Gareth Morgan:

Hello, my name is Gareth Morgan. I’m here in Scottsdale, Arizona at the Myeloma 2022 meeting. I’m with two good colleagues, Leo Rasche, and Francesco Maura. We’ve just been in the genomics session. I’d just like to ask you, Leo, what did you think of the session and what did you think the take home message was?

Leo Rasche:

Oh, the session was great. But it’s difficult to have a good take home message because we’re diving deeper into all the certain subtypes of myeloma, about the etiological events leading to the first myeloma cell, all the subgroups. We talked about the evolutionary pathways, which eventually lead to relapsed/refractory disease. However, all this data is somewhat collected before the era of immunotherapy, and as we have discussed, in the context of unknown treatments. It certainly was a very important session. I think what I liked most was the studies which had been done on mice because here we start to answer these questions. What is happening when we treat these mice with immunotherapies and what is the genomic or the link between genomic and success of immunotherapies.

Gareth Morgan:

Can I take that question, which I think is a good question and ask Francesco what he thinks about that. Do you think immunotherapy will totally change how we risk stratify a patient?

Francesco Maura:

The short answer is yes. As every treatment, like when bortezomib was introduced more than 10 years ago, the risk changed-

Gareth Morgan:

Did it really? (laughing)

Francesco Maura:

Well, the point is what emerged. I think one of the take home messages, which again is not a real take home message, it’s a question, are we able to define high-risk? We are able to define with what we have today or what we have actually yesterday, because most of the classifications are based on technology and genomic or clinical features defined many years ago. The answer is, yes, we can kind of define who is high-risk, who is not. There are two big limitations. The first is that what we define as high-risk is a group of patients. It’s not the individual risk. So these are relative risks, meaning if the patient comes tomorrow in your office, you can say you are ISS 3, so you are at high risk. But you know that a fraction of those patients will have very long outcome. That’s a relative risk of a hundred patients like you, 80% will progress in three years. That’s not the individualized risk.

Francesco Maura:

The second is that all these scores that we have today, completely ignore treatment and completely ignore all the genomic information that you, like that [inaudible] amplification 1Q and others have reported so far. I think we need to get, and we are working on it, to include these two important aspects into the high risk. And the individual prediction, we have software now to do this. These machine learning artificial intelligence that actually work on that purpose, moving from relative to absolute risk. And for treatment, we just need to collect better the data. And CoMMpass is one of these effort where treatment is included, but never used, for example.

Gareth Morgan:

I kind of agree and disagree with both of you in some way. It’s always a nuanced view in a way, in that extremely high proliferative disease with p53 mutations, and everything we know about cell cycle progression. I think that’s still going to be a poor prognostic group, even in the context of the best immunotherapy. We heard some more data about trying to define poor prognostic disease or identify disease earlier. How do you think we are going to use that information in the clinic?

Leo Rasche:

I agree that high proliferation will remain a risk marker, even in the era of immunotherapy. I think it’s your great work showing us that a single cell could drive relapse. So if this single cell has high proliferation rate, then it will pop up very early or faster than others. High proliferation will remain a risk marker. However, if you have a treatment which is able to eradicate 100% of the cells, then high-risk is overcome, right? This is what we are, maybe not now, but in lymphoma, we are already there. That’s why I think at some level, high-risk will not remain the category in the future when we have therapies, which are able to eradicate myeloma and to cure a significant proportion of patients.

Gareth Morgan:

What about, I’m not sure which one of you it was that showed the beautiful slide that a single cell can lead to a relapse 10 years after treatment. I think it was you, Leo. (laughing)

Leo Rasche:

(Laughing) Yeah, that’s true. That’s why I think dormancy, this is the real issue we are facing. Because if there is a dormant cell somewhere in the bone marrow or in an organ, we do not know where these dormant cells are. This cell is not being killed for example, by a CAR T-cell. Or we just do not know whether immunotherapies are able to kill dormant cells, because all of these novel immunotherapies, they relate to the induction of apoptosis. So is apoptosis something a dormant cell is able to undergo?

Gareth Morgan:

Probably.

Francesco Maura:

To follow up to your question, I agree with Leo, and also with you. I think that there is a group of patients that whatever you do for the genomic and immune settings they have right now, it’s really hard to induce remission or sustain remission. These are what they call the ultra-high risk, which is not very original, but these patients are not even included in clinical trials, because they don’t match the standard. They have kidney failure, they are too frail, and so we don’t even know exactly what these patients are because they’re not even included in clinic. So you need to look at retrospective cohorts to really detect those patients.

Francesco Maura:

In our experience with lymphoma, for example, we’re a little bit more knowledgeable about how immunotherapy works. We did a study that was presented at ASH on genome and CAR-T, and what we found is that the known genomic features that are associated with poor prognosis, high-risk in lymphomas, aggressive lymphomas, are not prognostic after CAR-T. But new features that people don’t even know existed before in lymphoma, or probably they knew but they never considered, are highly prognostic, like presence of [inaudible 00:07:36] no one never heard about [inaudible 00:07:38] lymphomas probably, or like used as prognostic factors.

Francesco Maura:

Most of the patients progress. [inaudible 00:07:43] all the patients progress. There are features. There is that the risks change according to the treatment, which is not regional per se, but I think it’s what we are going to see in multiple myeloma, introducing earlier immunotherapy or later, you will see different markers coming up. Like Leo has shown, biallelic loss of BCMA is not a recurring mechanism, was published in natural medicine, was clonal. So that was for sure a mechanism of resistance. One case out of hundreds, but that’s an event that doesn’t exist in any diagnosed myeloma patient. New treatments require new ways of thinking and new approaches to understand.

Gareth Morgan:

What I think you’re trying to say, and concluding, is that there’s a continued need to do these molecular studies. It’s not all done and finished, that as we introduce new treatments, you need to explore their mechanisms of resistance and relapse. Only by doing that are we going to be able to tailor the treatment to individual patients. So thank you for that, and we’ll finish there.