Clonal Evolution

Researchers conducting the Clonal Evolution research project hope to identify point mutations and baseline clonal heterogeneity as prognostic markers for multiple myeloma.

A major breakthrough in multiple myeloma research was the recognition of the high degree of clonal heterogeneity in multiple myeloma and its modulation by therapy. The heterogeneity can be appreciated using very deep (1,000 times) sequencing of a panel of 77 genes recurrently mutated in multiple myeloma.

In this project, SPORE researchers are studying 726 patients with this gene panel to determine the clinical significance of gene mutations and tumor heterogeneity, in some cases comparing the results in matched relapsed samples.

Most of the sequencing that has been done in multiple myeloma has been in samples from patients with earlier stages of the disease. Very little is known about the spectrum of mutations in patients with late-stage refractory multiple myeloma — patients most in need of better therapies.

To address this issue, the Multiple Myeloma SPORE project team is performing whole-exome and RNA sequencing in 60 patients with late-stage disease.

Questions being addressed in the Clonal Evolution project include:

  • What is the clinical significance of the recurrent point mutations in multiple myeloma?
  • What is the clinical significance of baseline tumor heterogeneity measured by the 77-gene panel?
  • What is the effect on clonal selection of a two-drug versus three-drug combination?
  • How does the addition of an immunomodulatory drug to a protease inhibitor affect clonal selection?
  • What mutations are associated with immunomodulatory drugs and protease inhibitor resistance in patients with late-stage multiple myeloma?

Anticipated outcomes of the project include:

  • Validating and deploying a clinically actionable next-generation sequencing test in multiple myeloma
  • Identifying point mutations as genetic prognostic markers
  • Identifying baseline clonal heterogeneity as a prognostic marker
  • Identifying the spectrum of point mutations selected for therapy with pomalidomide and dexamethasone with or without carfilzomib
  • Identifying the spectrum of point mutations present in patients with late-stage, refractory multiple myeloma