[Music] what is clonal evolution or clonal tides and how does this impact the frequency of genetic testing one of the difficulties in defining myeloma is that myeloma may be defined at the time of diagnosis and we may identify specific genetic variations specific genetic mutations that occur in that myeloma but we're looking at the bulk of the myeloma and one of the things that happens that we know is that just like evolution defines survival of the fittest what happens in myeloma is when you treat you are starting to treat the cells that are vulnerable to that particular therapy and there may be subgroups of cells that emerge that no longer respond to that therapy and they may have slightly different genetic variations and mutations which means that when you look at a myeloma it is actually evolving over time so that as the therapy is being applied to that particular patient you may kill off 90 of the cells that are sensitive to that therapy but through this clonal evolution survival of the fittest you're now growing out that what was a small population now becomes a dominant population because it becomes resistant to that particular therapy and over the course of treatment you can see what some people have referred to as these clonal tides where clonal evolution will occur when one population now emerges resistant to the therapy what does a physician do they treat you with maybe a new therapy kills off 90 of the cells but then there may be another subpopulation that now starts emerging that represents that resistant population so over the course of an entire disease uh time course over years you may have these clonal tides or clonal evolution where new populations of myeloma cells are emerging because they become resistant to the therapy so the result of this kind of development of these clonal tides means that the the major population which is often tested may have a certain set of common genetic mutations or variations but the clonal population that emerges may have different genetic mutations now since some of these genetic mutations may give you a better idea of what therapies might be most effective it's a good reason then during these clonal evolution at a various time points during the disease treatment and possible new progression to constantly test these cells at each point during therapy to observe these new genetic variations that occur so clonal evolution is a concept that we are learning as we study myeloma more and we know more about this disease we know that multiple myeloma starts most of the time with an mgus and then it starts to develop mutations that make this cell more independent of the body and do its own thing and makes it more aggressive makes it grow faster and then it starts causing damage to the body but when you have a machinery that's already damaged and is not following orders from the brain itself and the body and it does its own thing that machinery is going to continue to be distorted as those cells divides and when myeloma is dividing they're going to give those mutations that they had to their offspring or the new cells but those new cells can develop new mutations and that is what's called clonal evolution as the disease evolves during the course of the years and as we expose that disease to different therapies we are causing some mutations in the cells from the treatment that we give but at the same time just this normal evolution of the cancer cell itself is going to be developing new mutations that can make these cells either more aggressive or more resistant to treatment or sometimes more sensitive depending on what the mutation is so whenever we treat disease and we achieve a remission and somebody relapses it's important to retest to see if there's any new clones or any new mutations that would help us change the way we treat that patient and and change the whole panorama of that patient so one the cancer that one starts with is not the cancer that one is gonna have ten years later there's always going to be an evolution as long as their cancer cells alive and those cells continue to divide so um i would contend that if you're intending to go for cure in somebody that all patients up front that are going to be intensively treated they're not expensive tests it pales into insignificance in comparison to the therapies that we use and the information about the subtype of disease and the risk assessment is invaluable and so definitely up front when you relapse it's going to be different i could make a strong case to look at relapse and each relapse i'd like to make an argument that in the future you might do if you're not in a complete response and you can measure some disease that it might be important to know that information because you could treat the disease with a targeted treatment when the patient's in remission so we might see the way we approach the management of myeloma long-term change over time and as we're able to use circulating dna from the tumor taken from the blood it may become increasingly possible to do that because no patient wants to have very regular bone marrows what is clonal heterogeneity think of it as temporospatial heterogeneity so it's heterogeneity in time and in space so different parts of the body made up differently you progress you gain more genetic and so at relapse the disease is different to when it's a presentation so normally tumors get more aggressive than more mutations the importance of this intraclonal heterogeneity is that in the past when we thought it was just a linear progression if you were resistant to a treatment you would always be resistant to that treatment when there are maybe four clones one clone could dominate at one time of the disease and be resistant but when relapse comes it could be another clone that's dominant and that may be sensitive to that treatment and the people that may have invoked the term clonal tides to dis describe this where the bulk of the tumor is made up of a different genetic constitution at different parts in the disease process can your myeloma genetics change over time um it can it can't change so the as craig had mentioned and as i'll mention too that they're different clones of disease and people can develop novel uh novel mutations or new mutations as they go through therapy so one possibility one thing that does happen on occasion is that someone will not at the time of diagnosis they will not be 17 feet deleted and then as they go through different therapies over the years sometimes they can develop a 17p later and so so we do when patients relapse we usually do check the the fish test inside genetic testing again to make sure that there are no surprises or changes we'll come to that point and i will argue that we do not usually i in my own practice i don't usually that would involve a bone marrow accident at the time of every progression and i don't i don't personally do that at a certain point because as credit hoffmeister said you know psyogenetic abnormalities are common in diagnosis and they actually accumulate as disease goes and so the likelihood of having high-risk disease by cytogenetic testing you know when you have fourth line therapy or grip-line therapy or 6-9 therapy is extremely high but also the behavior your disease behavior is sort of defining itself in a way like it's you know if if you're on fifth line therapy and you you get four months out of a regimen and then you have to switch in a way cytogenetics aren't informative the fact that you had to switch therapy after four months is what's informative the one exception and we've been doing it and all of our centers have been is which i'll talk about in more detail is molecular profiling which is different than cytogenetic testing synergy accessing is just looking for prognostic sort of factors but molecular profiling is looking for predictive something that predicts a response to a certain therapy because there's a certain molecular abnormality you're screening for target you're not screening for just sort of general how's the weather it you know it takes a long time to develop multiple myeloma patients often have a pre-malignant condition called monoclonal gammopathy and undetermined significance for years or decades and it's been estimated in fact that often myeloma the initial event might have started in people's 20s or 30s and associated with that progression there are the development of subclones where one portion of the myeloma develops a mutation that's not in another portion and as we treat patients we might see that our treatment is very effective against the main subclone but that there's a small subclone that contains different mutations for which the treatment is not effective and so what happens as one major clone goes away another smaller cone grows and we've we've called that the phenomenon clonal tides because as we alternate therapies in multiple myeloma we one clone goes away another comes up and then we treat the clone that came up and the first one comes back again and it's an argument for using multiple drugs together at the same time so that we can sort of suppress all the clones as much as possible the the side effect of that is however that patients have more side effects the more drugs they take so one has to balance these two things