The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma
Josh N. Vo, Yi‐Mi Wu, Jeanmarie Mishler, Sarah E. Hall, Rahul Mannan, Lisha Wang, Ning Yu, Jin Zhou, Alexander C. Hopkins, James C. Estill, Wallace Chan, Jennifer Yesil, Xuhong Cao, Arvind Rao, Alexander Tsodikov, Moshe Talpaz, Craig E. Cole, Jing C. Ye, Sikander Ailawadhi, Jesús G. Berdeja, Craig C. Hofmeister, Sundar Jagannath, Andrzej Jakubowiak, Amrita Krishnan, Shaji Kumar, Moshe Levy, Sagar Lonial, Gregory Orloff, David S. Siegel, Suzanne Trudel, Saad Z. Usmani, Ravi Vij, Jeffrey L. Wolf, Jeffrey A. Zonder, P. Leif Bergsagel, Daniel Auclair, Hearn Jay Cho, Dan R. Robinson, Arul M. Chinnaiyan
Abstract
Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease's molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45-65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in IL6ST are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management.