Do all my myeloma cells same chromosomal mutations? What is clonal heterogeneity? (Part 1)

what is clonal heterogeneity and what is clonal evolution or clonal tides one thing we have learned with multiple myeloma is that we're not dealing with just one type of cancer cell in myeloma there's a lot of subgroups of cells that compose multiple myeloma and that's why the word multiple is part of the the name so if one person is diagnosed with myeloma if we look closely at the cancer cells we're going to see that there's different groups of cells that are more similar to them than the whole entire group so almost like a family and when you're looking at the family and you're looking at your brother and your or your sister and you're comparing your your immediate family with your cousins and more distant relatives there's going to be more differences between those different families and the same thing happens with myeloma in myeloma we have different subgroups of cells and each subgroup has certain characteristics whether they have a specific mutation or a more sensitive or more aggressive more active or more dormant so we have like a mixed pot of cells with different abilities different skills and that's what makes multiple myeloma so heterogeneous when we treat myeloma we have to keep that in mind and that's why we choose therapies that have a combination of more than one treatment we normally do triplets and nowadays with monoclonal antibodies we're even contemplating doing quads and that is because we want to try to target all the different subpopulations of that disease that we have in one patient now if you have a patient that has different strains of the same type of cancer in one body imagine how that's gonna vary between patients it is so variable and there's so many subclones that is very impossible to compare one person's disease with another and that's something that's very important to keep in mind because whenever we treat cancer we might be targeting certain certain groups of those clones and not kill all of them and then the ones that do survive might be the ones that grow back but the other thing is that the same way you a particular person was treated with one regimen and had a a good response it doesn't necessarily mean that another person is going to have the same response because the cells that they're going to have are going to be different and then their cell phones might also be different i think the major lesson that sequencing has taught us is that clonal which means one cell goes wrong and then replicates itself so myeloma is the archetypal example of a clonal disease it makes one antibody and that antibody is the m spike so you see it because they're all the same so it's clonal but when you look not all of the cells are the same so that's called intraclonal heterogeneity or subclonal heterogeneity which is important because it means that the tumor can evolve and so it evolves to escape treatment if you put a selective pressure on the tumor the cells that are sensitive die and the resistant ones grow out and there's an awful lot of um important implications of that knowledge which is if you look there or there the tumor can be very different you might have a mutation there that would respond to treatment but it might not be be there if you want to cure somebody you have to have a broad acting treatment that kills all of the cells if you just use a specific one targeted to one mutation a cell that doesn't have the mutation will grow out to replace it you can think of it as evolutionary biology an ecosystem so the tumor is composed of different ecosystems all of which have to be addressed if you're going to cure the patient clonal heterogeneity and evolution this sounds really complicated but it's something most of you knew walking in here but we made a big deal of it when we discovered it because somebody could publish about it so at the beginning on the left hand side you see a myeloma patient from when they didn't have myeloma cells more myeloma cells lots of myeloma cells now the colors really describe the different tribes that you have in myeloma and at the time of diagnosis and this is the time of diagnosis right here there are two to six tribes of myeloma in the average patient different genetics different response to drugs basically ver somewhat different diseases and this is all under the cover of the same igg lambda that you have as your monoclonal protein so that monoclonal protein is made up of output from two to six different tribes of myeloma cells so what happens patient gets chemotherapy and there's a lot less myeloma cells but there are still a number of tribes there and at the time of relapse which is what it is at the far right usually one clone predominates it doesn't mean that the other clones aren't there some of them aren't and some their new ones can develop but on average at the time of relapse one clone really takes over and is really responsible for the vast majority of the monoclonal protein or light light chains secreted this is called clonal heterogeneity it's relevant because most of you already knew this and most of you already knew that some of your myeloma cells are responsive to some treatment and some of your myeloma cells are not but i think a very sobering finding was that if one biopsies different foci of myeloma in one patient there may be different cytogenetic characteristics and different mutational features at different sites now i've used the line and i realized how old i am because none of the younger doctors smile or laugh but i'm always struck by saying from the wizard of oz when dorothy says we're not in kansas anymore toto because this is not what other cancers are particularly known for this great heterogeneity and i'll talk also about this concept of clonal tiding in addition to the fact that different areas may have different characteristics and then you've already seen that the genetic and gene features can change over time in a patient and the clinical features can change so a word about the different clones in myeloma it's been shown and again this is our canadian colleague jonathan keats who's in in scottsdale arizona with t-gen now they have described that at diagnosis an individual with myeloma has five to seven subclones they're all myeloma they look the same under the microscope but they're nuanced differences between these different subclones and in this pie diagram and this is a diagnosis and this is different relapses the proportion of each clone is represented by how much of the piece of the pie each color has and you can see at diagnosis this red subclone predominates but after treatment there is the emergence of the orange clone and then with more treatment the red and the orange clone at relapse there's more treatment it's a clone that's green that is accounting for the relapse and then here we're back to orange again orange again and then in the terminal phase of the disease where the disease is particularly ugly this is a plasma cell leukemia you can maybe appreciate that there's a sliver of blue here but that didn't emerge as an important clone till the very end so that the different treatments and other factors we don't understand uh lead to predominance of a different clone at different times now if you can imagine if these clones have different sensitivities to different drugs which has not been particularly well demonstrated but we certainly see this in the clinic you could understand why a drug that quit working at one point might be useful later on if a different clone that's sensitive is accounting for the relapse this picture is also used to explain why three drugs may work better than two you can kill more or suppress more of these subclones and i think the final point that we're testing in a trial in canada is an observation that if someone is on something like for many years for relapse we used linoletamide and dexamethasone as a doublet when patients progressed we would simply add another drug we usually in canada add oral cyclophosamide at low doses and sometimes that would bring the disease back under control you don't do that in lymphoma if someone is progressing through a group of drugs like chop retection you don't add another drug and fix the problem you have to change all the drugs so the idea maybe is that the failing regimen is controlling some of the subclones and we just need to take care of one or two to bring the disease under control and i think this argument is supported by the fact that when patients go on clinical trials there's a washout you have to stop everything we hate the washout and many years ago it was three or four weeks well what we would find is the m spike's going up the treatment is failing but you stop the drugs that aren't working and the disease goes crazy so some of those sub clones presumably are still controlled now this has not been tested and this is hypothesis but i think it does explain some of the things we've observed in clinic and that we've intuitively done but it does need to be subjected to formal trials