**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Raphael Szalat
Medical Oncology and Hematology section, Boston Medical Center, Boston, Massachusetts, United States.
Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
The work was done in Boston University and Dana-Farber Cancer Institute

**Main Body of the Abstract**
Immunoglobulin light chain (AL) amyloidosis is caused by clonal B or plasma cells proliferating in the bone marrow that produce monoclonal immunoglobulin proteins that misfold and aggregate in tissues. While AL plasma cells share cytogenetic aberrations with plasma cells from multiple myeloma, their transcriptome and immune bone marrow microenvironment (BME) composition are not well characterized. Here, we collected serial BM aspirates from six AL amyloidosis patients, healthy donors and other plasma cell disorders and performed single-cell RNA-seq combined with CITE-seq and TCR sequencing to characterize AL plasma cells and the immune BME before and after daratumumab based therapy. Compared to non-AL plasma cells, AL plasma cells were featured by differentially expressed genes related to the presence of t(11;14) such as CCND1, but also by genes not previously reported such as Integral Membrane Protein 2B (ITM2B), which is known to be involved in beta-amyloid processing,  and others that may constitute novel therapeutic targets. Gene set enrichment analysis revealed differential activity of essential cellular pathways including mainly endoplasmic reticulum associated protein degradation, protein transportation and apoptosis. Compared to other plasma cell disorders at diagnosis, AL BME had more cellular diversity, higher CD8 memory T cells levels and CD68+ monocytes with significant deregulation of IL-1β pathway. Hematologic and organ response following daratumumab therapy were associated with further increase in CD8+ memory T cells level and T cell clonotype selection along with persistent monocytes alterations, highlighting the role of the immune BME in AL amyloidosis pathogenesis and response to treatment.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Raphael Szalat
Medical Oncology and Hematology section, Boston Medical Center, Boston, Massachusetts, United States.
Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States
The work was done in Boston University and Dana-Farber Cancer Institute

**Main Body of the Abstract**
Immunoglobulin light chain (AL) amyloidosis is caused by clonal B or plasma cells proliferating in the bone marrow that produce monoclonal immunoglobulin proteins that misfold and aggregate in tissues. While AL plasma cells share cytogenetic aberrations with plasma cells from multiple myeloma, their transcriptome and immune bone marrow microenvironment (BME) composition are not well characterized. Here, we collected serial BM aspirates from six AL amyloidosis patients, healthy donors and other plasma cell disorders and performed single-cell RNA-seq combined with CITE-seq and TCR sequencing to characterize AL plasma cells and the immune BME before and after daratumumab based therapy. Compared to non-AL plasma cells, AL plasma cells were featured by differentially expressed genes related to the presence of t(11;14) such as _CCND1_, but also by genes not previously reported such as Integral Membrane Protein 2B (_ITM2B_), which is known to be involved in beta-amyloid processing,  and others that may constitute novel therapeutic targets. Gene set enrichment analysis revealed differential activity of essential cellular pathways including mainly endoplasmic reticulum associated protein degradation, protein transportation and apoptosis. Compared to other plasma cell disorders at diagnosis, AL BME had more cellular diversity, higher CD8 memory T cells levels and CD68+ monocytes with significant deregulation of IL-1β pathway. Hematologic and organ response following daratumumab therapy were associated with further increase in CD8+ memory T cells level and T cell clonotype selection along with persistent monocytes alterations, highlighting the role of the immune BME in AL amyloidosis pathogenesis and response to treatment.



Bone marrow plasma cells and immune microenvironment transcriptomic architecture in AL Amyloidosis during Daratumumab based therapy PA44 (#432)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.