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88 Comprehensive Characterization of the Bone Marrow Microenvironment Transcriptional Remodeling in the Progression from MGUS to Smoldering and Multiple Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Spatial Dissection and Multiomics Analysis of the Multiple Myeloma Tumor and Immune Microenvironment
Hematology Disease Topics & Pathways:
Research, Translational Research, Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Saturday, December 9, 2023: 10:15 AM

Itziar Cenzano, PhD1*, Miguel Cocera1*, Azari Bantan2*, Marta Larrayoz, PhD3*, Amaia Vilas-Zornoza1*, Patxi San-Martin1*, Paula Aguirre-Ruiz3*, Beñat Ariceta1*, Jin Ye2*, Diego Alignani1*, Aitziber Lopez1*, Aleksandra Kurowska2*, Fatimah AlSultan2*, Raghad Shuwaikan1*, Vincenzo Lagani, PhD2*, Jesper Tegner, PhD2*, Iñaki I. Martin Subero, PhD4,5*, Jose A. A Martinez-Climent, MD1, Xabier Agirre, PhD1*, Borja Saez-Ochoa, PhD3*, Bruno Paiva1*, Jesus San-Miguel, MD, PhD6,7, Mikel Hernaez, PhD8*, Isabel A Calvo, PhD3*, David Gomez-Cabrero, PhD2,9* and Felipe Prosper, MD, PhD10,11,12

1Hematology and Oncology Program, Centre for Applied Medical Research (CIMA), Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
2Bioscience Program, Biological and Environmental Sciences and Engineering Division (BESE), King Abdullah University of Science and Technology KAUST, Thuwal, Saudi Arabia
3Hematology and Oncology Program, Centre for Applied Medical Research (CIMA), Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain, Pamplona, Spain
4Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
5Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
6Hematology and Cell Therapy Department. Clinica Universidad de Navarra, Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain
7Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain
8Computational Biology Program. Cima Universidad de Navarra. IdiSNA., Pamplona, Spain
9Translational Bioinformatics Unit, Navarrabiomed, Universidad Pública de Navarra (UPNA), Pamplona, Spain
10Cancer Center Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), IDISNA, CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain
11Centro de Investigacion Biomedica en Red de Cancer (CIBERONC)., Madrid, Spain
12Hematology and Cell Therapy Department. Clinica Universidad de Navarra, IdiSNA., Pamplona, Spain

Multiple Myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation and accumulation of clonal plasma cells (PCs) in the bone marrow (BM). Despite significant advances in treating MM patients, most patients eventually relapse and succumb to the disease. Understanding the mechanisms driving progression from precursor conditions into clinically active MM may contribute to implementing early curative approaches. Accumulating evidence indicates that the tumor formation and progression process is influenced not only by the malignant cells but also by the microenvironment components and interconnectedness between them. However, the understanding of the contribution of the non-immune BM microenvironment (BME) to disease progression and relapse remains largely unknown.

Our aim was to identify the transcriptional changes in the endothelial cells (ECs) and mesenchymal stromal cells (MSCs) during the transition from premalignant stages to MM to identify potential mechanisms of transformation and therapeutic targets. To this end, ECs and MSCs were immunophenotypically isolated from BM samples of healthy aged donors (n=19) and patients with (MGUS, n=10), Smoldering Multiple Myeloma (SMM, n=13), and MM (n=36). Bulk RNA sequencing analysis of ECs revealed enrichment in terms related to cell cycle and fatty acid metabolism in MGUS, SMM, and MM patients compared to old adults. Indeed, a selective upregulation of pathways associated with calcium signaling, cytokines, and angiogenesis was detected in ECs from MM patients. Regarding MSCs, our results revealed an increase in bone remodeling, inflammation, oxidative defense, and DNA damage repair in MM patients. Interestingly, during the transition from MGUS to SMM, MSCs exhibited enrichment in functions associated with cell morphogenesis and epithelial transition, while lipid-related functions were decreased.

To gain a deeper understanding, single-cell RNA sequencing analysis of BME and PCs was performed in unique immunocompetent murine models recapitulating the principal clinical, genetic, and immunological characteristics of MGUS and MM patients (Larrayoz et al., 2023). Using as a reference a previous BME characterization in mice we conducted (Ye et al., 2022) and in line with findings in human patients, our results unveiled a compromised BME characterized by the angiogenic profile of ECs and the increase in the immune-related state of MSCs associated with the progression of the disease. Furthermore, MGUS ECs displayed enrichment in ion homeostasis, immune response, and cell signaling-related pathways compared to healthy controls. While MM ECs exhibited a significant increase in immune terms, migration, and vascular-related pathways when compared to MGUS ECs, indicating a more angiogenic functional profile. Moreover, MSCs in the MGUS stage depicted significant activation of pathways related to immune defense, detoxification, lipid metabolism, and bone remodeling. Likewise, genes upregulated in MM MSCs were associated with calcium signaling, cytokines, and interferon response-related pathways, demonstrating the inflammatory signature of MSCs that may be in relation to the immune exhaustion underlying MM transformation.

Finally, subsequent single-cell derived cell-to-cell interaction analysis using Liana was conducted to characterize the interactions between malignant PCs and their niche and delineate the communication dynamics of the tumor-BM ecosystem. Our results showed that PCs interact with ECs mainly through Itga1 and Cd44, while they communicate with MSCs mainly via Egfr and Sdc1. Remarkably, the interactions initiated during the MGUS stage between ECs and PCs persisted, and MM-specific interactions were involved in adhesion, migration, and angiogenesis pathways. In the crosstalk between PCs and MSCs, MGUS-specific interactions were associated with fat and bone-related processes. In contrast, MM-specific interactions were related to the extracellular matrix, collagen organization, and immune-related processes.

In conclusion, our findings provide several novel insights into the transcriptional profiles of the non-immune BME during MM disease progression as well as the cellular interactions established with malignant PCs that can drive a pro-MM environment. Additional analyses are ongoing to further comprehend the BME's remodeling through MM development.

Disclosures: Martinez-Climent: Roche-Genentech: Research Funding; BMS-Celgene: Research Funding; Janssen: Research Funding; Priothera: Research Funding; Palleon: Research Funding; AstraZeneca: Research Funding. Paiva: GSK: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; EngMab: Research Funding; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche Glycart AG: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Oncopeptides: Honoraria. San-Miguel: MSD: Other: Advisory Board; Novartis: Other; Karyopharm: Other: Advisory Board; Janssen-Cilag: Other: Advisory Board; Haemalogix: Other: Advisory Board; GSK: Other: Advisory Board; Celgene: Other: Advisory Board; BMS: Other: Advisory Board; Amgen: Consultancy, Other: Advisory Board; Abbvie: Consultancy, Other: Advisory Board; Takeda: Other: Advisory Board; Regeneron: Other: Advisory Board; Roche: Other: Advisory Board; Sanofi: Other: Advisory Board; SecuraBio: Other: Advisory Board.

*signifies non-member of ASH