What are some possible uses of MRD testing?

What are some possible uses of MRD testing?

So what is known about MRD and clinical outcomes? What's known about MRD and regulatory approval? What's known about MRD and decision making? So what is known is that MRD is associated with a longer progression free and overall survival in multiple meta analysis. That is the strongest prognostic factor is stronger than fish and cytogenetics, it's stronger than staging.

It is the strongest prognostic factor for multiple myeloma, both in patients that are transplant eligible and non transplant eligible and also in the relapse population. So a very strong prognostic factor. It is not yet the end point or the FDA has endorsed for drug approval, as I was talking about earlier. Also, it is not yet a tool that has been fully implemented in clinical care for decision making.

But just like anything else, there are early and there are slow adopters of things.

So for example, when a newly diagnosed patient is treated with combination therapy, if he or she

gets a transplant as a combination therapy, let's say the patient gets a transplant, what's the next step? Many times doctors would check and see if there is residual m spike, and if there is, they would then order consolidation therapy.

And if there is not, it would many times go to maintenance therapy. So if we think about MRD status, if the patient was MRD negative or MRD positive, that could be used in a very similar way. And there are some of the early adopting centers that use that type of testing the same way there are centers that give, say, eight cycles of combination therapy.

And if the patient is MRD negative, that they could collect the stem cells and do a delayed transplant. But the centers that want to see multiple randomized trials before they change the practice, they would not do that. And that is where the field is right now. There is a lot of controversy. So MRD could be used to step down the therapy and go right to maintenance therapy, for example.

There are many questions on the table. We all have different opinions. I think it's important for patients to recognize that there are more questions than we have answers and having second opinions and asking the doctor what is known and what is not known I think is very important.

The question is what is the possible use of MRD testing? And it stands for minimal residual disease. It is a technology that allow us to ask the question in case patients have already had disappearance of their monoclonal protein or their myeloma protein from the bloodstream and also have normal looking bone marrow where we cannot see the cancer cells anymore.

Can we go further to understand just how many of the residual cancer cells there still are? Currently, there are two different technologies to look at MRD testing. One is by staining the bone marrow cells with different antibodies and look for markers on the surface of the cancer cell that is called flow cytometry. The other technique used the genetics signature of the cancer cells for both technologies.

The question is, if you look for over ten, over a million up to 10 million bone marrow cells, can you still see any of the cancer cell? So the answer is going to be yes. We can still see some and this is the number or we don't see any. So folks who don't have residual disease, even when we look very, very hard, are going to be the folks who have such deep response that data has shown that patients in that group tend to have longer remission duration.

It also has become a tool for us to compare efficacy of different new things that are coming through the clinical trials. Because myeloma is a rare disease, you cannot test 50 drugs of the same time. So and we cannot wait too long to just see which drug give our patient the longest survival. We want to have a quick look with a tool that can really say this recipe works better than the other one, and that's why it's being created.

At the same time, what continues to be difficult is when we can run this technology and do a testing for each and every patient in front of us. If the result is positive or negative, what will we do with that data today? I don't use the MRD data solely to guide the treatment decision just yet because ultimately these are still patients who have a very, very good remission.

They are in fact in complete remission and that's where we want to get to. However, in case we talk about it already with any patients and they understand the limitation in our ability to know what to do with the data, whether it's good or bad. One point look, it's usually insufficient. You want to know in your own journey if you’re MRD negative and it continues to be negative or is it positive?

And now it's increasing number of the cancer cells that may have a bigger meaning comparing to are you positive or negative? And no, the thing that's still really controversial is when to do the testing, because if you're actually doing the testing at the different time, oftentimes, particularly in our patients after transplant, by the time they get on maintenance therapy, there’s actually improvement in that remaining number of cancer cells.

So making a decision too early based on one data point can also get people into trouble. We want the best outcome for our patients, but that intrinsic want shouldn't always translate to. So let's let's put all of our treatment into any particular patients because side effects is real and that affects the long term quality of life.

I think, at this point is very clear. Achievement of MRD negativity is the most important, important prognostic factor for multiple myeloma, and that knowledge of itself is critically important.

It won't be the focus of my talk, but just think about this from a patient perspective. If you're able to achieve that MRD negativity, you want to know the outcomes are much, much better if you if you reach that point. And the next question is, you know, what do we do with this information as we think about, quote unquote, changing therapy?

And I'll give you two examples of how I think we can use that. First would be in patients who are long term maintenance treatment, particularly patients who are in a CR, And, you know, after two years and three years, the conversation usually starts off. We continue therapy that we keep going the ideal world with a magic wand, with a pill that has no side effects.

You probably go forever. But in the real world, this is associated with fatigue, diarrhea and a number of other complications. How I bring it into the conversation as we do bone marrow in patients who are in long term maintenance, who are in cr and without we monitor their MRD status. And I would argue that for a patient who has a sustained MRD negative status, who, for instance, is experiencing significant burden of symptoms because of maintenance therapy, this would be one more piece of information that might allow them to make the decision.

to say I'm just going to stay on treatment. This is I'm going to I'm going to stop treatment because it's going to be important for me. Contrary. You know, if you have a patient who's still in MRD positive but is doing well, maybe they would like to stay for longer on an on treatment. And we don't have guidelines. It will be impossible to have the complete resolution for every single possible clinical scenario.

But I would say we can bring this into the conversation much like we bring any other biomarker. I think a mistake is to try to think of MRD something exceptional, something I make the analogy like the Supreme Court. So whatever MRD says we're going to do, I don't think that's the case. It's just a more informed clinical decision process.

So that would be one example. The second one, which I think is very important, there are multiple lines of evidence and multiple studies that are showing that getting that MRD negativity is important and is associated with good long term outcomes. But importantly, there's several studies that have shown that it doesn't matter when you get there, whether you get that post-transplant or even if you get it a year later.

So two examples that come to mind are the paper by Dr. Perrot that was published in Blood in 2008, and then the paper by Dr. Goicoechea, which essentially showed the same thing. You just get to that in MRD negativity. I always remind people there's nothing magical why we do four cycles and then we do transplant. It didn't come from a place of great wisdom as being the best therapy available is simply a historical practice.

And given what we know now that it seems to be important to make patients negative, we kind of use the phrase Let's finish the job. Or with patients, we get to polish what we're doing and if at all possible, we can convert you to MRD negative. We should try to do so. I will underscore and say that of course safely and this needs to be an informed conversation with a patient.

This is not something for which there is agreement within the community, but also based on the work of Dr. Parrot We know, for instance, if you're high risk cytogenetics myeloma and you don't become negative, you have a very, very high risk of early relapse. Furthermore, she showed that if you have high risk cytogenetic markers and you're able to make this become negative, then the results are better than if your standard risk and remain positive.

Now, if you're thinking, well, maybe this is just biology, some patients are destined to do well, there's no question there's a contribution like that. But on the other hand, if you just plot what has happened with MRD over the last ten years, just incredible growth in the fraction of patients that become MRD negative through their available therapies.

So I don't think we have to, you know, stop short of getting to where we want to go and in a safe way. Trying to achieve MRD negativity seems to be a good reason to to intensify and perhaps change or continue with treatment.