MRD2STOP: Can multiple myeloma patients stop treatment? | Ben Derman, MD | #ASH24

I'm Ben Derman.
I'm from the University of Chicago.
I'm an assistant professor, and I specialize in multiple myeloma.
And what I wanted to talk about was some of our data that's come out about a study we performed called MRD2STOP.

So just briefly, when we talk about MRD, it stands for measurable, some say minimal, residual disease.
And the idea is that even though when we do a bone marrow biopsy or even peripheral blood testing, there may still be small levels of cancer cells, myeloma cells in this case that we can't detect using conventional means, but with more sophisticated measures, we actually might be able to find something.

And what we've seen over time in myeloma is that the more cells that you can look at and still find no myeloma, the better the prognosis is for patients.
So patients live longer and live longer without their disease progressing.

And at this point, we have very sophisticated testing available for patients with myeloma.
The deepest that we can go is what we call ten to the minus sixth testing.
This means that if we look at a million cells in the bone marrow, we can detect even a single myeloma cell out of a million.

And ten to the minus six MRD negativities seems to be the best prognostic marker that we have in myeloma, or at least one of the best.

And so what we wanted to ask was actually a question that patients were asking us, which is I'm on lenalidomide maintenance therapy for my myeloma or I'm on single agent maintenance therapy.
Doc, when can I stop?

So we wanted to design a trial to answer that very question for our patients.
And that's exactly what we did.

So what we did is we took patients who we knew to be in very deep responses.
They were complete response in the bone marrow.
So there was no evidence of disease.
But not just that they were MRD negative at ten to the minus six using a test called clonoSEQ.
This is a very highly sensitive technique that gets us to this ten to the minus six level.

We also did PET scans because sometimes we know that patients may have disease elsewhere, even though they don't have it in their bone marrow.
So this was sort of an insurance policy for the patients to make sure we didn't have any disease elsewhere.

In the data that we recently published, we published on an experience of the first 47 patients in this study, we had almost three years of follow-up from the time of discontinuing treatment.
So this is exactly what we did.
We offered patients the opportunity to stop their treatment if they were negative by all these testing.

And two and a half years later, on average, we have been tracking their outcomes.
So we did serial bone marrow biopsies every year, much to the chagrin of patients, I would imagine.
But it gave us a lot of important information.

And we also did blood testing every three months with clinical visits, sort of the thing that you might do with, you know, patients seeing their doctor.
Anyway, what we found is that the progression-free survival, the time that patients are alive without for disease progression, it was the three-year progression-free survival was actually 85%, meaning 85% were still alive without progression.

And not only that, but 68% of the patients were still MRD negative at ten to the minus six at three years.
So this begs the question, are we possibly identifying patients that might have been cured of their disease?
This is the big question in our field.
Some people think no, myeloma cannot be cured.
Other people think, yeah, we think it could be.

And we were among those folks who said, clearly we're seeing patients with very deep, durable responses.
But in order for you to be able to say somebody is cured, I think there's a couple of things that we need to consider.
One is, are you still on treatment? Obviously, and you have to be off of treatment.
So we try to do that in this study.

The second thing is do you have any evidence of disease.
And that's where this MRD testing becomes super important, I think, to be able to define the absence of disease.

In this study, though, we wanted to go a little bit further and we said, okay, well, we can look at a million or 2 million or 3 million cells in the bone marrow.
But what happens if you look at 10 million cells?

So when a patient gets a bone marrow biopsy and aspiration done, there's actually a ton of cells in there.
But the assay that we're doing is only validated to analyze about 2 or 3, 4 million cells.

But we actually do oftentimes get over 10 million cells.
So we could even get to ten to the minus seven, which is not something that's previously been known.

And what we did in this study that was really unique is we actually performed a special type of filtering of the specimen.
We took a large bone marrow aspirate, all the aspirate that we usually take, plus a little more.

And then we filtered it down to just looking at the plasma cells, which express a molecule called CD138 on its surface.
And this allowed us to get a much smaller cellular population from this larger sample, but it's representative of the larger sample.

So this effectively got us to ten to the minus seven sensitivity.
And what we showed is that even though all the patients on our study were technically negative by the conventional tests that we send with clonoSEQ, using the same technique on a fraction of this filtered cell sample, we actually were able to find that about 15% of the patients had MRD positivity at this even deeper level, called ten to the minus seven.

And those were the patients that typically had a progression event.
So what we're thinking about is, okay, ten to the minus six is really good.
It's ready for already for prime time.
But if you want to get really fine about it and really try to clarify your risk, maybe we need to know this ten to the minus seventh level.

Now what we're presenting at ASH this year in addition to that is now we're going to take peripheral blood samples because, you know, the Holy Grail would be, hey, if you're really great, if we don't have to do a bone marrow, if we could just do peripheral blood.

So what we're doing is a technology called mass spectrometry.
Now, not all mass spectrometry is the same.
There's actually lots of different types.
We did something called clonotypic peptide sequencing with this approach.

So this is a bit more laborious.
You have to take a baseline sample for the patient of their blood.
And they have to have some m-spike or light chain that's detectable in there.
And then what happens is you try to trace back what is the specific protein that is detected in this blood sample.

And what was the DNA sequence that led to the production of this protein sequence, this peptide sequence.
And so it's a complicated algorithm that we with a company we work with, Sebia and Corgenix did for us.

But what we found is in 16 patients, just a subset of the patients that we looked at, we actually were able even at the time of the discontinuation when these patients were in really deep responses, they still had some infinitesimally small, protein that was detectable.

And when we track it over time, some patients had increases in this protein, which was followed thereafter by disease progression, and some patients had stable levels.
So it begs the question, does everyone, even the people who we think to be quote unquote cured, still have some detectable disease?

Or is it possible that, everyone might eventually progress given enough time?
And that's the question that we don't really know.

What I'm hoping is that that's not true, that we really are identifying people who are functionally cured.
Maybe their immune system will be able to keep whatever small potential disease is left in check.
But that's what we're going to find out with more information as time goes on.