Whole-Genome Sequencing May Distinguish Malignant Transformation From Precursor Multiple Myeloma
Clinical Summary:
- Francesco Maura, MD, examines the evolving role of whole-genome sequencing in distinguishing monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and biologically transformed multiple myeloma.
- Genomic profiling may identify patients with molecular features of malignant transformation before the development of clinical symptoms or organ damage, while highlighting the biological heterogeneity and variable progression risk of precursor plasma cell disorders.
- These findings support further investigation of genomics-based disease classification to improve risk stratification, distinguish malignant from nonmalignant precursor states, and guide more individualized monitoring and treatment strategies.
Francesco Maura, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses how advances in whole-genome sequencing are reshaping the understanding of multiple myeloma precursor conditions, including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.
Dr Maura reviews how genomic profiling may distinguish patients with evidence of malignant transformation from those with precursor disease, even when conventional clinical and morphologic assessments appear similar. He also discusses the potential role of immune surveillance in delaying disease progression and how genomic classification may improve risk stratification, refine disease definitions, and inform future approaches to monitoring and treatment.
Transcript:
My name is Francesco Maura, I'm a medical doctor at Memorial Sloan Kettering Cancer Center, and I lead the lab focused on genomics.
Today we discuss precursors in multiple myeloma, specifically monoclonal gammopathy of undetermined significance (MGUS) and smoldering. These entities have been defined in the 1980s by Bob Kyle, who sadly passed away a few days ago.
Right now, thanks to novel technology, we are understanding a little bit more the heterogeneity that we see in clinic for these patients. As we know, most of the MGUS never progress, but a significant fraction experience a progression, with different times to progression. Some patients progress very quickly, some patients progress after many years.
Morphologically different from solid tumors, where a pathologist or oncologist can easily define what is tumor or what is not tumor just by looking at the morphology or the histology of the biopsy, in multiple myeloma, plasma cells always look the same. So the problem then is how we define the patient where the transformation into neoplastic entities already occurred from patients that never occurred or will never occur.
In this context, we felt and we found that genomics, in particular whole-genome sequencing, has this potential to differentiate patients with evidence of malignant transformation that we call genomic multiple myeloma, not anymore smoldering. This looks identical to multiple myeloma or very similar. For patients that don't have any evidence of malignant transformation, we call genomic MGUS.
The interesting fact is that most of these genomic smoldering, characterized by genomic events that look like multiple myeloma, but they do not progress. It might take many years for them to progress and develop organ damage or CRAB criteria or SLiM criteria. So the question is why this is happening.
Of course, this is an area of investigation, but the most plausible hypothesis is that the immune system somehow provides some immunogenicity and some immune control on the disease burden. This, of course, has a profound implication in our clinic moving forward from a histology disease burden diagnostic to a more sophisticated genomic DNA sequencing one.
Of course, it will take time to allow clinicians in practice to develop these tools, and we will need the community, multiple myeloma community, to reach a consensus on what is transformed and what is not transformed, as our study was just a preliminary significant step forward.
