Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma.

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Extramedullary disease (EMD) is a high-risk feature in multiple myeloma (MM), associated with poor prognosis despite novel immunotherapies.
• Understanding the spatial architecture of EMD and its microenvironment is crucial for developing effective treatments.

Purpose of the Study:

• To dissect the 3-dimensional architecture of tumor cells and their microenvironment in EMD using spatial transcriptomics and single-cell RNA sequencing.
• To identify spatial expression differences of key antigens and characterize immune cell infiltration patterns within EMD lesions.

Main Methods:

• Spatial transcriptomics (tomo-seq and 10x Visium) and single-cell RNA sequencing were applied to 14 EMD biopsies.
• Analysis focused on dissecting the 3D architecture, immune cell distribution, genomic heterogeneity, and metabolic programs within EMD.

Main Results:

• Significant intrapatient and interpatient variations in immune and stromal cell distribution were observed.
• Plasma cells exhibited copy number heterogeneity and subclone emergence, indicating genomic instability.
• Exhausted T cells colocalized with MM cells, while activated CD8+ T cells and M1 macrophages infiltrated tumor-free regions, a pattern altered by bispecific antibody therapy.

Conclusions:

• Spatial transcriptomics reveals a complex multicellular ecosystem within EMD.
• Checkpoint inhibition and dual targeting strategies show promise for EMD treatment.
• The study highlights the potential of targeting the tumor microenvironment and immune cell interactions in EMD.