 Talk about, it's actually both the difficult and the most interesting subject to speak about because the changes that we've had in the myeloma world over the last few years and in fact over the 25 years that I've been working in myeloma have been extraordinary. I don't think that there is another disease in which we have had more clinical insights and more drug development than in multiple myeloma. I don't know that we have kept up biologically. We've managed to sort of empirically turn out a lot of new drugs, but I don't know how much that has translated into changes. So the point of this slide isn't to say look at all of these drugs and for everybody to remember them and apply them to their practice or to themselves, but the point is that we've had a whole bunch of drugs that have been approved recently. We have a whole bunch of drugs that are being studied that have been approved in other diseases and we have an enormous list and this is nowhere close to a complete list of drugs that are currently in clinical trials and I have several of my research nurses and I have several of my research data coordinators here and they will attest to the misery that this success has brought upon their personal lives but it has been extraordinary what we've been able to bring to the lives of our patients. So the subject that we get the most questions about when patients come to us, when I get phone calls from physicians and from patients and their family members is about immunotherapy. Now immunotherapy is a sort of difficult definition what is immunotherapy? Well we've been working with thalidomide, linalidomide, and pomalidomide for a number of years. There are other derivatives of thalidomide that are coming on. We call those immunomodulatory drugs. I don't have them up here on that list. We still don't really understand how those drugs work but they certainly change the immunologic milieu significantly so the reality of it is that we've been doing immunotherapy in multiple myeloma for a very long time. You heard David Viesel not particularly eloquently but speak about stem cell transplant in multiple myeloma and Josh was speaking, and if you think that David wasn't eloquent, Josh was even less eloquent speaking in the other room. Yeah, but about autologous stem cell transplant in multiple myeloma. Well the reality of it is the real big successes with autologous transplant multiple myeloma are not chemotherapy successes, they're immunologic successes. And the reason that those patients do as well as they do for as long as they do is because there is some resetting of the immunologic environment that allows the immune system to either re-equilibrate with the disease and keep it at bay when it had failed previously and the proof of that is that we have patients who don't achieve complete remissions after their stem cell transplants. Yet their disease remains stable for sometimes decades. So that is immunotherapy. But the questions now are about the drugs and the strategies that are coming along. So we have monoclonal antibodies. We have a whole series of monoclonal antibodies. We've had two monoclonal antibodies approved recently and what's a monoclonal antibody? Well, the oncologists and the other professionals in the room know exactly what monoclonal antibodies are. Somebody jammed something into a mouse, let the mouse make antibodies and now we've humanized them and we're using them in human beings. Now some of those monoclonal antibodies kill the cells directly. They interact with the target on the surface of the cell and actually induce apoptosis in the cell. I think more typically these monoclonal antibodies bind to the surface of the cell and attract the cells that are capable of killing things that are coated with antibodies. We have other monoclonal antibodies, checkpoint inhibitors, that have become the hottest thing in oncology in general that are being applied to multiple myeloma and they interfere with pathways that are meant to dampen our immune system. So we have monoclonal antibodies that work via all kinds of mechanisms. They fix complement, they attract cells that are capable of punching holes in the surface of cancer cells and K cells, things like that and they attract cells that are capable of phagocytizing tumor cells and those might be the most interesting ones because those cells then present antigens from the killed cell to our immune system and may propagate that immunologic response beyond just the antibody itself. So those are exciting. Then we have active ones and Ed Statenauer is speaking next door right now about CAR T cells. We have had an enormous series of questions from patients about CAR T cells because there was an article about a patient who was dying from myeloma who got CAR T cell therapy actually by Ed and achieved a complete remission. Now unfortunately that success in that one patient wasn't, didn't last forever and the overwhelming majority of patients who got that therapy don't respond as well as that sort of index case that we're talking about but CAR T cells are very interesting therapies. We can remove your T cells, engineer a receptor for a target on the cancer cell of interest and have that engineered receptor put into the T cell and let it activate the T cell, get it to proliferate and kill tumor cells via that the person who first developed that strategy was a guy named Zellig Escher who actually just developed it as a tool in the laboratory. Carl June sort of moved that into the clinical realm and it is a particularly exciting strategy. Vaccines, there was a very large vaccine study going on in the United States in which tumor cells are fused with dendritic cells, one of the most competent types of cells in terms of presenting