A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma

Blood. 2008 Oct 1;112(7):2935-45. doi: 10.1182/blood-2008-02-142430. Epub 2008 Jun 5.


Although the in vitro expansion of the multiple myeloma (MM) clone has been unsuccessful, in a novel three-dimensional (3-D) culture model of reconstructed bone marrow (BM, n = 48) and mobilized blood autografts (n = 14) presented here, the entire MM clone proliferates and undergoes up to 17-fold expansion of malignant cells harboring the clonotypic IgH VDJ and characteristic chromosomal rearrangements. In this system, MM clone expands in a reconstructed microenvironment that is ideally suited for testing specificity of anti-MM therapeutics. In the 3-D model, melphalan and bortezomib had distinct targets, with melphalan targeting the hematopoietic, but not stromal com-partment. Bortezomib targeted only CD138(+)CD56(+) MM plasma cells. The localization of nonproliferating cells to the reconstructed endosteum, in contact with N-cadherin-positive stroma, suggested the presence of MM-cancer stem cells. These drug-resistant CD20(+) cells were enriched more than 10-fold by melphalan treatment, exhibited self-renewal, and generated clonotypic B and plasma cell progeny in colony forming unit assays. This is the first molecularly verified demonstration of proliferation in vitro by ex vivo MM cells. The 3-D culture provides a novel biologically relevant preclinical model for evaluating therapeutic vulnerabilities of all compartments of the MM clone, including presumptive drug-resistant MM stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Proliferation / drug effects
  • Chromosome Aberrations
  • Clone Cells
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm / drug effects
  • Hematopoiesis / drug effects
  • Humans
  • Melphalan / pharmacology
  • Models, Biological*
  • Multiple Myeloma / therapy*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Plasma Cells / drug effects
  • Plasma Cells / pathology
  • Pyrazines / pharmacology
  • Rats
  • Stromal Cells / drug effects
  • Stromal Cells / pathology
  • Tumor Cells, Cultured


  • Boronic Acids
  • Pyrazines
  • Bortezomib
  • Melphalan