IMS 2025 | Genomic signatures to predict which patients with SMM and MGUS will progress

So as we know, MGUS and smoldering are precursor conditions for multiple myeloma and all patients are preceded by these conditions, but these conditions are pretty common. 5% of the population above the age of 60 have these alterations. So the question is which are the ones that progress and which are not? Which one is the one that we should follow in our outpatient and the one that can just be checked by the general practitioner once per year? So to answer this question, we develop a very large collaboration with multiple institutions such as Mayo Clinic, University of Miami, MD Anderson Cancer Center, Moffitt Cancer Center, University of Milan, and Memorial Sloan-Kettering to assemble a large cohort of 374 patients with smoldering or MGUS with available genomic and clinical information. We develop the concept of malignant transformation, which I think is a key step forward for our understanding of what and how multiple myeloma develop. So the malignant transformation has the same logic of solid tumor. In solid tumor, if you have a polyp in the GI or nodules in the breast and you find that this tumor is transformed with malignant cells, you call that carcinoma in situ. If you don’t see the signatures, you call it benign nodule. So in myeloma, we don’t have this definition. We call them smoldering or MGUS, which are basically, we don’t know what’s going to happen. And so with this genomic classification based on the DNA alterations, we found that the CIV can fractionally smoldering and part of MGUS are already like myeloma, genomically. So they are already tumor. So they are transformed. That doesn’t mean that we progress in 5, 3, 4, they can progress in 10 years. We have patients with a full transformation that progress after 15 years. So that’s another important aspect is why this transformed tumor takes 15 years to progress. So the answer is because probably there is some immune control and understanding the future of this immune control will create the condition for developing more sustained and durable responses. On the other hand, the patient without myeloma transformation, they never progress. So we can identify this population and that’s a potential clinically relevant implication. Finally, for the patients with that risk of progression with a tumor transformation, we also identify a clinical and genomic integrated signatures to predict the patients that will progress within two, three years. So the question now is if this patient is progressing so fast, probably the immune control in those patients is lost. And so what should we do? Should we do immunotherapy like single agent or should we treat them with more aggressive myeloma treatment? Of course, these are important questions, a lot of work to be done, but we’re very grateful for being part of a great team of collaborators. And collaboration and network is everything in this field and we’re very glad to be part of it.

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