Can knowing your MRD status help guide treatment?

What is response Adaptive therapy to knowing your MRD status help guide treatment.

Let's talk a little bit about the response. Adaptive therapy in myeloma. So in myeloma in general, the treatments have been developed pretty much like a one size fits all. We start on a treatment plan, often goes for an induction, sometimes consolidation and maintenance, and that tends to continue until the disease no longer responding or too extreme has toxicity that requires the treatment to stop.

But we all know myeloma behaves very different from one in one person to another, and that same treatment can lead to a different quality of responses. So the notion of using that information to adjust the therapy is not new. That has been using many other diseases, including many diseases that we consider curable. So the idea of response adapted is essentially to start a therapy, but then to be able to increase incremental treatments or increase the therapy.

If the response is not being as good as you need to be, or conversely, de-escalate the therapy, reduce the therapy, or even stop therapy if the response is the best. For the longest time, this was not pursued in myeloma for various reasons, but the main one is that good, great responses were uncommon. You know, only recently we have the majority of patients achieving complete response with upfront therapy.

When we look at those patients, we know that MRD becomes then the most sensitive or the best predictor of long term response. So it makes sense if we're going to pursue a treatment de-escalation, you do so on the patients who become MRD Negative. So there is that's still not a mainstream way to treat myeloma. The trials that start to elaborate that concept are still being drawn or being designed, but many of us have used that information.

For example, if you have a standard or even a high risk patient who has a deep and sustained response, and particularly the patient is not tolerating well, the ongoing maintenance therapy, we feel more comfortable with stopping therapy. It's also becoming very clear to the patients who have a biologically high risk disease with high risk chromosomal abnormalities who remain MRD positive post optimal therapy, for example, induction and transplant.

They tend not to do very well. So many of us take the liberty to go on and increment the patient. So as a patient that instead of going to single agent maintenance, we might go to double agent maintenance or even use a period of consolidation.

MRD Testing is a very controversial area right now. Right now, some people are using this to say, well, if you have a sustained MRD negative response to a particular therapy, then maybe you could go off of treatment.

Other folks are using this to say, well, if you have higher disease in your MRD positive, then perhaps we should intensify therapy. My approach is that that's far too early for prime time. Right now. We know that MRD negativity is a really good prognostic test. That tells us that you've responded really well and that it may stay in remission for a long time.

But it's far too early to use it to make treatment decisions in times like this in terms of either stopping or intensifying therapy.

MRD negativity in the clinic is not currently being used for any clinical decision making.

MRD is being looked at. However, with regard to the duration of induction, whether consolidation is needed in some trials, whether a transplant is needed, and it's also being used for the duration of therapy. But these are all investigational applications.

I continue to think of this as sort of an evolving theme. Certainly clinical trials are asking the question for both ends. If patients have had negative MRD testing serially on multiple occasions after they've been on maintenance therapy for some time, can they stop therapy?

I don't think that there's enough data to support that practice. But if it is an agreement between the patient and the physician, I would imagine that a serial follow-up to be sure that as you come off of therapy or as you decide to not go on maintenance therapy based on the MRD testing, that that doesn't translate to a poor outcome.

It means you need to have follow-up MRD testing to be sure that nothing has changed. On the other hand, people who have MRD positive residual disease, I do not usually try to use that data alone to start more therapy because ultimately MRD testing is subjected to error. And also we will not be able to do the MRD testing every month, unlike the blood tests that you do for your M protein.

That's an easy ask. Frequent MRD testing is going to be difficult. So if one makes a decision to treat based on an MRD positive state, wanting to get to a negative on any given month, we won't be able to easily say whether the side effects are worthwhile because you cannot see anything in the bloodstream until you repeat the bone marrow next time.

I have patients who have been MRD negative for over ten years. There are not yet any guidelines on how to manage this from a treatment perspective. There is no guideline yet assessed as the therapy could be stopped.

But there are patients that decide after a few years of being MRD negative, that they choose to take a break from therapy. And I've seen many patients that have chosen to do that and they still remain MRD negative over time. If you continue to check.

Unfortunately, there could be a recurrence. This is still an area for investigation.

One of the big barriers, I think, for this important question to go forward is that all the MRD assays, as I mentioned before, are bone marrow biopsy-based. So I think if we had blood-based technologies that would really open up the field to further explore these important questions.

If an individual is MRD negative and then becomes MRD positive, when would you consider starting treatment?

As with all new technologies that are very sensitive, that could be an issue of noise versus signal. So to be very direct here, a patient who has been treated, a myeloma patient, treated with combination therapy, who is MRD negative followed over time.

And at the follow-up time, say a year later, the patient is now MRD positive. Does that patient need to change the therapy? Well, there is not yet data to formally answer that question. If you check again in a few months, sometimes in my clinical experience that patient could turn negative again. But there are also patients that could stay positive and unfortunately there are some individuals where that positivity could continue to evolve into progressive disease.

We do not yet have enough information to counsel patients. My clinical experience, based on currently available literature and my own clinical daily experience, is that an individual that turns negative and loses that MRD status during the first year is a different situation versus a person who has been negative for a long time. And that could be some borderline positive.

There is positivity, but it's almost negative. I think in my experience, if it turns positive during the first year, I would be more sensitive to check it sooner again and make sure that we fully understand what's going on because this could be reflective of a dynamic of the disease that tends to come back for someone who has been followed up for a longer period of time.

It could also be kind of a false signal. The assays are not perfect. And I would check again. I would not just jump to new conclusions and change the therapy in any of these situations. I would always follow up. So I think it's important to emphasize that there's a lot of missing information. We need to generate more data to be better at counseling and giving the correct information.

But what we do know is that these situations do not prompt immediate change of therapy. So there is no emergency.

A lot of people may want to know if MRD can be used to guide treatment decisions. The answer to that right now is we don't know. And because of that, we're doing clinical trials where we take people who are, for example, MRD positive and decide to give them more treatment than would be standard of care. Or maybe they're MRD negative and we decide, hey, maybe we can stop treatment.

For example, in the case of Revlimid and maintenance, in the absence of this knowledge, I would not advise making a decision based on MRD although I think a lot of us are wishing that we had more data to do that. I really hope that as clinical trials mature in the next three or five years, we will be able to answer that question more completely.