What is functional risk?

What is functional risk?

I was actually asked to speak about a topic called functional risk. We have all of this risk stratification and you can talk about all the fancy gene expression, profiling, extra imagery, all of that stuff, but that's all pretreatment. And what about what happens after treatment? And I think that's what is really interesting to me. And you can kind of break it down into three parts.

First is the type of relapse somebody might have, because there was a very interesting paper that if somebody has a biochemical progression versus the CRAB symptoms versus a very aggressive like extra medullary plasma cell leukemia, it matters. And as you might expect, the biochemical aggressors do much better than the high risk. Then there's also the kinetics of the relapse. Is it primary refractory, which is you don't respond to initial therapy. It's becoming increasingly rare because we're getting to more and more quad therapies, for example. But primary refractory disease is bad. And there was a study that showed that when you look at these patients, their genetics, when you profile them, they behave differently than the patients who are just standard newly diagnosed.

And then some people will have a remission, but then they very quickly relapse. So that's early relapse, such as less than 18 months from initial therapy. And then there's also people who may have attained MRD negativity, but then they lose it or people who never get MRD negative. Those are also bad. And compared to the patients who continue on.

And then the last type of functional risk is being drug refractory. So what I mean by that is we know that, for example, lenalidomide maintenance and induction and transplant maintenance is really effective and prolong overall survival, which is why we use it. However, in studies in relapsed myeloma, when you look at people who've gotten the same treatments, let's say daratumumab bortezomib dex versus bortezomib, that's the so-called castor study. Patients who got DVd or dara velcade dex, had a progression free survival of 16 months in general. But if they were refractory to lenalidomide, that drops to less than nine months.

And so if you're using drugs to the point where the patients are becoming refractory to that treatment, that can have downstream sequelae. So we really need to make sure that we understand that we should be using it early. And that has to show be shown by an overall survival benefit because if you're using a drug and it's leading to down term downstream problems, you're not helping the patient.

So I think the point of my presentation was really to look at risk, not just when you're diagnosed and some an analogy often like is, which, you know, the baseline risk stratification is static and it's like a photograph, the functional risk or dynamic risk. It's like a movie, right? And what's more interesting, a photograph or a movie? I think a movie is always more interesting. And I think it's capturing what's happening to the patient. And I think it gives patients some hope that you're high risk. Maybe you're not going to be high risk if you're in a sustained MRD negative. There's reason for very much optimism, and it also remains standard risk patients like, that there's this expression in oncology, you have to hope for the best, but be prepared for less than that. Because you don't know what's going to come your way. And I think it's good to have that equipoise when you go into these types of situations.