Is maintenance therapy continuous or a fixed duration? Why? What is response adaptive therapy? How can MRD status be used guide maintenance therapy?

Continuous maintenance therapy is the current standard of care for myeloma patients. However, growing research is exploring a new approach. Fixed duration maintenance therapy based on achieving and sustaining MRD negativity. This evolving strategy, known as response adaptive therapy, aims to tailor treatment length to a patient's individual response.

In this Health Tree University lesson, leading myeloma specialists share their insights on this emerging concept and highlight clinical trials that are testing whether some patients could safely stop maintenance therapy after reaching deep and lasting responses.

Is maintenance therapy continuous or a fixed duration?

What is response adaptive therapy?

Maintenance is one of the big hot topics right now in myeloma. And right now the paradigm is just treat until progression or intolerance. But we're starting to say, well, do we really need to do that for everyone? Can you stop it or do you need to continue? And there's been a number of studies to help inform this.

So there is a study called the Stamina Trial.

CTN 0702 and it said should we give two years or continuous. And that trial said continuous does better, keep them on it.

But then a really interesting trial called the master trial, which has been presented a number of times by Luciano Costa, one of our great myeloma colleagues, said, well, wait a minute. Maintenance may be different or mean different things for different risk stratifications.

So in the master trial, he took patients who achieved MRD negativity and then stopped their therapy, stopped their maintenance. And when we look at it, we group them into three categories no high risk cytogenetic abnormalities, one high risk or two or more. And when you compare it and you look at it, the people with 0 or 1, the overwhelming majority are maintaining their remission without maintenance therapy.

But the people with two or more high risk cytogenetic abnormalities are relapsing.

So right now the short answer is we treat til progression. But what we're starting to understand is that for patients who achieve a deep enough remission, if you have the right type of disease, the good risk stuff, you may do just as well continuing maintenance or not.

So we're really trying to get granular about that. But that's what the early data is showing us.

There's a lot of, trials and discussion going on with maintenance, which I think is very exciting that in each and every step of the myeloma therapy, things are being reevaluated and we are updating and optimizing our therapies.

We look at the first trials, maintenance does increase or prolong the progression free survival, meaning that the disease stays away longer if we do maintenance in general. The standard recommendation is to do maintenance as long as it works.

So until progression.

In general not only high risk patients but in general there is the question of should we and how do we tailor maintenance for each and every patient? Should we have two or more drugs for those that are high risk?

MRD positive. Can we then or can we de-escalate or stop maintenance for those that are on the other end of the spectrum that are MRD negative or not high risk? So we here at MSK, have an ongoing trial, and this is somewhat based on one of the trials from the UK myeloma group, where they saw that after three years, those that were MRD positive, there's still a benefit to continue maintenance for those that are more negative,

It's questionable how much benefit we get with maintenance after the three years.

Based on this evidence or based on this data, we here at MSK, Doctor Korde, she's leading a trial of maintenance discontinuation. So for those that have sustained MRD negativity for three years, there is an option to stop maintenance.

Early data from this trial, and also from the trial that Ben Derman is leading in Chicago that was published.

We see that the majority of patients after 1 or 2 years are still MRD negative.

There are a few that have turned from MRD negative to positive. However, not all of them have started maintenance again, so some of them can still be monitored because it can still take a long time until we actually see disease that we need to treat.

So we take that group that are probably not the high risk group, more of the standard risk with sustained mid negativity for three years.

The standard recommendation is still to continue maintenance. But that's the patient group where we can consider and talk to each and every patient. Should we do this of course we want to see the the data from the trials.

But that's the patient group where we can de-escalate. For those after three years that are MRD positive, there is a benefit of continuing maintenance. For the high risk group, I would still recommend keeping maintenance. And here is also the group where we would discuss all the way from the beginning, doing more than than just one drug maintenance or probably two drugs maintenance for those that have one or more, and particularly those that have, two or more high risk cytogenetic features.

