgene therapeutics. This project focuses on CC-220, a Cereblon binding agent that is currently being studied in clinical trials at Celgene.

Longitudinal Immunogenetics of Car-T Resistant Myeloma

Goal: Our project will leverage the comprehensive management by our clinical myeloma team and the expertise of our translational scientists at Mount Sinai to answer key questions such as: 1. How does clonal heterogeneity and evolution contribute to CAR-T resistance in imid-and antibody refractory myeloma? 2. How does the tumor microenvironment contribute to resistance to CAR-T in advanced myeloma? 3. How can immuno-genetic understanding of primary MM after CAR-T relapse help rationally develop and sequence therapeutics for CAR-T failure? These studies are intended to directly test the hypothesis that the clonal heterogeneity of drug resistant cells, along with loss/exhaustion of immune effector cells in the tumor microenvironment contribute to disease relapse in relapsed myeloma.

Translational Studies for Elotuzumab (anti-SLAMF7) in Combination with CC-220

Goal: 1. Phase 1b/2 clinical trial of Elo Iber low dose dex to evaluate safety and clinical efficacy 2. Integrated genomic and immunologic analysis of patient samples through the course of treatment to map the dynamic evolution of the tumor microenvironment (TME) and interactions with MM.

Correlative study to ‘A Phase 2b, Open-Label, Single-Arm Study of Selinexor (KPT-330) Plus Low- Dose

Dexamethasone (Sd) in Patients with Multiple Myeloma Previously Treated with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib, and an Anti-CD38 Monoclonal Antibody (mAb) and Refractory to Prior Treatment with Glucocorticoids, an Immunomodulatory Agent, a Proteasome Inhibitor and an Anti-CD38 mAb.’ – Work order 1

Goal: The objective of this study is to evaluate the efficacy of treatment with Selinexor in patients with multiple myeloma previously treated with previous targeted anticancer therapies.