antigens to our immune system and those dendritic cell tumor cell fusions are then given back to the patient in the hope of stimulating an immune response in the patient and there are other strategies as well including all kinds of targets. So I talk to you now about the checkpoint inhibitors. So checkpoint inhibitors have been approved, they were first developed in melanoma, sounds sort of like myeloma, but not half of our patients always talk about their melanoma but we are talking about myeloma. These drugs have not been nearly as successful in myeloma, but it turns out that when we combine them with image, with lenalidomide, with pommalidomide, we can take patients who are refractory to the pommalidomide or lenalidomide and who have no response to the checkpoint inhibitors. So we're going to talk to you now about myeloma and how to respond to the checkpoint inhibitor, pembrolizumib or nevolumimab and when we combine them we get excellent responses and some of these responses are quite sustained. Now what we don't know is if there is a population of patients in which we actually get over the hump in which we will educate the immune system to sort of propagate that response indefinitely and those are things that we're going to lose. We're going to not lose but use. Noah Baran is piloting a study here in which we're trying to leverage that in patients who are post-transplant. So some very exciting kinds of things. Denosumab, you guys use it in the treatment of hypercalcemia, it is a drug that has not been approved in myeloma, certainly has a potential for benefit and we will see other drugs in those categories used as well. So we started to talk about this. So we have CAR T cells that look at a number of different targets. So again, CAR T cells, most of what they do although there are some variations in this is that a T cell requires two signals in order to become activated and proliferate and in normal circumstance, the native T cell will engage those two targets on the surface of a cancer cell, it will start to proliferate and it will kill targets that have those paired antigens. What the current CAR T cell strategy does now is they combine both of those activating signals into a single receptor. But they engineer the receptor by attaching a monoclonal antibody to it. So you have a monoclonal antibody against whatever in our institution here against BCMA, a fairly ubiquitous target on B cells but particularly plasma cells and you form a chimeric protein. So those two activating signals that are normally in two separate receptors into one protein and on the end of that protein you have the antigen binding characteristic of the monoclonal antibody. So these cells when they encounter a BCMA positive tumor cell they proliferate and they can then kill the target cell they are activated and proliferating and kill. So we know that it works, we know that we can kill these cells, we don't know that we can cure myeloma with this kind of strategy but we're just starting to do it, the cell doses that we are using right now are still relatively low, the dangers are relatively high but this is certainly something that is going on. We can, yeah. So the bite antibodies in by all? So there are no bite antibodies that are actually in clinical trials yet. There are bite antibodies that are coming along and have slides that we'll talk about that. So mills, there's a whole science, one of my friends at Hopkins is particularly interested in this. We can remove tumor cells from, we can remove T cells from tumor. We can expand those T cells that are specific for the cancer. Part of the reason that these cells fail is because the cancers are very, very smart. They can teach those cells to not proliferate and not respond but when we grow them and can engineer their environment, sometimes we are capable of putting them back into the patient and having them kill tumor cells. So far, this stuff hasn't been particularly successful but most of the reason that this is not successful is because we don't really understand where all the checkpoints fall. We have drugs that we call checkpoint inhibitors but the reality of it is that we are just starting to understand the environment in which these cells work most efficiently. So we will eventually be able to do that. Bob Corngold and his group here has particular expertise in expanding T cells. We can now start to identify what are the targets that those T cells attack and instead of using monoclonal antibodies that have many problems in terms of engineering car T cells, we may be able to cut out the intact T cell receptor and put them into our T cells. So engineer T cells with activating molecules that are meant to be in T cells. And so this is a very complicated biology. So this has been done to some level with New York Esau One. Unfortunately, it turns out that New York Esau One is also found on myocardial sites. So in treating patients with some of these strategies, there are potentially very large pitfalls like the T cells actually attacking the myocardium in addition to attacking the tumor cells. So all kinds of things. And then there's lots of things that we can do in the post transplant environment. Engineered DLI is something that is being tried. We have been collaborating with a company from Italy that actually allows us to turn the T cells off. We can give lots of T cells they can kill the myeloma cells quite efficiently. But in doing so, they can also kill the patients because of uncontrolled graft versus host disease. Well, we have the ability to now engineer the cells that we give back so that when they are doing more than we would like them to do, we can actually ask them to commit suicide. So there's all kinds of interesting