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

Nat Commun. 2021 Nov 29;12(1):6960. doi: 10.1038/s41467-021-26951-z.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Bone Marrow / drug effects
  • Bone Marrow / immunology
  • Bone Marrow / pathology
  • Cytokines / genetics
  • Cytokines / immunology
  • Drug Resistance, Neoplasm / genetics*
  • Drug Resistance, Neoplasm / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Gene Regulatory Networks
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Intraepithelial Lymphocytes / immunology
  • Intraepithelial Lymphocytes / pathology
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / immunology
  • Multiple Myeloma / pathology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Recurrence
  • Sequence Analysis, RNA
  • Signal Transduction
  • Single-Cell Analysis
  • Transcriptome*
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics*
  • Tumor Microenvironment / immunology


  • Antineoplastic Agents
  • Cytokines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell, gamma-delta