Uncovering Clonal and Subclonal Druggable Targets in Multiple Myeloma Using Omic Data

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial is the keystone program working towards personalized medicine in multiple myeloma (MM). CoMMpass has characterized over 730 samples from 669 patients, a subset having time-course data, using multiple platforms and has made these data publicly available. Screening for druggable somatic mutations and gene expression outliers revealed great potential for repurposing existing pharmacotherapies.

We have developed and curated a Database of Evidence for Precision Oncology (DEPO) that includes 442 mutations and 49 genes with expression changes implicated as drug targets from 34 cancer types. We found 43.6% of CoMMpass samples have one of 26 somatic mutations that could be targeted by 9 different drugs, suggesting many drugs may be repurposed for use in MM. HotSpot3D, a protein-structure-guided analysis tool, showed 3.3% (24/730) of samples have mutations involving BRAF and KRAS, clustering with known drug targets, and another 2.1%(15/730) have mutations in clusters formed from a prior TCGA pan-cancer analysis involving 22 cancer types. This indicates additional potential drug targets and functional mutations in MM.

Interestingly, 11 samples (including relapse), have subclonal mutations in both KRAS and BRAF with variable allelic fractions, implicating different treatment requirements for tumor subpopulations and disease stages. Additionally, druggable gene expression outlier analysis of 591 samples reveals an average of nearly 5 outlier genes per sample from among 49 known target genes, with 18.1% (107/591) of samples with MYCN gene outliers as compared to MYC 1.4% (8/591), despite MYC being a known driver of MM. Other top outliers are DLL3 10.2%, EGFR 10.5%, FGFR1 10.2%, and FGFR2 12.5%. Our study highlights candidate drug targets previously omitted in MM. Taken together, it suggests that heterogeneity analysis and pharmaceutical repurposing could lead to substantially improved outcomes.