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EMD Lesions Comprise Multicellular Ecosystems With New Therapeutic Avenues

January 29, 2025

February 2025

Katie Robinson

Katie Robinson is a medical writer based in New York.

Extramedullary disease (EMD), a difficult-to-treat, high-risk feature of multiple myeloma (MM), comprises T-cell exhaustion and profound genomic heterogeneity. This is according to a study published in Blood, in which researchers dissected EMD biopsies, uncovering a complex cell composition with checkpoint inhibition and dual targeting as potential new treatment options.

“We studied EMD in MM, a high-risk phenotype associated with poor survival and reduced response rates to novel immunotherapies such as CAR [chimeric antigen receptor] T cells or bispecific antibodies,” said corresponding author Leo Rasche, MD, of University Hospital Würzburg in Germany. “EMD lesions are not just sheets of plasma cells, but rather represent multicellular ecosystems with subclonal heterogeneity and diverse immune cells reminiscent of what we know from solid cancers.”

To understand the spatial organization of MM and immune cells in EMD, the researchers applied spatial transcriptomics using RNA tomography for spatially resolved transcriptomics (n=2), 10x Visium (n=12), and single-cell RNA sequencing (n=3) to 14 extramedullary lesion punch biopsies from patients with relapsed or refractory MM.

The lesions showed no uniform distribution of infiltrating immune and stromal cells. Evidence of genomic instability included considerable heterogeneity within plasma cells at the copy number level, with new subclones emerging in circumscribed tumor areas. Further, the researchers identified spatial expression differences between two antigens for bispecific antibody therapy — G protein-coupled receptor, class C, group 5, member D (GPRC5D) and tumor necrosis factor receptor superfamily member 17 (TNFRSF17), also known as B-cell maturation antigen (BCMA). Several immune cells, including T cells, infiltrated the EMD masses and were confined to positions segregated from MM cells.

“We found heterogeneous expression of BCMA and GPRC5D, two key antigens for immunotherapy, in these lesions. Thus, a combination of BCMA- and GPRC5D-targeted treatments may help to overcome the antigenic heterogeneity in EMD,” Dr. Rasche said.

“In addition, we found exhausted T cells expressing PD1 and TIM3 co-localizing with myeloma cells in EMD, which may open a therapeutic avenue for checkpoint inhibitors. Interestingly, we also found cytotoxic CD8-positive T cells and M1-type macrophages at the tumor margins or in tumor cell-free areas within the lesion but not near the myeloma cells. The coexistence of fit and exhausted immune cells that are spatially distant from each other is behind the concept of hot and cold tumors in oncology,” Dr. Rasche said.

Limitations to the study included difficulties with tissue preservation and composition related to the use of the 10x Visium spatial transcriptomics platform in MM. Additionally, the method was not optimized for bone marrow biopsies, not allowing a concurrent analysis of EMD and bone marrow samples, and the resolution was only close to the single-cell level. The biopsies were taken from heavily pretreated patients and represented only a small fraction of the EMD mass, potentially excluding the regions of interest. Another limitation was the small number of biopsies, mainly from skin or muscle lesions, which curbed additional analyses, such as genomic profiling and functional T-cell experiments.

“While single-cell RNA sequencing technologies have greatly enriched our understanding of MM and other hematologic malignancies in recent years, new spatial technologies will unravel the complex architecture of tumor cells, microenvironment cells, and the immune system,” Dr. Rasche concluded. “A three-dimensional approach is likely to be the immediate future of cancer research, focusing on complex tissues such as bone marrow or extramedullary metastasis.”

Any conflicts of interest declared by the authors can be found in the original article.

Reference

John M, Helal M, Duell J, et al. Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myelomaBlood. 2024;144(20):2121-2135.

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