Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

• Deep sequencing reveals significant genetic events in multiple myeloma
• Intratumor genetic heterogeneity is common in multiple myeloma
• Recurrent mutations can occur either early or late in the evolution of a tumor
• Genetic heterogeneity in cancer may limit effectiveness of targeted therapy

SummaryWe performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.