BETA What is clonal heterogeneity?

In lesson one of this course, we learned that subclones refer to distinct populations of cancer cells that arise from a single original tumor cell, each carrying slightly different genetic mutations, which can lead to variations in their growth rate, drug sensitivity, and overall behavior within the tumor, making the disease more complex to treat and contributing to relapse when certain subclones become dominant after therapy. Let's learn more about the concept of clonal heterogeneity. Do all the myeloma cells in a person diagnosed with myeloma have the same chromosomal abnormalities? Myeloma cells in a patient are very variable. So I want you to think of myeloma cells like a bag of M&Ms, that you have all the different colors and even though they all taste like chocolate and they're all the same type of candy, you have different colors. And multiple myeloma does the same thing. You have all these myeloma cells that are abnormal plasma cells, but there's going to be different subgroups of myeloma cells within your own body that are going to have distinct mutations. And sometimes you might see certain mutations in a group of those cells. Sometimes you might see mutations in all of the myeloma cells. So that's what we call in when we do studies in myeloma, heterogeneity. It just means that all of the myeloma cells in a patient tend to have variability and they're not all the same. And the same thing applies for patients. The myeloma in one person is not going to be the same type as the myeloma in another patient. They all have their distinct characteristics and features. So not all myeloma cells in a given patient have the same abnormalities of chromosomes or DNA mutations. Now some of these mutations and changes show up on chromosome testing like fish. Some of the mutations these myeloma cells have rely on more detailed analysis of their genetics called next generation sequencing, where we look at the genetic sequence of the DNA in the myeloma cells and we can find a lot more mutations that way typically than we can with just looking at the chromosomes. And we can see a varied number of chromosome changes or mutations at diagnosis. And typically those can be in a certain percentage of the myeloma cells. There may be others that myeloma cells that have a certain mutation, some that don't. And we do call that clonal heterogeneity because there's differences between the clones. And maybe a particular treatment might suppress the growth of one clone and allow more growth of another clone. And we, you know, then they have a different mix of clones and we call that clonal evolution. How does clonal heterogeneity influence treatment choice? This has been known for many years, almost 15 years now, work done by Jonathan Keats and colleagues many, many years back, for instance, very nicely followed one single patient over the course of their treatment history, showing how what is a dominant clone at any given point of time, many years later when the patient relapses, may no longer be the dominant clone. We don't use these clonal heterogeneity quite yet to make treatment decisions. Patient gets effective treatment. One practical implication though is often patients may wonder, I've already had lanolidamide. My doctor now wants to give me lanolidamide again five years later, seven years later with a different combination. And part of that is because of clonal heterogeneity. So we do know that for, because myeloma is a disease which we can control and control well for many, many years. It's not infrequent that patient's disease comes back two, three, four, five times. And sometimes we may go back to the drugs used. For instance, a patient may have gotten lanolidamide as an example when they were newly diagnosed. They relapsed, their doctors used some other treatments, but several years down the line there the myeloma comes back. It may be an option to go back to lanolidamide with, albeit with a slightly different combination. And the reason this potentially works in multiple myeloma, i.e. using the same drug again in a slightly different form or combination, is that the same clone that was present early on may resurface many years down the line, because we may not fully get rid of that clone. It may have gone down, but resurfaces again. So that is why myeloma doctors, even before we knew clonal heterogeneity in this full detail, have always felt that we can reuse drugs or classes of drugs and still get benefits, sometimes substantial benefit, in patients who already progressed on those drugs or those classes of drugs. So that's one practical implication. Where we hope this will go is with very accurate characterization of clonal heterogeneity and clonal evolution, that means how these clones change over time with treatments, there will come a time hopefully we can use these genetic testing to inform what is the ideal next treatment for a patient and or tailor treatments and combinations of treatments based on these genetic information. We're not quite there yet, but we are laying the groundwork for that kind of clinical application hopefully in the coming five to ten years. Does using combination therapy help kill the different myeloma sub clones more effectively? Absolutely, and that's borne out by clinical data that we already have. Very early days of multiple myeloma, when I say very early, we're talking about 20 years back, it was quite common to treat patients with just two drugs when they were diagnosed with multiple myeloma. Let's say lenalidomide and dexamethasone, telidomide and dexamethasone. Then we recognize that giving three drugs, that is bortezomib, lenalidomide and dexamethasone, was better than two drugs. Now we know in the last few years that perhaps for most patients giving four drugs, that is the addition of daratumum after this combination, is better than three drugs. So already even without accounting for clinical heterogeneity, clonal heterogeneity, we already know that two is, three is better than two and four drugs are better than three. And that to some degree speaks to the point you're bringing up, which is that likely there's clonal heterogeneity from the very initial diagnosis in these drugs, which have different mechanisms of action synergistically combined with each other to provide deeper, more durable responses in any given patient. We have not yet gotten to a point, I think, where we say this person has this particular clone or these particular mutations, therefore drug X is better than drug Y. That is not where we are at because we're still treating everybody uniformly with the same three, four drug combinations. But I do think that we will get to the point where we can use these kinds of genetic inflammation, clonal heterogeneity, other genetic markers to determine the optimal treatment for a given patient. 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 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 or your sister and you're comparing 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 are 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 going to vary between patients. It is so variable, and there's so many subclones, that it 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 groups of those clones and to 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 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 subclones 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 tumour can evolve. And so it evolves to escape treatment. If you put a selective pressure on the tumour, the cells that are sensitive die and the resistant ones grow out. And there's an awful lot of important implications of that knowledge, which is if you look there or there, the tumour can be very different. You might have a mutation there that would respond to treatment, but it might not 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. And so you can think of it as evolutionary biology, an ecosystem. So the tumour is composed of different ecosystems, all of which have to be addressed if you're going to cure the 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.