(Guest Lecture): Discussing MRD with Drs Gareth Morgan and Faith Davies

MRD or minimal residual disease testing is really a fancy way I guess of determining how well a patient has responded to treatment. So in old fashioned ways we would talk about a complete response which meant we couldn't see any disease on the blood tests. However with these newer tests we're looking at a much lower level or trying to look for a much lower level of disease. Most of the tests are done on the bone marrow and when we're doing these tests we're actually counting the number of normal plasma cells to whether we can see any myeloma plasma cells and how many plasma cells we can see. And because the tests can be done in a number of different labs, some labs will look at a million cells, some labs will only look at 500,000 cells, other labs may only look at 1,000 cells. And so it's really important when we're looking at the test result not only to find out whether the test is positive or negative but also to determine its sensitivity. So did they find one myeloma cell in 100 cells or did they find one myeloma cell in a million normal cells? And the reason that's important is that there is some data to suggest that the better the response to treatment, i.e. the deeper the response to treatment, the longer that patient may stay in a remission. It's not 100% but often patients who get a very deep remission, i.e. we can't see any myeloma cells in one in a million cells, those patients may have quite a long remission and may even be able to come off their maintenance therapy. The reason we want to know more about MRD is because we're potentially going to be able to use it in the clinic. We know at the moment that we can definitely use it to help us determine prognosis, so that's how well a patient's going to do in the long run. And we know that patients generally who respond very well to treatment, so who are MRD negative, tend to have a long remission. But there's also some newer ways that we may be able to use the test. Some of the questions that all patients ask is do I need a transplant or not? Or when I'm on maintenance therapy, how long do I need to keep on the treatment for? And it may be we don't have the definitive evidence yet, but it may be that patients who become MRD negative maybe don't need to have a transplant and could just go on to their maintenance therapy. Or potentially patients who've been on maintenance for say two years, if they're MRD negative, then maybe they could come off maintenance. What we do know at the moment is that we probably shouldn't be making such decisions like that based on one test. We should probably do two tests, maybe at three months apart or six months apart, to really check that that patient does have a long, what we call sustained MRD negativity. But we're certainly coming to doing clinical trials and thinking about trying to answer some of these questions, so we can personalise patient's treatment a little better. So you should always be careful as a patient when you're trying to interpret the results of an MRD test. It's all very context dependent. So becoming MRD negative is most important if you have high risk disease. If you have lower risk disease, the value of being MRD negative is somewhat debatable and it means different things for different people. If you have very low risk disease, so premyeloma, smoldering myeloma, NGUS, you really have to think what does achieving MRD mean. And in some cases you can treat people with early phase disease and no matter how hard you treat them, you'll never get them into a complete response or MRD negativity and they'll stay well for a very prolonged period, i.e. almost indefinitely. So always have the discussion with your physician about what they think it means and don't try to interpret it yourself. Then comes the other part of the question which is sensitivity. And so if you only have one cell in 10 to the 5 cells, which means 100,000 cells, that's almost nothing detectable. We can't measure below one cell in a million cells. That's important. Sometimes just getting below 10,000 cells can be very, very beneficial to your long term outcome. When it comes to one in 10, one in 100 cells, that really isn't MRD. That's residual disease and should be interpreted as that. One of the other important things about interpreting these results is that when we talk about being MRD negative, all we can say is in that particular sample we took, we were not able to see any myeloma. Now there's two things about that. The first thing is that often our tests are not sensitive enough. We can only detect one cell in a million. And so if there's another cell there and we didn't count enough cells, then actually the patient may still have myeloma. The other issue about this is that we're often just taking the bone marrow sample from one particular place. And so many people will maybe combine the MRD bone marrow test with a CT PET scan, for instance, or an MRI scan, just to see if there's any myeloma anywhere else. And then a number of laboratories are actually trying to work on developing a test we could run in the blood so that we didn't need to do the bone marrow test to be able to detect these things. The International Myeloma Working Group guidelines have actually tried to incorporate this into their definitions. And so they will have a definition that says whether you're MRD positive or not, and whether this was done in the bone marrow, whether it was done by next generation sequencing or flow cytometry, two different techniques we use in the lab, and what the sensitivity is. So 10 to