Relapse-Associated Genetic Alterations and Drug-Specific Resistance in Myeloma
Posted: Friday, August 27, 2021
According to research presented in Blood Advances, genetic alterations commonly found in patients with multiple myeloma who experience relapse may be functionally linked to treatment-specific resistance. Drug resistance screening performed by CRISPR-Cas9 also suggests that patients for whom DNA damage repair pathway genes have become inactivated may be more responsive to cytotoxic chemotherapy.
“The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of multiple myeloma in the future,” concluded Jan Krönke, MD, of Ulm University Hospital, Germany, and colleagues.
The study included 16 patients who had been recently diagnosed with either multiple myeloma (n = 15) or plasma cell leukemia (n = 1). A total of 38 samples had been collected at diagnosis as well as at least once during disease progression for all patients. Resistance to lenalidomide, bortezomib, dexamethasone, and melphalan resistance was evaluated using CRISPR-Cas9 treatment resistance screens. Each patient was found to have a significant number of mutations. These mutations, including recurrent mutations in TP53, DNAH5, and WSCD2, were either newly acquired or found to have evolved from a limited subclone.
A total of 15 of these mutations were associated with treatment resistance. Specifically, mutations in cereal on E3 ligase complex members, PCDHA5 and ANKMY2 structural genes, RB1 and CDK2NC, and TP53 were linked with resistance to lenalidomide, dexamethasone, bortezomib, and melphalan, respectively. Of note, a relationship was observed between gene inactivation for DNA damage repair pathway regulators and increased sensitivity to cytotoxic chemotherapy.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.