strategies there. I talked to you about the dendritic cell fusion vaccines, interesting stuff, many, many targets that are being used. One of the things that was very, very exciting about a year and a half ago was a report of a patient at the Mayo Clinic who got a very, very high dose of the measles vaccine. It turns out that the measles virus specifically infects activated plasma cells, proliferative plasma cells, and that they gave an enormous dose of the engineered virus that is used to vaccinate patients against the measles, and that it specifically infects the plasma cell and actually can kill the plasma cell. Now, they had a success in one patient, that patient relapsed quite quickly. But just to extrapolate from another area in which this kind of work is being done, so glioblastomas, a cancer that we have much to achieve in the future is infectable by the polio virus. So you can take an engineered polio virus and you can kill glioblastomas with that. Now, most of the patients will have a transient response and then subsequently relapse, but you can actually give a checkpoint inhibitor to those patients and get an enormous response that ultimately can, looks like it can cure some patients with glioblastomas. Now, admittedly, this is a very, very minor population that achieves that level of response, but we are just starting to do that in multiple myeloma. And there's a whole bunch of companies out there that are not just working with the measles virus, but are looking at other viruses that are tropic to specific kinds of cancers or engineering those viruses to make them tropic to particular kinds of cancers. And as we learn more about immunotherapy, these two fields are going to come together. So we're going to be infecting our patients with the measles virus. We are then going to be turning on and off their immune response to those measles virus infected cancer cells. And we're going to see this kind of stuff evolve, I hope fairly quickly over the next decade. So all kinds of things like that. So to go through each of these things one after another, I don't know that that's really the point of this. I think the main point is to say that we have a lot of interesting things. The PVX, I don't know what that is, so the PVX for 1.0, why this is more interesting in smoldering myeloma? I think people feel that a lot of these therapies are going to be more effective in people who have more intact immune responses. I have some sort of philosophical objection to saying we should be taking all myeloma patients and treating them, all smoldering myeloma patients and treating them. We still don't know who are the ones who are going to progress to active myeloma and those who are not, we're still not sure that those strategies can't have a negative impact on either the likelihood of progressing or in terms of selecting for resistance when we in fact have therapies that are better therapies. So unless we are very damn sure that we can identify those who will need treatment and that the treatments that we are giving them aren't going to hamstring us in terms of treating with more established and more effective therapies later on, I find it a little bit difficult to do that. I will readily admit that I am probably in the minority in feeling that way, but I think that that kind of strategy needs to be thought out very, very carefully. So monoclonal antibodies in phase two. So, implicitly, and darsilex are the two that are approved. We have a whole series of monoclonal antibodies that are very interesting. I can't tell you which ones. I think are going to be the best ones. There are a number of monoclonal antibodies with different targets, and there are now monoclonal antibodies that have been engineered to include toxins so we can target the cells using the monoclonal antibodies. We have had great success, although not without toxicity in using an engineered monoclonal antibody here. In patients in whose disease has responded to nothing else, we have had very, very durable responses, not without a lot of complaints because the drugs are not as benign and trivial as the more traditional. I guess traditional is hard to use in drugs that we've only been using for a short number of years, but these engineered monoclonal antibodies are certainly very exciting. We have a couple of other ones that are coming online. Hopefully they'll be less toxic and more effective, but I think that this is certainly a very exciting way to go, and we have lots of other drugs that can sort of leverage these as well. All of these drugs, and Matt and I don't particularly get along well, but Matt represents cell gene, and all of these drugs work better when we use them with lenalidomide, when we use them with pomalidomide. Now, why that is, I certainly am not sure, but it's quite remarkable that these drugs that have some efficacy become dramatically more efficacious when we add an imid, and we have really no idea why that should be the case. So it is a very exciting world just empirically that even though we don't understand the biology, it's as we mix and match these drugs to find out how effective they are. Just Darzel X, which became commercially available just in the last year, has a response rate of about 30%, and in the real world probably less than that, but when we use it in combination with lenalidomide, the response rates double, and these are in patients who are completely refractory to lenalidomide. So why that is and what it is that makes it possible for that to happen is stuff that we have to understand. Why should a patient in whom lenalidomide does not work when we use it in combination with an imid, in combination with a monoclonal antibody? It's just sitting there on the surface of the cell. It doesn't really kill the cancer directly. What is it about the imid that makes the cancer cell more sensitive to being killed by the monoclonal antibody? Or perhaps more importantly, what is it that the imid does to activate the immune effector cells to kill those things? And if we understand that, we're going to have an enormous amount of work to do in terms of applying those insights into the management of our patients. As I talked about, we have an enormous number of clinical trials that are going on in patients with smoldering myeloma. We, as a group, argue all the time about what we should be doing and is there a risk of doing harm. And, you know, there's a lot to be done. And if we could identify those patients in whom we know we're going to go on and actually develop symptomatic myeloma and apply therapies that are potentially curative, that might be a very exciting step. I find it difficult to take a smoldering myeloma patient and say it's time to treat them and then not try to cure them. And a lot of the clinical trials, I don't think have cure as their objective but have management as their objective. So it's a little bit difficult of a world. But the point of this slide is to show you how much work is going on. So the Compass study. So this meeting is sponsored by the Multi-Myeloma Research Foundation. And I'm not saying this because the Multi-Myeloma Research Foundation is here. I think this is the single most important study going on in the myeloma world, certainly in the United States. We have a representative of HOVON here who is the Dutch myeloma research consortium that has done very, very similar kinds of work. In the United States, we have never really done this. But this is a clinical trial in which we have sort of genetically mapped all of a thousand patients. And we are going to see what happens to these patients as they've been treated. So we've had a lot of clinical trials in which large numbers of patients have been treated in the same fashion. And then we've been able to identify what genetic variables there are that predict for better or worse outcomes in response to that particular therapy. Now this trial allows us to do a lot of things. It allows us to see what mutations occur as patients are failed by a particular therapy. It allows us to see other pathways that are relevant in other kinds of therapies. But it also allows us to see whether for a patient with a particular genetic background, is there a therapy that is better for that patient? None of the other clinical trials have actually attempted to do that. Peter has brought us a genomic, a gene expression profile platform that I think is going to catch on. They're starting a large clinical trial here in the United States that may allow us to answer some of those questions as well. But for right now, this Compass study is doing things that no other study has done before. We're fortunate here to be participating in that study. There is a new successor to that Compass study. The Compass study does this, but the successor trial does as well. One of the big things in oncology, you've all heard of foundation medicine and things like that, that are trying to identify particular genetic signatures that are associated with better or worse response to particular kinds of therapies. So I call this trial the son of Compass. But 1,600 open reading frames that are sequenced, both by next-gen sequencing and by RNA sequencing to identify potential actionable mutations, meaning therapies that can be directed at patients with particular mutations. So sort of the classic one in myeloma has been a BRAF mutation. There are drugs that are used in other malignancies, melanoma in particular, that target that BRAF pathway and about four or five percent of newly diagnosed myeloma patients have a BRAF mutation. Are those BRAF specific drugs going to work in those myeloma patients? But I think perhaps more importantly, we're going to stop having myeloma doctors and lymphoma doctors and melanoma doctors. We're going to have pathway doctors. We are no longer going to be talking about that you have a cancer that arose from your plasma cells or pre-plasma cells. And we treat plasma cell malignancies in this way. We are going to be saying across all malignancies that you have changes that affect this particular pathway. And so it is going to be the pathway that we treat, and not the malignancy, not the cell type that we're talking about. I'm sorry, this part captures the mutation, I showed you the mutation, but it doesn't have died between yet. But the reason that the MMRF is doing this is to help us in the management of our... But ultimately what we're going to see is these huge, all-encompassing trials. And if we know what mutations our patients have, we're going to be able to direct patients towards clinical trials that are perhaps more applicable to their particular genetic makeup. And again, the place where we fail in doing this kind of stuff is that much of the time the reason we respond or not respond has nothing to do with the cancer itself, but sort of the background of the patient, the immunologic milieu, or the microenvironment. I hate to talk about the microenvironment because the group that brought us that term and I don't see eye-to-eye on things, but there are many host variables that we need to identify. So monoclonal antibodies, we have lots of targets with lots of antibodies being developed. We're fortunate enough to be able to participate in these. We're seeing lots of combinations with monoclonal antibodies and with new drugs. We have done a lot of stuff with histone deacetylase inhibitors here and there are some new histone deacetylase inhibitors that are being looked at, but the point is