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

• Published in: Nature communications Vol. 13; no. 1; p. 3750
• Main Authors: Vo, Josh N., Wu, Yi-Mi, Mishler, Jeanmarie, Hall, Sarah, Mannan, Rahul, Wang, Lisha, Ning, Yu, Zhou, Jin, Hopkins, Alexander C., Estill, James C., Chan, Wallace K. B., Yesil, Jennifer, Cao, Xuhong, Rao, Arvind, Tsodikov, Alexander, Talpaz, Moshe, Cole, Craig E., Ye, Jing C., Bergsagel, P. Leif, Auclair, Daniel, Cho, Hearn Jay, Robinson, Dan R., Chinnaiyan, Arul M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29-06-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 45/23; 45/91; 631/67/1059/2326; 631/67/1990/804; 631/67/68; 692/4028/67/1990/804; Disease resistance; Drug resistance; Genetic factors; Heterogeneity; Humanities and Social Sciences; Interleukin 6; Malignancy; MAP kinase; multidisciplinary; Multiple myeloma; Mutation; NF-κB protein; Patients; Science; Science (multidisciplinary); Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31430-0

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.
The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.