BETA - What are some shortcomings (limitations) of the results obtained from a bone marrow biopsy (BMB) test? What is a liquid biopsy?

In this video, we will discuss some of the limitations of bone marrow biopsies and shortcomings of their results. Also, discussed in this video will be the possibility of the liquid biopsy in the future and what could be the benefits of this type of test. What are limitations of bone marrow biopsies? What are some shortcomings of the results obtained from a bone marrow biopsy sample? What are liquid biopsies? At the moment, when we're doing testing for multiple myeloma and what mutations it has to determine what risk they are, if it's high risk disease and more likely to come back and more aggressive, or if it's standard risk, we normally do a bone marrow biopsy. And we do a bone marrow biopsy at the time of diagnosis so we can have an understanding as to what we're dealing with when we start treatment. And we also do bone marrow biopsies at time of relapse so we can understand if there's any new mutations or if we're still dealing with the same type of myeloma cells that we were dealing with at the beginning. But there are several flaws with bone marrow biopsy and that is that a bone marrow biopsy only gives us a sample of one particular area of the bone. And as the name multiple myeloma says, multiple myeloma is composed of many different clones of myeloma cells. So not all of the cells are going to have the same type of mutations and we won't see these myeloma cells spread out evenly throughout the body or the bone marrow. There's going to be Apache areas of myeloma cells and some areas are going to have certain mutations or certain clones. And other parts of the bone we could find different types of clones. So a liquid biopsy has become a very appealing thing for us to use whenever we're wanting to study myeloma and the mutations that it has. Because a liquid biopsy gives us the ability to take a blood sample and study the DNA that's actually released from the cells or shed from the cancer cells into the blood. We can also study the genes and mutations that are seen in myeloma cells that have been shed from the bone marrow or that are traveling through the blood migrating to a different side in the body. So liquid biopsy gives us the opportunity to be able to study this content without having to do a bone marrow biopsy, which is going to, I'm sure, be a great thing for patients because they don't have to get stuck every time we want to do studies. But at the same time it's going to give us a more broader idea of all of the myeloma cells that are in the body, not just that one specific area that we're sampling. So in a nutshell, I would say that liquid biopsies are a very convenient way of obtaining a nice sampling of the myeloma cells that are all over the body without having to do an invasive procedure like a bone marrow biopsy. Now are we there at the point where we can start using liquid biopsies for regular treatment in the clinic? Unfortunately we're not quite there. There are still clinical trials that are ongoing that are trying to compare if the information that you obtain with the liquid biopsy is the same as the information that we obtain with the bone marrow biopsy. And while the studies are suggesting that the information in terms of genetic expression and genetic mutations is very similar between both, we still need to do a little bit more digging and a little bit more trials to make sure that we are having a good representation and that we might not be misleading our treatment based on the results that we're getting with the liquid biopsy. One measure of disease burden is the percentage of plasma cells in the bone marrow. In a normal individual, there's typically about 1% of the marrow will contain these plasma cells. But in the case of myeloma, where you have an expansion of the plasma cells, you may have 5%, 10%, 80% of the marrow may have these tumor cells. So one of the things that oncologists will look at is a measure of the percentage of plasma cells in the marrow, which will be an indication whether the therapy is working, are those marrow percentages decreasing. There is one potential difficulty that can occur. In some patients, the myeloma in the bone marrow will be somewhat equally distributed in the bone marrow so that if a sample is taken, it's representative of the whole bone marrow. However, in some patients, the myeloma tumor cells may actually congregate in one location. Now the problem is if you don't sample in that particular location, you're going to get kind of a false reading of where the most active disease is. So that in some cases, if you sample one area, you may get 70% tumor cells. If you sample another area of the bone, you may only get 5%. So that's why imaging techniques are often paired with the sampling of the bone marrow, because the images can often show you where there are local disease sites where an oncologist is going to want to go in and particularly sample that area. 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. Now there's a new test that comes out, which is one of the clearing areas for myelomas is that even though the myeloma may be present in the bone marrow, some of it sloughs off into the bloodstream. So you can imagine that if you have myelomas at different locations, they'll all kind of slough off into the bloodstream. Now there's not going to be a lot of myeloma cells, particularly early in diagnosis in the blood, but we now have techniques that are so sensitive that you can now take a blood sample and identify the genetic characteristics of the myeloma cells in the bloodstream. And if that's true, you might actually get a better picture of the heterogeneous population that may be located in different sites in the body, but they're all being spilled into the blood. So you get this conglomerate look of all the possibilities. The bone marrow biopsy, one major issue is of course that it's an invasive procedure that requires a biopsy to be done. And sometimes patients can have anxiety from it or stress to go through that procedure and the pain for some patients, though we do pain medications and some patients don't have any pain with it, but every patient's different. And then sometimes some institutions will do bone marrows under sedation for patients who had painful biopsies before or anxiety from biopsies. However, in terms of the limitations of the test actually, when we think about a bone marrow biopsy, think about we're taking a sample from one site of the bone marrow. And so if the disease is quite patchy or there's patchy distribution, we may think that we've cleared it or there's very little here, but there may be a patch somewhere else with a little more disease. And so it may not be a full reflection of the burden of disease. Another thing is myeloma is very complex in the sense of there is disease in the bone marrow, which makes the protein in the blood, but then you can also have extra medullary tumors, meaning it's tumors outside the bone marrow, medullized bone marrow, and those tumors are not then detected by a bone marrow biopsy. So it's possible that a bone marrow biopsy is negative, but on a PET scan we're seeing other tumors. So while the test is a good understanding of burden of disease in people whose disease is mainly reflected in the bone marrow, in somebody whose disease is mainly extra medullary, it may not be as good a reflection.