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Updated: Oct 11, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell
Stephan M Tirier1, Jan-Philipp Mallm1,2,3, Simon Steiger1
1Division of Chromatin Networks, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany.
Abstract:
Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.
Insights
Drug resistance in relapsed/refractory multiple myeloma (RRMM) involves evolving cancer cell subclones and a reprogrammed bone marrow microenvironment (BME). Understanding these changes offers new therapeutic strategies for patients with refractory multiple myeloma.
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.
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