Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell...

Area of Science:

• Hematology
• Oncology
• Genomics

Background:

• Multiple myeloma frequently develops treatment resistance over time.
• Relapsed/refractory multiple myeloma (RRMM) is characterized by genomic heterogeneity and bone marrow microenvironment (BME) alterations.
• The molecular drivers of drug resistance in RRMM are not fully understood.

Purpose of the Study:

• To analyze the transcriptional landscape of heterogeneous tumor cell populations in RRMM.
• To investigate the complex interactions between myeloma cells and the BME.
• To elucidate the mechanisms underlying treatment resistance in RRMM.

Main Methods:

• Single-cell RNA sequencing was performed on 20 RRMM patients before and after treatment.
• Analysis focused on clonal evolution, transcriptomic signatures, and BME composition.
• Interactions between myeloma cells and immune/stromal compartments were examined.

Main Results:

• Subclones with chromosome 1q-gain exhibit a distinct transcriptomic signature and expand during treatment.
• RRMM cells induce an immunosuppressive BME via cytokine upregulation and myeloid cell interactions.
• The BME shows accumulation of PD1+ γδ T-cells and macrophages, alongside depletion of hematopoietic progenitors.

Conclusions:

• This study identifies key transcriptional features of RRMM subclones.
• Mechanisms of BME reprogramming contributing to drug resistance were elucidated.
• Findings have implications for improving clinical decision-making and therapeutic strategies in RRMM.