Researchers have offered a comprehensive understanding of the progression of multiple myeloma from a treatable condition to a high-risk disease by providing insights into its genetic diversity and subtypes, according to a recent study published by Skerget et al in Nature Genetics.
Background
Multiple myeloma is the second most common hematologic malignancy in the United States, with an estimated 35,750 new cases and 12,590 deaths from the disease in 2024. New targeted agents and therapies have resulted in improved outcomes; however, most patients with multiple myeloma eventually relapse.
“Despite efforts to understand the molecular basis of the disease, predicting patient outcomes and identifying high-risk patients has remained a challenge,” stressed co–study author Sagar Lonial, MD, FACP, Professor and Chair of the Department of Hematology and Medical Oncology at the School of Medicine as well as Chief Medical Officer at the Winship Cancer Institute at Emory University.
Study Methods and Results
In the prospective, longitudinal, observational clinical CoMMpass study, researchers analyzed data from 1,143 patients with newly diagnosed, previously untreated multiple myeloma. To understand the diverse array and frequency of genetic events that can contribute to the development or progression of multiple myeloma, they conducted a molecular analysis of seven different data formats extracted from whole-genome, whole-exome and RNA sequencing data. This enabled differentiation between partial and complete loss of function of the TP53 gene, a key driver of progression in multiple myeloma and many other cancer types. They then detailed a median 4-year follow up of the complete baseline cohort and described the subtypes of myeloma—including a high-risk subtype that is less sensitive to therapy.
The researchers defined the frequency of gene alterations in multiple myeloma from diagnosis to relapse, offered a more thorough understanding of the genetic diversity and subtypes of the disease, uncovered the complexity of newly diagnosed multiple myeloma and disease behavior at relapse from treatment, quantified how the multiple myeloma tumors of standard-risk patients converted to high-risk tumors at relapse.
Notably, the researchers determined the primary molecular features associated with different subtypes of multiple myeloma and identified high-risk patients at both diagnosis and progression. These molecular analyses were found to be more effective predictors of disease behavior compared with current staging systems.
“These data underscore the durable value of the collaboration that [the Multiple Myeloma Research Foundation] facilitates and sustains. As one of the only public data sets with regular updates, CoMMpass will continue to define mechanisms of resistance and novel changes associated with disease progression—and open up new therapeutic opportunities,” underscored senior study author Jonathan Keats, PhD, Assistant Professor and Director of Bioinformatics at the Translational Genomics Research Institute.
Conclusions
The findings revealed critical genetic markers that can better predict multiple myeloma progression and identify patients at risk of transitioning to more aggressive types of disease. The researchers suggested that better understanding the high-risk subtype of multiple myeloma can allow for the development of more effective treatment strategies.
“The breadth of the [Multiple Myeloma Research Foundation] CoMMpass study enabled us to identify distinct copy number and expression subtypes of [multiple] myeloma as well as both recurrent and rare molecular events that occur at frequencies that would not be detected in smaller patient cohorts. We can now see the rate at which patients transition to the high-risk subtype at progression,” Dr. Lonial indicated.
“This study refines our understanding of how frequently patients transition from a more treatable type to high-risk disease, highlighting the need to focus on high-risk subtypes and disrupt this progression,” emphasized George Mulligan, PhD, Chief Scientific Officer at the Multiple Myeloma Research Foundation. “As a research organization dedicated to the urgent pursuit of more effective treatments for every patient [with multiple myeloma], we are gratified that our team’s efforts have shed new light on this challenging disease and that our CoMMpass study continues to accelerate both science and solutions,” he concluded.
Disclosure: For full disclosures of the study authors, visit nature.com.
