Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

Blood. 2016 Sep 29;128(13):1735-44. doi: 10.1182/blood-2016-06-723007. Epub 2016 Aug 11.


To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma, we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of biallelic inactivation events affecting tumor suppressor genes, especially TP53, the end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian-type clonal evolution. The number of copy number aberration changes and biallelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma-propagating cells to survive multiagent chemotherapy and to result in relapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cell Proliferation
  • Clonal Evolution*
  • DNA Copy Number Variations
  • Disease Progression
  • Female
  • Gene Expression Profiling
  • Genes, Tumor Suppressor*
  • Genes, p53
  • Genes, ras
  • Genomic Instability
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Models, Genetic
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Multiple Myeloma / therapy
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics
  • Recurrence
  • Risk Factors
  • Stem Cell Transplantation
  • Transplantation, Autologous


  • Phosphatidylinositol 3-Kinases