Do all my myeloma cells same chromosomal mutations? What is clonal heterogeneity? (Part 2)

What is clonal heterogeneity? Greg asked me, make some comments about how genetics matters when it comes down to treatment. And Leif already alluded to this with this particular graph. Each one of those colors represents what we call subclones. So that's what you can think of them as like mini tribes within the myeloma. So if we take 100 cells from a myeloma bone marrow, there's some that have this feature, some others have this other features. However, there are two things that are critically important about this. Number one is, these cells are a lot more alike than they're different. This is like those games they show you two pictures and they say find the difference. That's what this represents. So they're tiny differences, but they can make a world of a difference in how someone responds to a treatment or not. So that's number one. Number two, I'm going to change this graph into something different. What we see is that some of the common goal, depending on what treatment it's applied to a person, but there are some things that always stay with that myeloma cell. Now that's what I show by that little black dot in the center. That's kind of the soul of the myeloma cell, a soul we don't like. That may be a translocation. So if someone has a myeloma that is 11, 14, every single one of those cells is going to be 11, 14. There's going to be tiny different changes that make those cells different. Now why do I tell you all of this? The point of this, which Leif alluded to, is because if you press in one area, then maybe there's the opportunity to escape in another area. Our current thinking is that we need to be more encompassing of trying to block all the exits for the cells. And that in our mind means usually go with three drugs instead of two drugs and usually treat for longer and try to treat for deeper. That's an important, a very, very important concept. So that's one of the reasons why we like to think about this concept. Now how does this matter? You're a patient saying, well, how does this matter? Like this is a great example of opportunities and diversity and how the cells can adapt. Because if you have cells that have all sorts of little changes, it could be a few cells here that maybe are not going to respond to Revlimid. And if that person is placed on Revlimid, all these other cells will go away. But those that are Revlimid refractory are going to start growing and taking over. So what this variability or diversity or heterogeneity gives is the myeloma cells an opportunity to still persist despite treatment. That is what we're trying to overcome. And actually, Greg asked me to show this slide, which I sometimes show when I talk to doctors, which is a story about the lion and the gazelles. And as you know, this is African story that every morning they both wake up and the gazelles say we have to start running and be ready to run because the lion is around. And they know that you cannot be as slow as a gazelle. The lion wakes up and goes, you know, I need to start running. I don't need to be that fast. I just need to catch a slow gazelle and I'll eat. And they eat, of course. But what happens is over time, over millions of years, the gazelles are still there because the lion needs to run as fast as the fastest gazelle. And that's what we're trying to do with the design of myeloma clinical trials. We're trying to get ahead of the very fastest gazelle. And that's what we're trying to do with a combination of drugs and treatments. 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. And sometimes you might see some groups of myeloma cells that don't have any mutations. So that's what we call when we do studies in myeloma, heterogeneity. It just means that the myeloma in a patient is not 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. What is a clone? A clone is a cluster of cells. Whenever we talk about clones in myeloma, we talk about subgroups or subtypes. So a good example is when somebody's diagnosed with myeloma, they say you have multiple myeloma and you have IgA or IgG or IgE or IgD or in occasions IgM multiple myeloma. That kind of gives us the name of the type of myeloma that you have. The family name, just like Rodriguez and my brother is Rodriguez as well and my dad and mother are Rodriguez. But within the family, there's a lot of differences within the people that make up that family. So in myeloma, you have different groups of myeloma cells and each one is going to have its own features and characteristics. Some of those are going to be the mutations that they have and some of them are going to be very like their parents and some of them are going to be very different than what their parent cell was like. And that's what we call clones. Anytime there is a cell that divides and one of the cells that come from that division is slightly different than the mother cell or the previous cell, that cell is considered different than its brother cell. And as those cells divide, they're going to start making cells that are similar to them and those are going to make their own separate clones. So just like in a family, if I have kids, they might have more traits that are similar to me compared to if my brother has kids, he's going to have traits that make them look more like my brother. The same thing is going to happen with myeloma cells. As these cells continue to divide, they're going to acquire their own elements and their characteristics, whether it be aggressiveness, mutations, flaws, resistance to chemotherapy or other features that are going to make them unique compared to the other groups of cells. So in myeloma, we always have different clones of cells and some clones can be the dominant clone and a lot of the times a dominant clone suppresses other subtype of myeloma cells within a patient. And if that dominant clone is killed, there is a possibility that one of those smaller clones can take the lead and become the dominant clone down the road or at the time of relapse. But it's important to monitor all the different types of clones in myeloma because we could sometimes be treating somebody and targeting a large dominant clone, which is very easy to treat, while one of the clones that has been there just hiding or harboring could be a more aggressive clone that if we allow this clone to grow, can actually be more aggressive and harder to treat. So whenever we do testing in a sample, whether it be bone marrow or hopefully in a liquid biopsy, we want to make sure that we factor in all of the different clones in myeloma and monitor as we treat what those clones are doing. Are they dying with the treatment that we're doing or are they actually growing and expanding, suggesting that they are resistant to the chemotherapy that these patients are receiving? How many clones exist in someone's myeloma? Clones in multiple myeloma are going to depend on where in the disease we're sampling. In early stages of the disease, like MGUS, we might just have one clone of normal plasma cells or myeloma cells. And the thing that triggered that clone to turn into MGUS was probably a mutation, a driver mutation that caused a healthy plasma cell to be abnormal and turn into MGUS. Future driver mutations can then transform that MGUS clone into more aggressive cells that are going to cause proliferation of the cells and expansion of the clones. And when I say expansion of the clones, it means that as the cells multiply, you're going to be obtaining new mutations and you're also going to have a more diverse type of mutations in more cells that you have. That doesn't mean that those clones are going to stay forever. If you achieve a remission after induction therapy and transplant, there's a probability that you might stay with just one or a few amount of clones and one of those or some of those clones are then going to be the culprits for relapse. If you are diagnosed with myeloma and you do not achieve a remission with the induction and the transplant and you still have detectable disease afterwards or you still have significant disease afterwards, you're going to have more clones there. Now the clones of myeloma are distinguished by the types of mutations that they have. And gene expression profiling helps us identify the different clones. And it can be starting with a clone when you first have the initial mutation that transforms to MGUS to maybe 15 clones when you have flored multiple myeloma and have had the disease in your body for a while and is now causing damage to your body. We have different types of clones in the myeloma cells based on the mutations that they have. And we have learned to group mutations into different categories or classes or subclasses of myeloma cells because unlike solid tumors, myeloma cells do not have that many mutations. They can be between the tens to the low hundreds mutations within a myeloma cell. That doesn't mean that all of the mutations are going to be causing the myeloma. Only driver mutations are the ones that are going to cause these myeloma cells to proliferate and grow. And the other mutations are called passenger mutations. But we have learned that there's patterns of mutations that tend to be grouped and form clusters of myeloma types or subtypes. But when we talk about clones, it all is going to depend on how proliferative the myeloma cell in the patient's body is.