Does everyone need to become MRD negative to have a good outcome?

Does everyone need to become MRD negative to have good outcomes?

So one question that comes up often in the clinic is that does every patient really have to become MRD Negative. There are patients that are MRD positive, and they stayed MRD positive for years. This is another area where we don't have very large databases with long, long follow up to fully counsel every patient.

My clinical experience here is that there are individuals that never become MRD negative. They are MRD positive and they can stay positive for more than ten years and they do not progress. They do really well. I think the disease biology may be of that nature, that it just sits there and sends away either a little bit protein or there is no protein, but it's still MRD positive.

I think it's probably wrong to give additional therapy to get rid of these markers. It's almost like makeup for the laboratory list. I would not do that and the guidelines would not support the use of more therapy in these instances. So it's a matter of the dynamics of the disease process. I think that the data right now suggests that the patient that remains sustains MRD negative over time is not that different from a patient that sustains just barely positive over time.

It seems to be quite similar clinical outcome. the patient could be free from the disease for a very long time, for many years. A patient that turns negative and loses the negativity in the first year and bounces back and then being is being followed, that patient is more likely to have a relapse. And then patients that start therapy and then they don't have a good response at all is a very small group these days.

But there are some patients that don't benefit. There is less than a partial response. I think this is reflected about the fact that the therapy does not really touch the disease and the therapy needs to be changed. So those are like the good clinical outcomes and the patients that need more attention. You need to change the therapy.

So there definitely are a subset of patients who never achieve MRD negativity. Some of them never even achieve a complete response. So and they still have really, really good outcomes. So years pass, sometimes over a decade passes and they don't experience disease progression despite having a continuous and detectable amount of para protein or that abnormal protein in their blood, these patients are usually those with standard risk disease.

The data would seem to indicate that for high risk disease, right. Those with, you know, DNA abnormalities that confer high risk for high risk disease, that seems to be more important to achieve. MRD negativity. You don't usually see these long term survivors with residual disease if they're high risk. But there definitely is a subset of patients with standard risk myeloma who experience excellent outcomes despite never being MRD negative.

And I think that is one of the shortcomings of like a universal MRD based approach because there are some people who would be overtreated. We like to think and we have some evidence that shows that these people revert to a MGUS type stage, meaning so by MGUS you know, and that is a precursor condition monoclonal gammopathy.

of undetermined significance by treating the cancer. It sort of works into this dormant MGUS type state. That MGUS state is still producing a protein, so they are not MRD negative from those MGUS, cells are still Detectable, but it's dormant and it can it can be like that for years. There are some tests that can identify those patients, but they're not commonly used.

They're not widely available, they're not approved for, for, for, for wide use. So we still struggle with identifying who are those patients that can stay MRD positive and still do well. Often we identify those patients retrospectively, meaning somebody's already done really well. They could've been seven, eight, nine, ten years and they are still MRD positive And we're like, Yeah, you're the kind of person.

But what we don't know when we see a person in clinic today is, is that the type of person who can do well despite remaining MRD positive. One of the hints is that they're usually standard risk disease.