What chromosomal abnormalities are considered high-risk cytogenetics markers?

High-risk myeloma patients often face greater challenges. They're less likely to respond to treatment, can quickly develop resistance, and may require more intensive therapy than those with standard-risk myeloma. However, even myeloma that initially appears to have standard cytogenetics or normal clinical characteristics can behave aggressively and be reclassified as high-risk. Since myeloma risk can evolve over time, it's critical to assess it not just to diagnosis but also throughout treatment, especially at relapse or when the disease stops responding. In this lesson, we'll explore these cytogenetic abnormalities that serve as high-risk biomarkers and what they mean for treatment and prognosis. What chromosomal abnormalities are considered high-risk cytogenetic biomarkers? We have many different ways of deciding whether patients are high-risk. This can include things like where the myeloma is, whether the myeloma is in the blood, whether the myeloma presents as lumps and bumps or extra-modulary disease. We also have a way of defining high-risk by genetics. Now, that's not the genetics of the whole patient, just the genetics of the myeloma cells. Recently, there's been a group of international experts who've been looking at the definition of high-risk and who have refined it. We now have our new genetic definition of high-risk. That includes four main groups. The first group is patients who have deletion of 17p chromosome. Whereas before, it was counted as any number of cells that were deleted, now it has to be a cut-off of 20%. We have those patients that have a mutation in 17p. We also have those patients that have a problem with chromosome 1p. On top of that, we have those patients that have a translocation. If you have a translocation, you also have to have a problem with either chromosome 1q or chromosome 1p. It's a little bit more complicated, I would guess, mainly because we've managed to refine it because we were noticing that many patients were actually being labelled as having high-risk, who actually were not high-risk and were doing very well. The main group of those patients would be some of the patients with a 414. That's a translocation where a bit of chromosome 4 gets stuck onto a bit of chromosome 14. We discovered that actually half of those patients were doing pretty good. We found out that it was only if those patients had that translocation and had a problem with chromosome 1q or 1p that they were doing more poorly. When we look at the chromosomes, you can either gain a whole chromosome or you can gain or lose part of a chromosome. For chromosome 1q, we're usually looking at a gain of that chromosome. We call that 1q+. Some patients can actually gain many copies of that chromosome. They're often called 1q amp. But usually it's the whole of the chromosome or many bits of that part of the chromosome. For each chromosome, you should have two. If you lose one or get a problem with one, the theory is the other one shall still work. However, if you lose the other one as well, then you don't have any to do the work. That is what we call biallelic. It's two, so the bi means two. What specific translocations, when seen with chromosome 1 abnormalities, are considered high risk markers? Myeloma plasma cells frequently have translocations and most of the translocations will involve chromosome 14. A number of them are considered higher risk. Those are those patients with a 414, a 1416 or a 1420. But if they occur, they have to occur in combination with a 1q or a 1p abnormality. There are many other chromosomes involving that area. It's important to know about those because many of those are not counted as high risk. Those would be ones such as the 1114. What is the difference between a 17p deletion and a point mutation in 17p, also known as a TP53 mutation? How is a TP53 mutation detected? We know that chromosome 17p is important and that many patients can have a deletion, so lose part of chromosome 17p. We've tended to pick that up with a test called FISH. That tends to get routinely done. More recently, we've also discovered that sometimes if patients lose one arm of chromosome 17, remember me saying there's two, they can actually get an abnormality in the other arm of chromosome 17, which we call a mutation, which is just one spot that's not quite right. If a patient has both of those, then that can mean that they're high risk. One of the problems with this is that to detect a mutation, you need a special test, which is called a sequencing test. That has not been commonly done in myeloma. It's a common test for leukemias, but it's not a common test in myeloma. Now there is a big international push for physicians to be doing these tests at diagnosis for patients where they not only look for a deletion, but they also look for this mutation so that we can really tell patients what their risk is. Since the recording of this video, the IMWG revised the definition of high risk multiple myeloma to include beta-2 microglobulin level greater than 5.5 milligrams per liter in a multiple myeloma patient with normal renal function as an indicator of high risk disease, even without other adverse features. This elevated B2M level when kidney function is normal suggests a higher tumor burden or more aggressive disease.