Researchers of the University of Michigan Rogel Cancer Center, who studied the molecular landscape of more than 500 patients with an aggressive form of multiple myeloma, found a much higher prevalence of activated key oncogenic pathways in these patients than previously thought. Above 45-65% of the NF-ฮบB and RAS/MAPK pathways each had alterations. The study was published in Nature Communications.
Further away, Arul Chinnaiyan, MD, Ph.D., director of the Michigan Center for Translational Pathology, and his team found a link between the mutations and RASopathies, a certain group of genetic syndromes, in patients with relapsed refractory multiple myeloma. This was the first observation of its kind.
The team compared the molecular makeup of patients with untreated multiple myeloma to those with the relapsed, refractory version of the disease. Comparing these patients allowed the researchers to describe the drivers of the more aggressive form of multiple myeloma.
“It also led us to discover the mechanisms of resistance that occur in patients whose disease relapses and is resistant to treatment,” said Chinnaiyan. โWe found that more than a quarter of the patients had developed some kind of resistance mechanism. The genetic alterations that occur in these patients make them resistant to commonly used treatments for multiple myeloma.โ
This study was funded by the Multiple Myeloma Research Foundation and included patient samples from its Multiple Myeloma Research Consortium, a collaborative network of 22 leading cancer centers focused on investigating the most promising early-stage therapies. Clinical sequencing is driven by the Mi-Oncoseq Program in Michigan Medicine, led by Chinnaiyan and Dan Robinson, Ph.D.. Building on the knowledge gained through this work, researchers have initiated a study that assigns patients to individual arms of a clinical trial based on their molecular profile to match alterations to potential therapies using a comprehensive, evidence-based approach. sequencing.
Chinnaiyan says that while this current study was retrospective, he is hopeful about the future. โWe are developing tools and insights to translate these strategies into real clinical impact for patients.โ
“Treating relapsed multiple myeloma can be extremely difficult despite the tremendous progress we’ve made,” said Hearn Jay Cho, MD, Ph.D., medical director of MMRF. โDiscovering new targets and therapies that act on them may be useful in the future for patients who develop resistance to current treatment, such as monoclonal antibodies directed against CD38. In keeping with our mission, MMRF is committed to supporting research initiatives that accelerate the discovery of new treatments and further advance the care of all patients with multiple myeloma.โ
Article cited: “Genetic heterogeneity and mechanisms of drug resistance in relapsed refractory multiple myeloma”. Nature Communications. DOI: 10.1038/s41467-022-31430-0
Additional authors: 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 KB Chan, Jennifer Yesil, Xuhong Cao, Arvind Rao , Alexander Tsodikov, Moshe Talpaz, Craig E. Cole, Jing C. Ye, Multiple Myeloma Research Consortium, P. Leif Bergsagel, Daniel Auclair, Hearn Jay Cho, Dan R. Robinson
Funding: Multiple Myeloma Research Foundation (ORSP 19-PAF05802); National Cancer Institute (NCI, grant R35-CA231996); the Early Detection Research Network (grant U01-CA214170); the Prostate Cancer Foundation. JNV and AMC are financially supported by the NCI Clinical Proteomic Tumor Analysis Consortium (grant U24-CA210967). AMC is a Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar, and an American Cancer Society Professor.