Clonal Evolution

Researchers in the Mayo Clinic Multiple Myeloma SPORE 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.

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

Most of the sequencing that has been done in multiple myeloma has been in samples from earlier-stage patients. 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 researchers are addressing 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 (PI) affect clonal selection?
  • What mutations are associated with immunomodulatory drugs and PI-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 for multiple myeloma
  • Identifying baseline clonal heterogeneity as a prognostic marker for multiple myeloma
  • Identifying the spectrum of point mutations selected for by therapy with pomalidomide and dexamethasone with or without carfilzomib
  • Identifying the spectrum of point mutations present in patients with late-stage, refractory multiple myeloma

Project investigators

Co-leaders of the clonal evolution research project are: