What is risk stratification? What is risk adaptive therapy?

What is risk stratification? Risk stratification myeloma is a tool that myelopositions use to try to predict how the myeloma may behave in the future. And it's not a perfect test but one way that we try to do that is by looking at the genetics of the myeloma particularly at diagnosis. And so there's this test called floretsis and cytohypertization or fish testing that looks for common genetic abnormalities that are seen in myeloma patients. And over time data has been generated to suggest that certain genetic abnormalities may suggest a more high risk of myeloma which means that myeloma tends to respond well to therapy but has a tendency to recur faster whereas other types of myeloma can be considered standard risk myeloma those without these high risk genetic markers that would respond well to therapy but would hopefully stay in remission for a long period of time. Besides genetics what other factors are used to determine risk? Risk can refer to of course the biology of the myeloma itself but there's other risk factors that are definitely important to consider a patient's cornevities whether they have other medical conditions such as diabetes, heart disease, lung disease, their age, their frailty. So these are all important. So let's talk about risk stratification first. Risk stratification is where you assign patients to different subgroups based on their probability of progressing early on or not. So one of the most popular ways of risk stratification is by using the international staging system or ISS. There's a newer version called the revised ISS and this is the myeloma stage that we assign patients. Importantly it's determined only at diagnosis and it's based off of blood tests and bone marrow biopsy results and you can be assigned to one of three separate stages one two or three. If you're in stage one you have a better prognosis and your survival is estimated to be longer. If you're in stage three you have a shorter prognosis with a shorter survival and so what we're doing is we're stratifying or grouping patients into different risk groups so that we have an idea of what kind of myeloma we're up against before we ever begin therapy. Is it possible for a patient who is classified as standard risk at diagnosis to evolve to high risk over time? Patients with standard risk multiple myeloma can have myelocity evolve as time goes on depending on different exposures of treatments and that they would develop something called clonal evolution. So basically this means that over a period of time there can be genetic changes in the patient's multiple myeloma cells that make them more resistant to certain therapies that make them able to survive better despite getting multiple different types of treatments and so when we do both myribiopsies later on and check the genetics of the myeloma we do see some in some cases evolution to what we call high risk disease where patients develop new genetic aberrations or mutations that would be consistent with a more aggressive type of myeloma. Myeloma is a heterogeneous disease that different clones and obviously resistance mutations and so you can start as standard as myeloma but as the course of the disease evolves certainly you can acquire mutations and one of them that we think about certainly that confers high risk is 17p deletion that can be an acquired mutation. Abnormalities of chromosome 1q also now we recognize as high risk can also be acquired so it suggests that yes your risk can change and just having myeloma relapse in and of itself suggests that you've already had some degree of higher risk. Can high-risk myeloma return to standard risk after treatment? Generally speaking if a patient has those genetic markers that would which would make us consider them to have high risk multiple myelo those cells would likely persist even to a small degree later on as well so once a patient does have high risk multiple myeloma despite the fact that we might not detect these high risk markers down the road if we do a subsequent bone marrow we would still consider them high risk in most cases because we probably still assume that there's probably a very small sub-clone of myeloma cells or small amount of myeloma cells they just aren't detectable that we just can't detect at the time when we repeat a bone marrow that would still harbor some of these high-risk markers so it generally speaking once a patient has high-risk myeloma we'd still consider the high-risk myeloma moving forward. Now with that said you know these genetic markers that we use to try and predict risk stratification of myeloma are not perfect and so I do have potentially some patients that had high-risk genetic markers that certainly did not behave like high-risk myelin retrospect and so perhaps they've been on maintenance therapy or maybe off therapy for a little period of time and for a long period of time you know seven or eight years and in such cases you know biologically certainly they didn't behave like high risk so then I would doubt the significance of potentially that genetic aberration or mutation contributing to the high-risk disease. So unfortunately once you have high-risk myeloma you're always considered high-risk myeloma and I guess the good thing about that doesn't mean that you know that's the end of the story certainly you can still treat aggressively and the exciting thing with some of the newer therapies we have is there's somewhat risk agnostic that immunotherapy especially you can still get patients who are high risk to very deep responses. We risk stratify a diagnosis certainly but you need to consider it along the course of the disease. So what I mean by that is someone could be what we call RSS stage one for example but if you relapse less than 12 months after your transplant you're actually in a high-risk group of patients so you know things can change. You need to think about risk not as a single point idea but as a dynamic model. What is risk adaptive therapy? So when you say risk adaptive therapy is you're tailoring the treatment based on the disease risk. So if you ask me I think myeloma is still evolving and we don't have risk adaptive therapy settled yet but it's evolving and there are a lot of studies trying to look at you know different disease different treatment based on the disease risk. For example if somebody is a high-risk cytogenetic the type of induction that you're going to do the decision to transplant early and perhaps the type of maintenance you're going to do so those kind of things you kind of you know decide upfront in the high-risk setting. There are certain co-morbidities like for example the patient with the renal failure they are very high-risk subsets so you also decide particular regimen for those patients and try to improve the renal you know in renal failure so that they have better outcomes. So that is a risk adapted therapy you know that is evolving that is already in practice. The other aspect what is also being you know being studied in myeloma is dynamic risk adapted model for example based on some specific tools like minimal residual disease because we know based on the multiple studies that patients who achieve MRD negativity as compared to the MRD positive patients they do relatively much better especially in the high-risk setting you know high-risk cytogenetics the MRD negativity you know has a pretty significant prognostic value. So I think with the dynamic risk adaptive model which I mean is that offering treatment either escalating the treatment or de-escalating the treatment based on the MRD status at certain point of time is another model of risk adapted therapy and that is being investigated in the clinical trial right now. We don't have data to to say that this is what needs to be done based on the MRD status but that is already being investigated and hopefully we'll know more about this you know dynamic risk risk adapted model as well. Now just assigning patients a risk group honestly is not super helpful to the patient because it may create anxiety and there's nothing different I can do if I tell you if you're at stage three or stage one we essentially treat all patients the same. What would be more useful is risk adapted therapy where we can do a test that would assess their risk and then adapt treatment according to that risk. There are not a lot of risk adapted approaches in myeloma but there are at least some and they are developing. The one that people are excited about is minimal residual disease testing and so patients whom are MRD negative might benefit from undergoing a different treatment path for example eliminating maintenance therapy. That's being studied we don't know the answer to that. Another example would having a translocation 1114 in your bone marrow indicates a better chance of responding to venetoclax. So patients with that biomarker would would be a good patient to assign venetoclax treatment to. Where risk adapted therapy would come into play and particularly would be in the maintenance setting where for instance a patient who undergoes a stem cell transplant would then typically start maintenance therapy three to four months after the stem cell transplant and by and large the myeloid community myeloficians feel that little myeloma means is probably be insufficient to try to keep the myeloma at bay for a long period of time and a patient with high risk myeloma or more aggressive genetic markers and in such patients we may likely elect to do a more aggressive means in the strategy most likely a combination of lenalidomide plus a proteasin inhibitor like bortizomib or carfilzomib. Would induction therapy be different for someone with high risk myeloma as opposed to standard risk myeloma? That's a that's a great question I think there's a lot of discussions about if we should treat such patients more aggressively or less aggressively. Generally speaking I think the induction therapy tends to be a more homogeneous in terms of how we approach patients whether they're standard risk high risk at least in my personal practice is that I try to give the the best therapies available in the beginning for patients hopefully give the best quality response for the longest period of time and so in my own personal practice I've been using four drug-based regimens for both my high risk and standard risk myeloma patients generally speaking and so but there can be some risk adaptive therapy even for newly diagnosed patients some physicians may like to only do three drugs for standard risk and four drugs for high risk may consider using a drug called carfilzomib or high risk disease and bortizomib for standard risk disease and there's different nuances that may be considered in how these treatment choices are made and lots of different opinions about how this should be approached to newly diagnosed myeloma without concrete data so you can also consider risk adapted therapies as what would be best in terms of quality of life and also what the patient could tolerate the best as well so a patient for instance have significant probabilities you know then a three drug regimen such as darylchomebilenolidamidexamethasone may be a better option based on data compared to doing a more aggressive four drug regimen and so these are all very very important considerations to think about particularly when seeing a patient with newly diagnosed myeloma in the clinic how can risk adaptive therapy be used in the induction setting high risk in terms of making decisions for transplant certainly I think it's very helpful because if you look at the determination trial especially the high risk patients there's a huge difference in those who went to transplant in terms of progression free survival versus those who didn't so I think in terms of up from making a decision can transplant significantly benefit you it helps and then also in terms of maintenance which I'm going to be talking about in people of high risk myeloma we tend to use a more aggressive maintenance strategy as well so I think risk stratification is important because it helps us direct therapy and tailor therapy it means that you are treating patients differently according to their risk that could be like we have in the european guidelines that we for instance treat patients with a tandem transplant if they are hiring cytogenetics so that's risk adaption also it could also be that if you have a patient who does not reach mrd negativity for instance after first line treatment you intensify the treatment or give something in addition that's a different kind of risk adaptive therapy should mrd status be used to adapt therapy I think you probably will get different answers from different persons but since you're asking me I will say a clear no today we know that mrd negativity is a good prognostic sign in a particular patient we do not know that intensifying treatment will in patients who are mrd positive will improve their prognosis my belief is that we we need to wait for this data before we can change this I've heard patient stories from from other doctors who have had an mrd positive patient after a quite intensive therapy and they say okay we want this patient to be mrd negative and they push on with a lot more therapy and after that still mrd positive much more side effects it's difficult when you don't have the data that supports that this is actually a good thing for the patient so I think we need to wait for those data first it's such a valid question that it needs to be studied in good randomized trials and they are ongoing in the future could mrd status play a role in risk adaptive therapy that's by doing this randomized studies which are ongoing now which do they have sort of let's say three typical dimensions one is patients who are still mrd positive after a good for the first line treatment is where this is most discussed in first line so far still mrd positive randomize that patient to continuing standard of care therapy maybe maintenance treatment or intensifying the treatment to see if you can get these patients to be mrd negative in a to a larger degree and looking at their long-term outcome after that the other sort of opposite the dimension is the mrd negative patients can we de-intensify treatment then stop treatment patients often do want to be without therapy because that's nice and no side effects and some patients would like that in any case but patients would like it even more if we could prove that for the mrd negative population or parts of that population it doesn't come with a lesser good outcome in the long run so we need to prove that and the third dimension is patients who are mrd negative when do we start to treat their relapse 10 years ago we treated relapse at clinical disease again now we mostly treat at biochemical relapse but that's you know a monoclonal component up to five or something like that which is much sooner but still quite much disease compared to being in complete response so if they are mrd negative should we start relapse treatment at loss of md negativity or mrd relapse that's another question which is being targeted in some other studies