@article{dcca2da8ffd44efbbfc9786db441200f,
title = "The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma",
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{\textquoteright}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.",
author = "{Multiple Myeloma Research Consortium} and Vo, {Josh N.} and Wu, {Yi Mi} and Jeanmarie Mishler and Sarah Hall and Rahul Mannan and Lisha Wang and Yu Ning and Jin Zhou and Hopkins, {Alexander C.} and Estill, {James C.} and Chan, {Wallace K.B.} and Jennifer Yesil and Xuhong Cao and Arvind Rao and Alexander Tsodikov and Moshe Talpaz and Cole, {Craig E.} and Ye, {Jing C.} and Sikander Ailawadhi and Berdeja, {Jesus G.} and Hofmeister, {Craig C.} and Sundar Jagannath and Andrzej Jakubowiak and Amrita Krishnan and Shaji Kumar and Levy, {Moshe Yair} and Sagar Lonial and Orloff, {Gregory J.} and David Siegel and Suzanne Trudel and Usmani, {Saad Z.} and Ravi Vij and Wolf, {Jeffrey L.} and Zonder, {Jeffrey A.} and Bergsagel, {P. Leif} and Daniel Auclair and Cho, {Hearn Jay} and Robinson, {Dan R.} and Chinnaiyan, {Arul M.}",
note = "Funding Information: This work was primarily supported by the Multiple Myeloma Research Foundation (ORSP 19-PAF05802). Ancillary support was provided by the National Cancer Institute (NCI, grant R35-CA231996), the Early Detection Research Network (grant U01-CA214170), and the Prostate Cancer Foundation. J.N.V. is supported by funding from the NCI Clinical Proteomic Tumor Analysis Consortium (grant U24-CA210967). A.M.C. is a Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar, and American Cancer Society Professor. We thank Stephanie Ellison for her assistance in manuscript review and editing. We also thank Yelena Kleyman-Smith, Jin Chen, and Pankaj Vats for assistance in cloud analytics and other computational analyses. We acknowledge the efforts of the Mi-Oncoseq clinical sequencing team. The authors would also like to recognize the tremendous generosity and selflessness of the multiple myeloma patients and their families for participating in these studies. Funding Information: This work was primarily supported by the Multiple Myeloma Research Foundation (ORSP 19-PAF05802). Ancillary support was provided by the National Cancer Institute (NCI, grant R35-CA231996), the Early Detection Research Network (grant U01-CA214170), and the Prostate Cancer Foundation. J.N.V. is supported by funding from the NCI Clinical Proteomic Tumor Analysis Consortium (grant U24-CA210967). A.M.C. is a Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar, and American Cancer Society Professor. We thank Stephanie Ellison for her assistance in manuscript review and editing. We also thank Yelena Kleyman-Smith, Jin Chen, and Pankaj Vats for assistance in cloud analytics and other computational analyses. We acknowledge the efforts of the Mi-Oncoseq clinical sequencing team. The authors would also like to recognize the tremendous generosity and selflessness of the multiple myeloma patients and their families for participating in these studies. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-31430-0",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
number = "1",
}