MYC in Progression and Treatment

In this research project, MYC in Progression and Treatment, SPORE investigators are studying the role of MYC dysregulation in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.

The identification of MYC translocations in BALB/c plasmacytomas more than 30 years ago led to an intense study of MYC in multiple myeloma. High-density genomic techniques and next-generation sequencing show that a genetic rearrangement of the MYC locus is the most common mutation in multiple myeloma. This mutation is present in 43% of untreated patients overall and in 70% of patients with hyperdiploid multiple myeloma.

An unbiased gene expression profiling (GEP) analysis identifies MYC and its target genes as the major difference between monoclonal gammopathy of undetermined significance and multiple myeloma. The introduction of a MYC transgene into a mouse strain that spontaneously develops MGUS results in a mouse model that uniformly develops multiple myeloma. These findings indicate that MYC dysregulation can cause the progression of MGUS to multiple myeloma in mice.

SPORE researchers aim to determine if this progression also occurs in humans, and whether a rearrangement of MYC is a genetic feature that can distinguish benign MGUS from malignant multiple myeloma.

This distinction is critically important to understand because the goal of therapy should be the elimination of all malignant cells, not necessarily the clonally related but benign MGUS cells.

In addition, the clinical significance of MYC rearrangements is unknown.

Immunomodulatory drugs (IMiDs) have been reported to lead to a cereblon-dependent downregulation of MYC, and they appear to be most active in hyperdiploid multiple myeloma (approximately 70% MYC rearrangements). But they have almost no activity in t(11;14) multiple myeloma (approximately 15% MYC rearrangements).

These observations underscore the need to determine whether rearrangements of MYC are a biomarker of IMiD response.

Questions being addressed in this research project include:

  • Do rearrangements of the MYC locus distinguish benign from malignant clonal plasma cells?
  • Does outcome correlate better with eradication of cells with the MYC rearrangement than with the clonal IgH rearrangement?
  • Do IMiDs preferentially target cells with MYC rearrangements?

Anticipated outcomes of the MYC research project include:

  • Identifying a genetic marker that distinguishes MGUS from multiple myeloma
  • Determining a new goal for anti-multiple myeloma therapy (eradication of the MYC rearrangement)
  • Identifying patients who would benefit most from IMiD therapy