the 5 or 10 to the 6. But they also have another degree of being MRD negative, where they add in whether you're also negative with the PET CT scan as well. So lots of little subtleties in and around that definition. When you think of MRD, think of a bag of sugar as being the body. And imagine if you had kind of large pot, maybe two pounds of sugar, and you put 15 grains of sugar in that were colored red. And you put that in the pot, mixed it all up. And then think of the bone marrow as sampling from that. You sample it with something that will pull out maybe 100 or 1000 grains at a time, and then you look at it. You imagine how often that can even be positive, where you pick up some disease, or actually you don't get any of the red grains whatsoever. And so you can have a marrow, you can look as if you're MRD negative, but that's because you haven't been able to sample the region that has the red grains in it. And it's just like that in a patient in the clinic. So it's a very simple process. So even if you're MRD negative, it doesn't mean there's no residual cancer cells. And we know you can relapse from just one cancer cell. Most myeloma cancer kind of lives in the bone marrow. And so when it's living in the bone marrow, it's stuck in there. And so if you want to see it, put a needle in the bone marrow and you can look at it. But what we know is not all of those cells are stuck in the bone marrow, and they recirculate with the blood. And those are called circulating tumor cells. So if you look in the blood, the peripheral blood, just from an ordinary blood sample, there's a chance that you might pick up the tumor cells. If you have lots of disease, then the chances of finding one of those cells is high. The trouble in myeloma is if you only have a low amount of disease or it's early in the natural history, the chance of finding those cells in the blood compared to the marrow is about 1000 fold less. So while it can work, it's always going to be less sensitive than looking in the bone marrow. Are those circulating tumor cells the same as plasma cell leukemia? And I think the answer to that is probably not. But there might be a critical threshold over which if you have a certain number of cells, that that exerts an adverse prognosis and those may be precursors to plasma cell leukemia. But it's physiologic for plasma cells to be in the bone marrow, to circulate and home back to the bone marrow, and to go through that process over and over again. So you can find tumor cells in the blood, but it doesn't mean you're going to develop plasma cell leukemia. So the later in the disease process, the more progressed, the more likely you are to have circulating tumor cells in the early phases of disease. It's rare and not so likely. What is the most sensitive test in the bone marrow? My explanation can confuse people, but I think it represents the truth. The most sensitive tests are done on the bone marrow and it's always probably at least 1000 fold less sensitive in the peripheral blood. The advantage of the peripheral blood is you can do it frequently, whereas doing a bone marrow is unlikely even to be done once a year. And there are advantages to sampling the blood more regularly so as you can gain prognostic information in real time. So MRD alone is not enough information. It's clear that some people can be MRD positive and stay stable for a long time. And so the behavior of the cancer during response is dependent upon two different factors. One is the depth of response, and we can kind of measure that. The other is how fast those tumor cells grow. So arguably high risk of tumor cells that grow quickly and low risk of tumor cells that grow slowly. And so there's two good examples of it. So if you have high risk disease, you've got rapid responses, MRD negative, three weeks later the disease will grow back and come back. So that's one extreme. The other extreme we call the CD2 subgroup, which are the kind of myeloma cells that have an 11-14 translocation and express CD20 on the cell surface. And those patients, we know they're going to respond slowly. We know they're never going to go into a deep response. And we also know that they're going to do well long term because biologically they're slow growing and behave well. And so things are never crystal clear and patients have it presented to them as if this is just a straightforward choice, MRD positive or negative. It's actually not that. It's about biology, response, treatment, duration of treatment. So just being MRD negative doesn't mean you should come off treatment. It can mean that you can safely come off treatment, but it doesn't mean you should. So some of the research questions that are going on at the moment are actually looking at those patients who are MRD positive and trying to characterise their remaining cells a little bit better. Because the feeling is if we can learn something about those cells, so if we can either learn how quickly they grow or what signals they have in them about whether they should be growing or not, that might be able to tell us whether that patient is going to be one of those patients who is an MGUS phenotype, so who's just got those cells and they're just hanging around doing nothing. Or are they going to be one of those patients where those cells have got something just ticking over very slowly and so therefore we need to keep an eye on that. And that's where all the research is at the moment. But one of the, it sounds crazy, one of the problems about doing that research is that often those cells are at such low levels we can't get hold of them to find