Good morning.

My name is Francesco Maura from University of Miami, and I'm here attending American and Society Hematology 2024 Annual meeting in San Diego.

And this year, our group, in collaboration with the Moffitt Cancer Center, Memorial Sloan-Kettering, the University of Calgary, is presenting an important abstract there showing how whole genome sequencing can predict patients that will fail or will have a great outcome after CAR-T and BCMA therapy.

So for people that are not confident with the concept of whole genome sequencing, whole genome sequencing is a technology that allow us to basically decode the entire DNA that makes us the person we are. And so we can use that to compare in normal cells in our body with our code, with the tumor, and see what is the difference between the two.

Myeloma is a tumor with a lot of differences. It's a very complex. And what we found are several genomic patterns. Which are these alterations that makes the tumor different. The DNA of the tumor different from the normal that associates with poor outcome or refactoring this after anti-BCMA CAR-T.

Interestingly, some of these alterations can actually be targeted by other therapies. So there are specific anti-BCMA but may not be affected other therapies or other targets. That suggests that genomic driven therapy, which means you shouldn't get the whole genome sequencing information before getting CAR-T or immunotherapy, could guide our decision in an area where we don't have one single drug, but we have multiple drugs, different CAR-T, different targets, and clinicians struggle right now to decide which drug we should give to which patient.

So I think that is a first step toward a more individualized strategies for patients. When patients get the right therapy without wasting money, toxicity and time.

Among the genomic findings, genomic alterations that we found, there are definitely two main groups. One is the genomic complexity alteration is like TP53. 1q gain. All these alterations that we know are bad for myeloma are bad also for immunotherapy. That creates definitely a need for this group of patients to understand why these patients are so aggressive, even in the context of immunotherapy.

What we think is that because they have genomic instability, they can lose easily other piece of chromosome or other alteration piece of DNA. And these pieces of DNA involve a pattern that makes the plasma cell less plasma cell.

So BCMA is a protein that makes plasma cells. Plasma cells is essential for plasma cell differentiation. So without BCMA plasma cells struggle to be a plasma cell. That's why very few patients lose BCMA after CAR-T is always there.

So when, we target BCMA, if some patients have a less plasma cell profile because they altered their genomical DNA, then this patient will respond less to CAR-T. Like strategies how to eventually upregulate BCMA or maybe understanding which other protein this patient express may allow us to improve our strategy and maybe identifying new targets for these patients.