Researchers have shared novel insights into the evolution of multiple myeloma from precursor disease, which may help physicians better identify patients whose disease is likely to progress as well as develop new interventions, according to a recent study published by Dang et al in Cancer Cell. How multiple myeloma evolves from precursor conditions such as monoclonal gammopathy of undetermined significance and smoldering multiple myeloma remains largely unknown.
“This research is a big step towards understanding the evolutionary roadmap that leads to myeloma,” explained co–senior study author Linghua Wang, MD, PhD, Associate Professor of Genomic Medicine in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “Additionally, there is a significant clinical unmet need to find and validate novel biomarkers to identify patients at high risk of progression who would benefit the most from early treatment interventions,” she added.
Study Methods and Results
In the recent study, the researchers analyzed the samples of 64 patients with multiple myeloma or precursor disease by using paired single-cell RNA sequencing and B-cell receptor sequencing in an effort to better understand the evolutionary processes behind the disease’s advancement.
Although fluorescence in situ hybridization is the current standard of care for identifying genetic abnormalities in multiple myeloma precursors, low tumor purity in the precursor stage has been a known limitation. By integrating the hybridization technique with single-cell sequencing data, the researchers were able to overcome this limitation and thoroughly analyze the transcriptomic landscape of the earliest precursor stages. This also led to better refinement of genetic subtypes.
The researchers noted that combining single-cell RNA sequencing and B-cell receptor sequencing may offer advantages in detecting clonal or aberrant plasma cells during the early stages of tumorigenesis. For instance, these plasma cells might already have undergone clonal expansion but remain less transformed—which may then exhibit genomic and transcriptomic characteristics similar to normal cells and result in misclassification when relying solely on the single-cell RNA sequencing approach.
Further, the researchers discovered substantial genomic and transcriptional heterogeneity present in the earliest precursor stages, including monoclonal gammopathy of undetermined significance, even within a single patient. Although previous studies have reported such heterogeneity, this study further uncovers that intratumoral heterogeneity may extend to established myeloma-related genes such as CCND1, CD38, BCMA, LAMP5, and MYC—some of which have been targeted in clinical trials.
After conducting an in-depth characterization of changes at various levels—transcriptome, genome, and clonality—in relation to cell differentiation status, the researchers identified distinct correlation patterns within genetic subtypes. The dynamic changes in gene expression associated with multiple myeloma throughout the differentiation process pointed to genes potentially related to disease progression.
Finally, the researchers identified 15 major subtypes of immune cells and stromal cells within the tumor microenvironment. They observed variations in the microenvironment composition as well as differences in the interaction between the tumor and microenvironment across samples of different genetic subtypes.
Conclusion
The researchers revealed that precursor states predominantly followed a linear evolution pattern, whereas advanced multiple myeloma displayed a branching pattern. They hope their new findings can help advance the understanding of the biological changes associated with disease progression.
“This study unravels the complexity of precursor plasma cells and their interactions within their environmental milieu at a much higher resolution than previously established, thanks to the technological constraints that single-cell [RNA] sequencing has now overcome,” emphasized co–senior study author Elisabet Manasanch, MD, Associate Professor of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.
The researchers plan to continue profiling available samples of multiple myeloma and precursor diseases and hope to further explore the potential for their discoveries to be translated into impactful clinical solutions.
Disclosure: The research in this study was supported by the National Institutes of Health, the High-Risk Multiple Myeloma Moon Shot initiative at The University of Texas MD Anderson Cancer Center, the Riney Family Multiple Myeloma Research Fund, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. For full disclosures of the study authors, visit cell.com.
