What does it mean if you have a mutation in chromosome 17 and a deletion and how does this relate to p53 status? That refers to the fact that you are looking at two p53 genes for every cell, correct? So the normal state is that two genes will be there in their intact form. That's the normal state. That's what we call wild type. The ways that p53 can be affected are many, not just so when we talk about deletions, a deletion refers to the whole area of the chromosome just being lost. You know, you have a pinching out of that area of the chromosome, taking the p53 gene with it and that just gets lost, right? So you're left with one copy. So when we talk about 17p loss or 17p deletion, we are talking about the physical removal of that whole area of the chromosome that contains the normal gene. So the question is what happens to the other copy? And the other copy can be affected through a number of different mechanisms. One could be through a mutation that interferes with its function. So the gene is there, but it is faulty. There is a change in the sequence of DNA that inactivates the gene. So you have one completely lost copy and another copy that is faulty. And that is a situation where you would consider that you have lost pretty much all the useful function of p53, right? But of course, the second copy of the gene can be lost in some patients through a process similar to loss of the entire region, as I mentioned before. So you could have both copies that are lost or completely gone or one copy that is lost and another copy that is there physically, but in a faulty version. So you really need to know what the status is before you can further ascertain the risk status of the patient. So through fish testing, you can see whether a copy of the gene is there or not. So the first mechanism that I alluded to. The second mechanism you would have to sequence and so determine the sequence of the gene to decide whether the gene that is there is in a normal wild type functional state or a mutation has removed or interfered with its function. And it becomes even more complicated if you think, if you go back to what we said before and you realize that any of these mechanisms could happen in a percentage of cells, but not in the cell next door. So it's becoming very complicated, but I think eventually this is one of the unmet needs in myeloma. We will need to become very sophisticated. We are already becoming sophisticated, but even more at really declaring the status of P53 each and every patient because we know how important it is for normal plasma cells. We will know how important it is for risk prognostication for our patients. Only P53 myeloma in our clinics is a very difficult disease to treat and these patients are at particular risk of faring poorly down the line. And so this is one of our utmost priorities at this point of how to tackle this particular, many high risk myeloma of course, but within the category of high risk myeloma, P53 mutated myeloma seems to be on the ultra high risk end of the spectrum. So we are very interested in the lab. We are focusing on how to generate novel models of P53 mutated myeloma. So we know which therapies, both established and experimental, these cells may respond to and bring those to the clinic. I'm going to take the discussion a little bit deeper. I've talked about copy number changes in the whole chromosome, one of the long or short of the chromosome gain or loss of segments of the chromosome and you'll recognize these terms, but also you can hone in on just specific gene abnormalities. And this has been really adopted in solid tumors in whom some of these abnormalities, if they're found in certain cancers, direct treatment using drugs that counteract these particular mutations. Now myeloma is a lot more complicated. You can see there's a set of mutations that recur in myeloma, but some of these as I mentioned are actionable. There are drugs for these that have been developed for patients with other cancers that carry the same mutation. For instance, BRAF is a big deal for melanoma and certain other cancers. So you can look at the genetic landscape of myeloma as a very complex picture and I don't really want to hone in on this slide, but you can hopefully recognize the primary translocations, the hyperdiploidy, these other secondary exchanges of material translocations and other mutations that tell us more about the weeds in the garden. Now I'm going to take it now another step deeper because you're a sophisticated crowd. It's not just the ISS score, the LDH to try to get a poor man's view of proliferation or the fish. It's now recognized that if the genes that are exchanged are added or deleted are actually mutated themselves and not the normal genes, that will subclassify our fish changes even more. I think that's why some people who have bad fish do very well. The first of this was recognizing that patients with 11-14 who have standard risk, there is a subset that don't do well at all. This is patients who do and do not have 11-14 and usually we're glad to see that because it reflects a disease. It's going to generally be well behaved, but there's some elegant studies that show that about one in ten patients with 11-14 have a mutation of their cyclin D1 that's moved to chromosome 14. This is a group that has an overall survival of less than two years. It's not very many, but these are people that we need to separate out and look for new treatments. The same type of finding has been described for translocation 4-14. If you have 4-14, people are usually concerned that this can be a bad sign, but the ones that really have the less favorable outcome are the one in four who this translocation results in involves a mutation of the FGFR3 gene that's actually transcribed and turned into a protein in the blood. These are the ones that we need to concentrate on. If the FGFR3 gene is not mutated or not expressed, patients don't do so badly. Finally, we hear a great deal about 17P deletion. That's the loss of the gene TP53. That's the loss of a tumor suppressor gene. You don't have breaks on cancer, if you will. If you have two normal TP53, conceptually you can block, you can suppress the tumor. If you have a loss of one 17P deletion, but you still have the other one that's normal, that may not be so bad. You can still conceptually suppress the tumor. If you've lost both, or you've lost one and the second one is mutated and not able to do its job, then we have a problem. From recent studies from another Canadian who's moved to Scottsdale, it's the individuals one and four with 17P deletion who have lost both of their TP53 genes. I think you can see the picture is much more complicated than first glance. Many centers, including our own, have created a panel. We have a 38 gene panel that picks up fish abnormalities, but also the key mutations. It's CLIA approved. We don't have provincial funding for it, but we're using research funds. We plan to start looking at our stem cell transplant patients to see who's really high risk and who isn't. Right now, for high risk patients in the transplant age group, we do double transplants, tandem transplants. Right now, we're using maintenance with two drugs, a proteasome inhibitor and linoleumide. Some patients probably don't need that, or don't need that. Some probably need even newer treatments. The logical next step is to integrate immunotherapy.