What is minimal residual disease. 

Well, let's talk a little bit about mrd mrd means minimal residual disease or as some of us prefer, measurable residual disease. So we're talking about nothing but a test that allows us to quantify the myeloma at a very low levels. So traditionally, we assess myeloma. We identify myeloma and assess the myeloma through therapy. But looking at a protein in the blood and in or looking at the bone marrow under the microscope. 

But you need really billions, if not trillions of cells to be able to produce an amount of protein that is detectable on the blood test or in the urine test or become visible under the microscope. Now that the therapies are so much more effective, you have more patients reaching complete response. And that means if you look at the bone marrow, you don't spot the plasma cells.

If you do the blood test, you don't find the paraprotein. So in those patients, until very recently, their disease was completely under the radar. We knew was there because most, if not all, we're going to see the disease come back. We just could not identify it. Now, using very advanced flow cytometry and and molecular technology, we now can detect the disease or even measure the disease at a much lower level.

And that's what we call minimal residual disease. So there's essentially two basically two technologies. One is called next generation flow that allows us to identify one cell out of 10,000. And we have one that's called next generation sequencing that allows us to identify down to one cell out of familial. So that really opens a new avenue myeloma, because now you have a lot of patients who are in complete response. 

So the protein is undetectable in the blood. They look at the bone marrow, don't see the plasma cells. But then you can find much more nuance about how much disease they have by measuring their disease. Using those techniques arbitrarily has been defined at less than one in 10,000 cells is what we call limit. The negative. So a lot of the literature doesn't give a number. 

You have, you know, ten cell or 20 cells per million, but uses the positive or negative. That means you have more or less than one cell in 10,000.

And minimal residual disease is a complicated topic. And I think patients need to take some time to think about it and read about it and ask their doctor about it, because it's just not simple. But the bottom line is that we want to know what's left of your cancer in the bone marrow and in and in your body.

It turns out that the way we used to measure multiple myeloma in patients is not good enough. So where we used to say someone was in a complete remission, which normally and it should be, it's a celebration. It's a good thing to again, to get to a complete remission that what used to be defined by looking through the microscope. 

And it was by today's standards, that's very crude. So looking through the microscope, you could only identify roughly one in 20 bad cells in the myeloma, out of out of 100 cells, five cells out of 100. We can now, using MRD testing, identify with our best technology. One abnormal cell in 1 million cells. So you can imagine the human eye is nowhere near that good. 

This is all reliant on new, amazing technology. If we can get by giving extra treatment, if we can get or better treatment, get the level of your myeloma and the bone marrow down well below five cells in 100. But get it down as low as only one cell in 100,000. One cell in a million or even one cell in 10 million is going to be a lot longer before the disease returns. 

Our goal now is evolving towards using this form of testing to decide whether you've had the best achievable response. It's all done, by the way, on bone marrow biopsy. So it's reliant at least in 2019, 2020, on a bone marrow biopsy in myeloma. 

We know that there's myeloma below the level of detection of our standard therapies. And in order to look at that amount of myeloma below the level detection with our standard therapies, we use something called MRD or minimal residual disease testing, and that uses. And that typically uses technology like next generation sequencing or very sensitive flow cytometry in the bone marrow to understand is there myeloma below the level of detection. 

Then then we can typically see. 

Obviously when patients develop multiple myeloma, they have a large number of abnormal plasma cells in their bone marrow. And the question is how does the patient do and respond to treatment? In the old days, we used to measure the monoclonal protein or the light chain and determine if the patient achieved a partial response, which means getting rid of 50% of myeloma burden or achieve a complete remission where the myeloma proteins in the blood or the urine disappear and the bone marrow biopsy does not show any extra abnormal myeloma cells or plasma cells. 

So we call that complete remission. However, some of the patient who achieve complete remission do relapse. And the question was why? Obviously, there were residual myeloma cells that we were not be able we were not able to detect in the blood, in the urine or in the bone marrow. So this residual disease was elusive in terms of our ability to determine. 

And technology has improved. And one of the technology that is used, for example, in detecting minimal residual disease is flow cytometry And the goal is to try to look at a large number of cells in the bone marrow and try to see if we can find a single myeloma cells or not. So if the patient had 100 cells analyzed and you didn't find any single abnormal cells in the bone marrow, then we call that a minimal residual disease, negative state. 

So basically what we're trying to do is determine if there is any residual disease at a very highly sensitive low.