This study provides a comprehensive analysis of the genetic landscape of multiple myeloma (MM) by sequencing 203 paired tumor/normal samples. The researchers identified significantly mutated genes, including *KRAS*, *NRAS*, *BRAF*, *FAM46C*, *TP53*, and *DIS3*, with frequent mutations in previously treated patients. They also found evidence of clonal heterogeneity, where subclonal mutations were present in some patients but not others. This heterogeneity was observed in both untreated and previously treated patients, suggesting that treatment may accelerate the fixation of certain subclones. The study highlights the importance of considering clonal heterogeneity when designing targeted therapies for MM, as subclonal mutations may not respond to targeted treatments. Additionally, the findings suggest that combination therapies, such as BRAF and MEK inhibitors, may be more effective in treating MM with subclonal mutations. Overall, the study emphasizes the need for a deeper understanding of clonal heterogeneity in MM to improve treatment outcomes.This study provides a comprehensive analysis of the genetic landscape of multiple myeloma (MM) by sequencing 203 paired tumor/normal samples. The researchers identified significantly mutated genes, including *KRAS*, *NRAS*, *BRAF*, *FAM46C*, *TP53*, and *DIS3*, with frequent mutations in previously treated patients. They also found evidence of clonal heterogeneity, where subclonal mutations were present in some patients but not others. This heterogeneity was observed in both untreated and previously treated patients, suggesting that treatment may accelerate the fixation of certain subclones. The study highlights the importance of considering clonal heterogeneity when designing targeted therapies for MM, as subclonal mutations may not respond to targeted treatments. Additionally, the findings suggest that combination therapies, such as BRAF and MEK inhibitors, may be more effective in treating MM with subclonal mutations. Overall, the study emphasizes the need for a deeper understanding of clonal heterogeneity in MM to improve treatment outcomes.