I'm in a complete response, why should I consider maintenance therapy? Should I consider maintenance therapy if I am MRD negative?

If I'm in a complete response, why should I consider maintenance therapy?

Should I consider maintenance therapy if I am MRD negative?

So when we're talking about complete remission, we're saying that we can no longer detect the myeloma markers in the blood or urine. Right. So this means your m spike is undetectable. Your free light chains are normal. And when we do a bone marrow biopsy that the bone marrow biopsy has less than 5% clonal plasma cells.

The problem is that that doesn't make us feel confident that the myeloma is completely gone. And so this is why we frequently will do consolidation like a transplant, even after somebody has negative markers, and why we will actually treat patients with maintenance therapy. Again, even if the markers are all negative. Now we have more sensitive detection techniques now, measuring minimal residual disease.

And there's different techniques and different levels to which we can detect minimal residual disease or MRD.

So one way that we can detect it is using a technique called flow cytometry. And this is able to detect, myeloma on the order of ten to the minus five. And so when we're seeing that then it's like one in 100,000 cells.

Right. And then there are other techniques that can detect myeloma on the order of ten to the minus six or 1 in 1,000,000 cells. And one commonly used technique is a technique called clonoseq. And so what we always wonder is if somebody is negative at ten to the -5 or 10 to the minus six, is that good enough?

Like do we actually need to continue things like maintenance therapy or anything like that?

And I think the answer is that it's fantastic to obtain MRD negativity, because we know that's associated with prolonged time before the myeloma returns or improve progression free survival. But we also know that that doesn't currently equal cure. And so because of that, there are a lot of studies that are investigating whether or not we can safely discontinue or deescalate maintenance or any myeloma treatment in patients like, that are MRD negative, but it's not currently standard of care.

So if I could just mention one trial called the master trial. They looked at this and it was so interesting because they used a marker called MRD Sure. And so once somebody achieved MRD negativity two times in a row, they were called MRD Sure. And then they were able to come off of maintenance therapy.

It turns out that patients that had 0 or 1 high risk cytogenetic abnormality once they achieved MRD negativity, could come off of maintenance therapy and experience a long time before myeloma relapse.

However, for patients that had two or more high risk cytogenetic abnormalities, even if MRD negative at two time points experienced early disease relapse. And those are the patients that probably could not come off of maintenance therapy.

And so I think it's clear that there are some patients that, even if they're MRD negative, are prone to experiencing disease, relapse.

But, that there are others that may not actually need all that additional treatment.

There are additional trials going on to try to answer this question. So nationally, there's a trial called the Drammatic Trial. That's looking at post-transplant maintenance and use of MRD to guide, duration of maintenance. There's, a study called the MRD2Stop trial.

And then there's a master-2 trial that's also asking these questions.

So I think the answer will be there in the future. But right now it's, I think, a very active area of interest.

Complete response is one of our goals. But I'll tell you that the way that we're evaluating for a complete response is perhaps with some rudimentary approaches where I have a lot of tools at my disposal, my institution, my pathologists have very kind of almost crude techniques of evaluating for residual myeloma that's measurable in the blood or the urine or the bone marrow biopsy.

Our eyes are good, our toys are good. We can find it when it's obvious, but that doesn't feel good enough. And minimal residual disease or measurable residual disease as the field is moving towards, is a way that we can use the techniques of 2025 and beyond future techniques to really dive way down deep in there to find that one residual rogue plasma cell.

I think of it as a ember in the ashes, if you will. I think I've put out the fire. If I've gotten a patient to a complete response. But one of the concerns is, is that there maybe that one ember that's hiding away underneath the ashes, that's just looking to kind of reignite, if you will. So complete response is great.

We think that getting to a place where you are not, we are not able to find myeloma kind of above the surface, if you will, but also that we can no longer find it below the surface we've put out. The embers in the ashes is going to allow for much more durable remission time, perhaps even overall survival time.

Which then begs the question to say, well, then, if you're in a complete response and you’re MRD negative, is that enough? Do I still need treatment? And we have just finished saying how important MRD negativity is in a point where we've gotten rid of and killed the embers in the ashes, but is one look enough? If I just do one biopsy and I say, no, no ashes here, no embers here, we've put out the fire.

Is it possible that that one point is enough to tell us that we've reached our goal? What we think we've come to, the conclusion is to say is that multiple checks that tell us that we are maintaining those, ashes without any of our embers in the fire is probably better than one data point.

So continued lack of measurable residual disease or MRD negativity.

What that time points are probably up for discussion. But for the sake of argument, let's say 12 months apart, if you can have two data points 12 months apart that confirm ongoing absence of measurable residual disease, that probably is the next holy grail and the next goal of our therapy, because one data point may not be enough to translate into the durable remission and improvement in survival that we're looking for.

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