Molecular pathogenesis of multiple myeloma and its premalignant precursor

J Clin Invest. 2012 Oct;122(10):3456-63. doi: 10.1172/JCI61188. Epub 2012 Oct 1.


Multiple myeloma is a monoclonal tumor of plasma cells, and its development is preceded by a premalignant tumor with which it shares genetic abnormalities, including universal dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway. A complex interaction with the BM microenvironment, characterized by activation of osteoclasts and suppression of osteoblasts, leads to lytic bone disease. Intratumor genetic heterogeneity, which occurs in addition to intertumor heterogeneity, contributes to the rapid emergence of drug resistance in high-risk disease. Despite recent therapeutic advances, which have doubled the median survival time, myeloma continues to be a mostly incurable disease. Here we review the current understanding of myeloma pathogenesis and insight into new therapeutic strategies provided by animal models and genetic screens.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Bone Remodeling
  • Cell Transformation, Neoplastic
  • Cyclin D1 / physiology
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Genes, Retinoblastoma
  • Genes, bcl-1
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunophenotyping
  • Models, Biological
  • Monoclonal Gammopathy of Undetermined Significance / etiology
  • Monoclonal Gammopathy of Undetermined Significance / genetics*
  • Monoclonal Gammopathy of Undetermined Significance / pathology
  • Multiple Myeloma / etiology
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology
  • Osteoclasts / physiology
  • Precancerous Conditions / etiology
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / pathology
  • Retinoblastoma Protein / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Stem Cell Niche
  • Translocation, Genetic
  • Tumor Microenvironment


  • CCND1 protein, human
  • Immunoglobulin Heavy Chains
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Retinoblastoma Protein
  • Cyclin D1