The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma

Josh N. Vo, Yi-Mi Wu, Jeanmarie Mishler, Sarah Hall, Rahul Mannan, Lisha Wang, Yu Ning, Jin Zhou, Alexander C. Hopkins, James C. Estill, Wallace K. B. Chan, Jennifer Yesil, Xuhong Cao, Arvind Rao, Alexander Tsodikov, Moshe Talpaz, Craig E. Cole, Jing C. Ye, P. Leif Bergsagel, Daniel Auclair, Hearn Jay Cho, Dan R. Robinson () and Arul M. Chinnaiyan ()
Additional contact information
Josh N. Vo: University of Michigan
Yi-Mi Wu: University of Michigan
Jeanmarie Mishler: University of Michigan
Sarah Hall: University of Michigan
Rahul Mannan: University of Michigan
Lisha Wang: University of Michigan
Yu Ning: University of Michigan
Jin Zhou: University of Michigan
Alexander C. Hopkins: University of Michigan
James C. Estill: University of Michigan
Wallace K. B. Chan: University of Michigan
Jennifer Yesil: Multiple Myeloma Research Foundation
Xuhong Cao: University of Michigan
Arvind Rao: University of Michigan
Alexander Tsodikov: University of Michigan
Moshe Talpaz: University of Michigan
Craig E. Cole: Michigan State University
Jing C. Ye: University of Michigan
P. Leif Bergsagel: Mayo Clinic
Daniel Auclair: Multiple Myeloma Research Foundation
Hearn Jay Cho: Multiple Myeloma Research Foundation
Dan R. Robinson: University of Michigan
Arul M. Chinnaiyan: University of Michigan

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31430-0

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