I think this is also the big question for lenalidomide maintenance. How long do I have to take it. Because you know, by the time you hit, you know, year one even it just gets to be a drag. So it always is a question and a discussion between provider and patient. We always try and figure out what's the best, how do we maximize quality of life while not losing our hold on the disease.

And so we try to figure out the optimal length of time. The studies that originally got lenalidomide approved, most of them actually stopped at around two year mark. Right. But here in the US, we've extrapolated and most practice here in the United States is based on getting continuous maintenance. So basically the maintenance never stops until it stops working.

And so we try to figure out, you know, moving forward if there's any way we can de-escalate that.

So I mentioned earlier, the MRC 11 trial, and this is a really nice study, just because of the number of patients, the number of randomization, and the wealth of data that we have there. And so a very interesting analysis came out where they were showing on a yearly basis for patients of all different response classes, patients that were in complete remission, patients that were MRD positive or negative, you know, how long were they maintaining a benefit, from lenalidomide.

And what it looked like was that at every single landmark. So when they checked it one year, when they checked at two years, the benefit was still there. So patients that were MRD negative still did seem to have a progression free survival benefit from being on the drug. And when they got to year three for the specifically for the negative patients, that benefit disappeared and it no longer was statistically significant.

And so that plays in really nicely to some of the other data that we're seeing. Right. So it seems that maybe about year three, if you're already MRD negative at that point, maybe you're not deriving a lot more benefit past that.

We had actually run a trial when we were over at Sloan Kettering looking at, lenalidomide maintenance over the course of about five years, looking at MRD every single year.

And we saw something similar for the patients that were MRD negative after two years. So they were MRD negative at zero, one, two years. None of the patients for median follow up was almost two years after that. So now we're looking at four years total. None of them progressed while we were observing them. And so that again sort of agrees with that data.

Right?

If you reach that 2 or 3 year mark, it looks like you're not going to achieve that much more benefit. It's debatable. You know, there's granularity there, but it looks like the benefit vastly diminishes. So there are trials looking specifically at that time point, moving forward to see if patients that are MRD negative at that 2 or 3 year time point may be able to stop lenalidomide under very close observation, obviously at this point in time, to see if it's a safe thing to do, to see if the disease will come immediately back or if they're still going to retain that initial benefit of their response.

These days we are using, as you can imagine, because, it relies on MRD, we're doing that in the clinic, and we are testing people, for MRD negativity, at the two and three year marks, because at this point, it's all based on retrospective analysis, and studies that weren't specifically powered for this endpoint. It is completely a discussion between provider and patient.

There's no, real proven benefits. Or safety, that that can be shown for taking lenalidomide off. But for me, if a patient is really suffering and they don't want to take it anymore, I would be much more comfortable to consider doing that if they were MRD negative at that 2 or 3 year time point.

So one of the questions that I think, you know, are asked about maintenance and this is now really more than ever being studied is if patients have to be on lenalidomide for long term. And, you know, we're talking about years of maintenance therapy. Obviously there's this risk of secondary primary malignancy. And so you know we have to weigh the risk versus benefit.

And we do have these discussions with patients. However there are studies now that are being done.

So we have a stopping trial. It's called the freedom trial, free from maintenance drug therapy in myeloma. And it's a phase two study where we're taking patients who have been on at least two years of maintenance therapy, and we do a bone marrow biopsy and check for MRD status. And so what we do is we check a bone marrow biopsy at two time points one year apart.

And both of them have to be MRD negative to be eligible to stop therapy. So this is what we call sustained MRD negativity.

So once we see that the patient has sustained MRD negativity, we're stopping lenalidomide maintenance in these patients. And we will continue to follow them every three months to see how they're doing, you know, see if they have any new pain, new signs of, you know, the disease, progressing.

We'll still check their protein levels every three months as well.

And then every year we will repeat that bone marrow to check MRD status.

you know, we hope that what we'll learn is there is a subset of patients that can safely stop lenalidomide.