BETA What is myeloma clonal evolution?

In this video, you'll discover how the genetic makeup of your myeloma changes over time, and why the DNA of your disease at diagnosis can look very different after several relapses. We'll explore what causes these changes, how they affect treatment outcomes, and why they can lead to drug resistance. Plus, we'll break down an important concept. What is clonal evolution, and why does it matter in your myeloma journey? You'll notice in this slide, the clonal starting point is red, orange, green, and gray. What that means is there are genetic characteristics of all of the red, which means most of the tumor had common genetic characteristics of a color red. But the orange means there were a few cells that had different genetic characteristics. And look what happens. As the patient was being treated with different therapeutics, the red started shrinking. That's good news. We're killing off the red genetic deregulated cells. But the green cells started coming up. So now the person's evolution is a clonal evolution in which the clone is now being selected for cells to resist the therapy. And wouldn't it be useful information to not only understand the genetics of the red guys, but understand the genetics of the green guys? And look what happens late in therapy where this patient had a very aggressive disease. All the cells are blue. The color is not the relevant point. It simply represents that a new genetic population occurred in that individual that was different than the original clonal characterization of that first tumor population. So if we want to understand how to treat myeloma, we have to understand the disease at its start. But we also have to understand the disease at its evolution. We know that myelomas can evolve. And that term evolution has a genetic understanding. That is, in evolution, we think about genetics of survival of the fittest. That's true in myeloma too. Myelomas oftentimes are heterogeneous populations. And oftentimes we can treat a myeloma where most of the myeloma cells will be effectively treated. But there may be a small population of cells that don't die in response to the therapy. And as in survival of the fittest, they will emerge and grow back. So there is an ongoing genetic evolution that we need to consider in multiple myeloma. And relapse is a very significant problem. It takes a long time to develop multiple myeloma. Patients often have a pre-malignant condition called monoclonal gammopathy that will determine 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 is as one major clone goes away, another smaller clone grows. And we've called that phenomenon clonal tides. Because as we alternate therapies in multiple myeloma, one clone goes away, another comes up, and then we treat the clone that came up, and the first one comes back again. 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 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. When we talk about clonal evolution, there's two main terms that are commonly used to describe them. Lineal clonal evolution or there's branching. Linear clonal evolution is stating that if you have a mutated cell with certain gene mutations, as that cell divides, it's going to acquire new mutations, but it's still going to contain all of the previous mutations because it's going to form just almost like a snowball effect. It's going to be acquiring new mutations without losing any old mutations that it had. Branching mutation is a little bit different. In branching mutation, when the cell divides, the new cells might have completely different types of mutations that the original cell did not have, but at the same time, it might not carry the mutation that the original cell had. So branching mutation is more variable and it's going to give us more subpopulations of myeloma cells than if we do linear. In linear, you're always going to be just adding new mutations to the mutations you already have. Branching is more like throwing up in the air and getting whatever mutations fall in that bucket. And it could be something completely new or it could be something that you had before mixed with a bunch of new stuff. Two different situations where we can see one type of mutation compared to the other. When you have fewer amount of cells, let's say somebody who's in remission, since you have such few amount of cells, there's a higher likelihood that you're going to be having linear clonal evolution because it's that small amount of cells that is going to start acquiring new mutations and then eventually evolving into different subclones and more branching mutation. When somebody has myeloma and their disease is not controlled, as those myeloma cells continue to divide, they have the possibility of mutating and diversifying using branching clonal evolution where they're going to have free range to kind of have more diverse mutations and some of the cells that are new might not have the old mutations and just form their own new family line of myeloma cells with its unique mutations. Whether one is more aggressive than the other, that is something I cannot state and I think we need to do more studying because it's not so much as to the type of clonal evolution, it's what type of mutations you're acquiring that makes your disease more aggressive. 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. The people at Mayo invoked the term clonal tides to describe this where the bulk of the tumor is made up of a different genetic constitution at different parts in the disease process. What is spatial heterogeneity? One of the other things we're finding in myeloma is that because there is this clonal evolution where the myeloma cells can change over time, there's also a spatial consideration and that is that if the myeloma changes over time, it's possible that whatever the myeloma looks like in the right hip may be a little different than what the myeloma looks like in the left hip. And as a result of that, we get an added complexity that says sampling a single site oftentimes doesn't give you the full picture of all of the genetic variations that might be occurring in that individual's myeloma. That is, different sites might actually have different genetic variations and as a result, if the genetics is related to how they respond, you may find that the myeloma in the right hip responds really well to therapy, but the variation that the left hip myeloma has may not respond nearly as well. So now we have a problem in that trying to evaluate the tumor, oftentimes physicians will ask for multiple sampling sites so that they get a better look at all of the components that may be occurring in that individual patient. If you found this video helpful, consider giving us a like and subscribing to Health Tree University for multiple myeloma. Our mission is to educate patients and their care partners and spread awareness about multiple myeloma. We'd like to thank our doctors, our sponsors, and of course our audience for making this video possible.