them. And so that's been one of the important things that's been happening is that the technologies and the techniques we can do to actually try and characterise those are much improving. So I think in a couple of years we'll know what those patients do clinically but we'll be able to match that with some of the science that's going on and that will be able to help to answer some of these questions. The concept I'd like to follow up on about the biology of the cells is they don't exist in isolation and there's this concept called immunoediting. And so immunoediting is what your immune system does to the cancers. So as you go into a remission, if your immune system improves and you can modulate that immune system, it's quite capable of controlling two tumour cells that start to regrow. And so we should never look at the things in isolation. So again, response, treatment, duration of treatment, impact on the immune system and the microenvironment. All of those things play into the clinical decision making process. Now that MRD testing is becoming more available, physicians are beginning to design clinical trials to try and find out how we can best use it. And there's, I guess there's two different ways people are looking at it. One is to try and make treatment better for those patients who don't have a good response. The other is trying to maybe decrease the intensity of therapy for those who do have a good response. So let's take the patients who do have a good response first. So some of those studies are, for instance, looking after four or five cycles of induction chemotherapy and saying, has the patient had a good response? If the answer is yes, they're in MRD negativity, then the patients are randomised to the two different arms. And it may be if you're MRD negative, you don't need to go through that intensive treatment. The other area, again, for patients who are responding well is that during the maintenance phase, if patients are consistently MRD negative, they are randomising to patients continuing maintenance and stopping maintenance. And it may be that we might be able to stop maintenance on some patients. As I say, the other way of looking at it is, let's say you've had four or five cycles of induction chemotherapy and you're actually still MRD positive. The question then would be, is could we try and do something different to try and get that patient to become MRD negative? And in some cases, that might be changing the induction treatment around a little bit. So for instance, if the patients had VRD, it might be adding in daratumumab or adding in carfilzomib. In other cases, it may be changing tracks completely, maybe trying to use a bispecific antibody or one of these newer treatments to try and get that patient into a good response. And people are not only doing it after induction, they're also again doing it at maintenance. And so in that setting, the question is, the standard would be Revlimid maintenance or lenalidomide maintenance. Could you potentially, for patients who are maybe MRD positive, add another drug in? Could it be that maybe having two drugs during maintenance is better for patients who are MRD positive? So it's really trying to refine treatment choices for patients who are MRD negative and to really improve treatments for patients who are MRD positive. There's some important things for patients to understand and doctors come to that. The information is everything and the more information you have, the better decisions that you can make. And so we're starting to have data on the patient's prior treatment, the patient's clinical condition, whether they're frail, whether they're fit, what the therapeutic aim is, what their geriatric risk score is, what their cytogenetics are, do they have cancer-specific mutations. So all of those play into making your clinical decision. A further piece of information is the response and the treatment they've had. And so precision medicine takes account of the biology of the tumor, the biology of the microenvironment, the patient's condition, the treatment and the response to the treatment. So all of that has to be integrated together to be able to make really a specific choice for any individual patient. And so you have to be really careful when you kind of see things on the net which says you have to be MRD negative, otherwise life is over. It's never that simple and you should always have a discussion with your physician and come to a kind of specific opinion about you, where you are and what's best for you. So MRD testing, as we know it now with these molecular tests specific to the individual tumor, I don't think is going to last long term. You can measure the M-spike and there are some new sensitive ways of measuring very low levels of the M-spike and that's going to be a much better way of monitoring disease long term. I do encourage people to monitor their disease but I think these mass spec approaches in the blood are really the way forward. We'll be able to measure down to very low levels, we'll see if it's stable, we'll see if it's coming back and then we'll be able to go back and look at thresholds and level of response where we know people are heading for long term stability or cure and people who are in need of additional treatment. Yeah absolutely, mass spec is a good approach and it's very powerful, should be very widespread and it's just around the corner and will be implemented very soon. Immunifex, which is a device that has antibodies on the gel and basically use a mass spec to measure it more sensitively than you would see on a gel, that's the difference.