BETA - What is the 11;14 translocation?

What is the 11-14 translocation? In multiple myeloma, you know, we have lots of what we call set of genetics and fish testing that kind of tells us what the genetics or the programming of the cells might be doing. And so one of those is 11-14, translocation 11-14. And about 20% of patients with myeloma have this. Usually it's at diagnosis. So sometimes we see genetic changes that happen over time as patients get different treatments and their myeloma kind of comes back and it might come back with something a little bit different the next time. But with 11-14, it's one of those things that we usually see at diagnosis and it usually continues through all the different treatments we do. And the nice thing about the 11-14 translocation is that we have our first therapy that looks like it could actually target patients with this change, with this aberration. So something called BCL2, that's just a part of the pathway that's increased for the myeloma cells with this specific change in that genetic translocation that we can actually target that BCL2 so that the myeloma cells are the ones that the venetoclax goes after. So we've had lots of studies with venetoclax with lymphoma and leukemia and it's already actually approved for certain leukemias because it works so well. In myeloma, we actually had a study that included all myeloma patients initially thinking that it would work for everybody. And unfortunately, it actually didn't work for everybody and caused some toxicity for the patients who don't have the translocation or an elevated BCL2. So that study really showed us that this really should be for a group of patients that have just translocation 11-14. So now studies are being done in just that group of patients. And it's a great drug. I will say that all the myeloma doctors really like using it, usually in combination for our patients who have this translocation issue. Usually it's a second, third, or fourth line. We don't use it up front as of right now because we have other therapies that also work for patients with this. So it doesn't mean that all the other proteasome inhibitors and IMIDs and all those things won't work. They work too. So what we're trying to figure out is what combination is going to work the best and get more of those options out there. A recent study that was presented showed that it didn't beat pomelist or pomelidomide and dexamethasone. That was trying to get an official approval for myeloma. Again, it doesn't mean that the drug doesn't work, but because it didn't beat it, which was what they were trying to show in the trial, it hasn't become approved yet. However, again, we can get the drug knowing that there's lots of patients that can benefit from it. So yeah, 11-14 basically means in your genes, every cell has 46 chromosomes, right? And so 23 are from mom, 23 from dad. And this does not mean you were born with a problem in the genes. But once someone gets myeloma, for whatever reason, in that myeloma cell, patients had a part of their chromosome 11 on one side and part of chromosome 14 that when the cell was dividing, those two sort of attached to each other when it wasn't supposed to, and then it kind of replicated. And that, again, there's all these little messages in all our chromosomes. And when things get rearranged, all of a sudden those messages can change as to what they were supposed to do normally. And so when that happens, again, that BCL2 piece that I was talking about, it goes up and that's how we can use it to target the myeloma cell. But the way we figure out what people have in terms of these translocations and genetic changes is usually on the bone marrow. And sometimes on plasma cytomas that we've biopsied, we are working on blood tests. We're not there yet, but finding plasma cells or myeloma cells anywhere we find them, we take them and we basically our pathologists will go through and do something called a FISH test that will see what changes are in those chromosomes. And that's how we figure out if someone has 1114 or 414, 17P deletion. Again, these are all the different chromosome numbers that we're referring to. And unlike some of the other ones, translocation 1114 actually isn't considered a high risk feature. So that's a little bit different than some of the other reasons why we do FISH testing. Usually we'll see 1114 at diagnosis. However, the way the FISH testing is done is not perfect. So again, why we're working on blood tests eventually that will hopefully fix all these problems we have. But a lot of centers won't enrich the plasma cells, meaning that when we do a bone marrow biopsy, they're on slides, the samples are sent to the pathologist, and it depends on how they actually look for the test to say is it going to actually be quality assurance, right, that you actually are finding something or was there a false negative or a false positive. And the problem is the false negatives. If you don't have at least 10% plasma cells usually in the sample, the test doesn't work very well. So if for some reason the biopsy itself when you're diagnosed didn't have very many cells or you just don't have as much myeloma in the bone marrow, then we might miss that test at the beginning. That later on, if you end up with more myeloma, we might find it. But again, for majority of patients, we think that it's probably at diagnosis and then it just continues. But there are some of my patients that we didn't find it initially, we thought the test was done well, but then we found it later. So I still test for all my patients. Every time we do a bone marrow biopsy or a biopsy, we'll still test for as much of these as we can. The problem is that you can only do so many tests sometimes with the sample. So again, once we get blood tests, I think it will change sort of these quality issues that we have. But putting that into context, you know, sometimes when patients come to see me and maybe they didn't have 11-14 at the beginning, I'll still test for it to make sure you really don't have it. Should 11-14 be considered high-risk myeloma? I mean, there are several aberrations in myeloma, as you know. The 17P is the most famous, the most dangerous, the 11-14, the 14-20, 14-16, they are well-known. The 11-14 is also well-known, it's a long time ago, but it's found in about 20% of all patients, so every fifth patient with myeloma might have the translocation 11-14. But there is, as you know, the A-laminar doses, which is very near as a diagnosis to myeloma, the expression is about 70% to 80%. And there is a target tested in the form against this translocation between chromosome 11-14, the venetoclax probably know that. And we tried in myeloma patient expression, the expressing data, 11-14, with some responses. So it's a new targeted medicine to some of the myeloma patients. I don't consider it to be a high-risk, but these patients tend to progress more rapidly than the common myeloma patients, but the expected overall survival is almost the same. So it's kind of high-risk, but it's not like the 4-14 or the deletion 17-P. Why the amyloidosis patient respond so well, I don't really know, but the responses to this drug with very low dose, not, we used 400 mg, the accepted dose is 800 mg, we didn't combine it with anything, and almost all patients responded. How did I know that? It was an emergency, a woman, 38 years old, at the intensive care unit with a severe heart failure. She was unconscious, and she was diagnosed with amyloidosis. We tried Geratumimab, no effect. We gave her one week of venetoclax, and the disease disappeared. We did a heart transplantation, and she's still alive, she's working 100% two years today from the transplantation. It was a desperate situation, but as a physician, I can use this drug, and I tested it on amyloidosis patients, and almost everybody with the 11-14 responded. The myeloma is another thing, partly it is only expressed in one-fifth of the patients, and then you need to combine it with other drugs, not only the venetoclax.