we have effective drugs. Now we have to figure out what is the most effective way to treat them. We have a ton of clinical trials here at the John Thorough Cancer Center. I'm just showing you sort of the algorithm that we use to pick clinical trials for patients. So it is incredibly complicated because we have been fortunate enough to have a lot of drugs thrown at us that we now have to figure out how to use and which ones are going to be effective. So the point isn't to memorize the JTCC algorithm, but to understand that it's difficult now to choose drugs. I talked about CAR T-cell. So the CAR T-cell study that we are doing here is sponsored by a company named Bluebird. It looks at BCMA as the primary target. I'm not going to detail how this is done. We actually have another cellular therapy trial that is opening here using an engineered NK cell rather than an engineered T cell to attack the cancer cells. So that is a very exciting thing as well. Iced tuximab is a competitor, I guess, at some level of daratumab, of dorsalex. So it is an interesting body. It is an interesting monoclonal antibody that seems to be slightly more active in terms of killing cells in tissue. I need to hurry up. Sorry. So it's another monoclonal antibody targeting CD38. So this is just some of the data. The point is that it is another monoclonal antibody with significant activity in patients who have been heavily pretreated that is now just going into clinical trials in combination. This is just, again, some more of the data. And I don't know how much the particulars of a clinical trial and the responses are of interest to the audience. I think the point is that these things work. Pembrolizumib is a drug that probably most of you know from melanoma and now from a number of other malignancies. It is a checkpoint inhibitor or monoclonal antibody against PD1. And I'm not going to go through all the details. I actually was the PI on a single agent PD1 trial. There is no activity of PD1. We had a couple of patients that had stable disease, but there were no objective responses to PD1 blockade in multiple myeloma. We are now using it in a clinical trial in combination with lanolinimide. And that trial is now expanding to include carfilizumib, pembrolizumib combination. So that may be a particularly interesting combination as well. Certainly something that we are very excited about. And does this slide say anything about the response rates? Yeah. So the point is overall response rate of 50%, but I think that this is the interesting thing so that in patients who are lanolinimide refractory, we are seeing about a third of the patients respond to the combination of pembrolizumib and lanolinimide. So I think that the idea of immune manipulations working is going to be exciting. So we have another monoclonal antibody this time against anti-PDL1 that is being used. And actually both Peter and myself are investigators on this trial. So using this in combination with pembrolizumib in a number of different combinations, and I'm not going to go through the biology of checkpoint inhibition. Let it be said that our immune systems weren't designed to protect us from cancer. We were supposed to be dead well before we got cancer. Our immune systems are there to protect us against infections. And one of the main evolutionary issues is to turn off the immune system once the infection has died down. And unfortunately cancers use that dampening of the immune system to their advantage in terms of teaching immune effector cells to ignore them. And these new molecules, these checkpoint inhibitors, of which there are now many, try to circumvent that part of our biology. So the trial that we are doing here has a number of arms. We are already seeing responses in patients in whom the background therapy we would not expect to be effective. So we know that PD-1 blockade is effective. Now we are learning that PD-L1 blockade is effective. We have another target that we are looking at that is particularly exciting. So there are many proteins that are trafficked in and out of the nucleus, and there are pores that specifically mediate that transport in and out of the nucleus. And there is a small company up in Newton, Massachusetts that has developed a series of molecules that can block that transport of proteins in and out of the nucleus. And the theory was that by blocking this we could capture tumor suppressor proteins in the nucleus, and that would then take very unstable cancer cells and tell them to commit suicide. And it looks like, I'm not sure that that mechanism is actually how the molecule works. It may very well be, but it actually does kill myeloma cells. And so there is now a clinical trial going on with these. There is actually now a newer derivative that is just starting clinical trials, and we have clinical trials here with both the parent compound and now the derivative that we're both, that we're excited about both of these. So Andre asked about bifunctional antibodies that you may have started to use when toximab for the treatment of leukemia. So there are antibody, there are bispecific antibodies and there's many different ways to make bispecific antibodies. So there are clinical trials that are in the midst of starting up with bifunctional antibodies that are specific to BCMA. And I'm just going to show you some data that in comparing in animal models CAR T cells versus bifunctional antibodies, they're indistinguishable. So it's actually easier to see in the next slide. So in terms of the ability to... the controls versus CAR T cells versus a bifunctional antibody, so we may have a much, much less expensive, much more off-the-shelf way of achieving exactly what CAR T cells can achieve using these bifunctional