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1942 Dysregulation of Cellular Immunity in High-Risk Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Plasma Cell Disorders, Diseases, immunology, Lymphoid Malignancies, Biological Processes
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Selma Bekri, PhD1*, Simone Katz2*, Geoffrey Kelly3*, Travis Dawson, PHD4*, Darwin D'Souza5*, Michael Mason6*, Alexandre Alloy6*, Shameek Biswas6*, Seunghee Kim-Schulze, PhD4*, Sacha Gnjatic7*, Samir Parekh, MD8, Sundar Jagannath, MD9, Alessandro Lagana, PhD8 and Hearn Jay Cho, MD10

1Tisch Cancer Institute, Icahn School of Medicine At Mount Sinai, New York, NY
2Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
3Department of Immunology & Immunotherapy, Icahn School of Medicine At Mount Sinai, New York, NY
4Department of Immunology & Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY
5Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
6Bristol Myers-Squibb, Seattle, WA
7Icahn School of Medicine at Mount Sinai, New York, NY
8Department of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
9Mount Sinai Medical Center, New York, NY
10Department of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Tisch Cancer Institute, New York, NY

Introduction: Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by the abnormal proliferation of plasma cells in the bone marrow. Approximately 20% of MM patients present with high-risk (HR) clinical and genetic features that are associated with aggressive disease course and poor prognosis. Novel immune therapies are changing the paradigm of MM treatment. A comprehensive understanding of immune dysregulation within the tumor microenvironment (TME) of HR vs standard risk (SR) MM patients could inform the development of targeted immunotherapeutic strategies for HR MM.

Methods: 55 HR and 25 SR patients were selected from the Mt. Sinai Hematologic Malignancies Tissue Bank (IRB# STUDY-11-01978). HR included one or more cytogenic abnormalities (HRCA) such as translocations t(4;14), deletion of chromosome 17 (del17p), and gain/amplification of 1q (1q+/++) based on the Second Revised International Staging System (R2-ISS). We also included nine patients with t(14;16) translocation alone or combined with one or two of the other HRCA. We performed comprehensive immune phenotyping of the bone marrow micro-environment on specimens from HR and SR patients using mass cytometry (CyTOF) and single cell RNA sequencing (scRNASeq) of bone marrow mononuclear cells (BMMC) depleted of CD138 positive MM cells.

Results: ScRNAseq of BMMC from HR MM patients revealed a robust cytotoxic and cytolytic signature on CD4+ T cells relative to SR, characterized by the upregulation of genes such as GNLY, NKG7, PRF1, and IFNG, and a higher frequency of Granzyme K-positive (GZMK+) CD8+ T cells, previously described as progenitors of exhausted cells. Both CD4 and CD8 T cells, along with monocytes, exhibited high expression of a group of Interferon-stimulated genes (ISGs) including IFI27, IFIT3, IFI44L, IFITM1/3, and OASL. Notably, high expression of this group of ISGs was associated with T cell exhaustion and poor prognosis in the setting of immune checkpoint inhibitor therapy for solid tumors. Mass cytometry analysis confirmed the activated state of T cells in HR MM patients, with increased expression of immune activation markers HLA-DR, CD38, and the senescence marker CD57. Furthermore, HR patients exhibited higher frequencies of mast cells, CD14+ Monocytes and plasmacytoid dendritic cells compared to SR, suggesting an inflammatory and immunosuppressive environment that may dampen effective antitumor immune responses.

Conclusions: These results indicate distinct bone marrow microenvironments of HR and SR MM. CD4 and CD8 T cells appear to be more activated in HR patients compared to SR. However, the higher frequencies of mast cells and plasmacytoid dendritic cells, and the prominent expression of ISGs associated with inhibition of anti-tumor immunity suggest dysregulation and exhaustion of T cell activity in HR patients. Collectively, these findings highlight the complex immune dynamics in HR MM and provide insights into the underlying immune dysfunction which may contribute to disease progression and therapy resistance in HR MM. Such insights have the potential to inform the design of targeted therapeutic interventions aimed at modulating the immune response and improving treatment outcomes for HR MM patients.

Disclosures: Mason: Bristol Myers-Squibb: Current Employment. Alloy: Bristol Myers-Squibb: Current Employment. Biswas: Bristol Myers-Squibb: Current Employment. Gnjatic: Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Regeneron: Research Funding; Takeda.: Research Funding; Genentech,: Research Funding; Boehringer-Ingelheim: Research Funding. Parekh: Amgen: Research Funding; Karyopharm Therapeutics: Research Funding; Caribou Biosciences: Research Funding; Celgene/BMS Corporation: Research Funding; Grail, LLC: Membership on an entity's Board of Directors or advisory committees. Jagannath: Legend Biotech: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Caribou: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy. Cho: Bristol Myers-Squibb: Research Funding; Takeda, Inc.: Research Funding.

*signifies non-member of ASH