antibodies. And these are just using fluorescent tumor cells. You can see that the bifunctional antibody yields the same kind of protection as the CAR T cell does versus the controls. So these bifunctional antibodies are very, very exciting molecules in general in oncology and perhaps going to be seen to be effective in myeloma in the near future. So I think one of the points that we always have to talk about is in the United States, we're incredibly bad at getting myeloma patients to participate in clinical trials. I think I've seen clinical trials published by Peter that where more than 90% of the eligible patients in the Netherlands participated in clinical trials. In the United States, just for participating in clinical trials at all in myeloma, which is one of the better diseases, we get numbers that are in the single digits. And the myeloma community is a particularly well-organized community with lots of advocacy. So the point is that we need to start taking some of our cues from the Europeans and how they do clinical trials and find ways to get our patients to participate. So when any of you guys sees patients that you think would benefit from the participation in clinical trials, find them. It doesn't necessarily need to be here. But we need to figure out ways to answer the questions and solve the problems that we have much more quickly than we do because we have so many tools now and we just are not learning fast enough how to use those tools. So, yeah. I mean, I think that that's the key question. And we have a little bit of data about we were on a conference call yesterday about that son of compass trial in which one of the investigators was talking about one of his patients that had become refractory to proteasome inhibition but had a mutation that suggested that the clone that was operating at that moment was likely to be a proteasome inhibitor sensitive. So they used the combination of a drug that wasn't approved in myeloma because of other mutations that they saw in combination with a proteasome inhibitor to good effect. Now, whether that answers your question, probably not. But the point is myeloma is genomically incredibly complex and there are not many themes. I have treated, I think at this point, four or five patients with BRAF, with MEK inhibitors. I have not seen a response rate. I have not seen a responder yet, although others of my colleagues have based on identifying BRAF mutations in my patients. So the answer is mostly no, but hopefully yes. Yeah. Can you comment? Obviously that's what I feel when you try to look at these actionable items, but we can have a lot of actionable items that are passengers and not drivers in the disease and what's the threshold of this infection of this because it's not just a tumor verb and given the fact that technology to detect them is so sensitive you can find a mutation in just for a second. Yeah. I mean, so we know that there are many clones that exist in myeloma patient from diagnosis and they don't all have the same mutation. So the question that you're asking is a very complex one, but I think even beyond that, if I had a patient who had a BRAF mutation, I wouldn't treat them with MEK inhibitor. I would treat them with carfilzament. I would treat them with Bordesimid because those are drugs that work. And even though we haven't... you know, this is the problem in myeloma is that we still don't know what are the driver mutations despite all of what we have done and it doesn't appear that they are the same driver mutations in all or even most patients. There is literally no theme and hence we direct our therapy more towards the biology of plasma cells than we do towards the specific mutations that the patient has. I think what the future is going to bring us is the combination of the two. It's therapies that are directed towards the biology of plasma cells in which we then superimpose the therapy that is specific for the pathway that is perturbed in that particular myeloma patient. And right now we haven't gotten there and we don't have the choice. Number one, we don't have the drugs that target those pathways. That will happen. And we don't have the choice. It's too complex. We don't even have that information in most patients. But sometimes we think of those mutations as being what could be really the next radical change is probably going to be more in between what's going to help us select among the sequence of treatment and that's a very difficult question because we have too many drugs. But I think the place that we're going to go is to take these very, very effective therapies we have that are plasma cell directed therapies. They're not myeloma directed therapies. The reason that we have the successes that we have is because we take advantage of the biology of plasma cells and we still don't have any drugs that attack the pathways that are the perturbed pathways in the individual patient. So we will start to learn that. It turns out to be way more complicated in myeloma than in virtually any other cancer that I know that we deal with. But that's going to be how we end up curing that. Curing patients routinely is by combining the pathway-specific therapies with the plasma cell biology-specific therapies. What's the most significant factor that you look in practice to predict from a small to ring myeloma that you're going to have? Do we have something that is reliable? No, I mean because it's a host phenomenon. So she's not in the room but people have heard me that she's going to actually speak today. She may have spoken already. So we have a patient who we take care of who was in her early 30s when she was diagnosed and she had smoldering myeloma but fairly high burden smoldering myeloma that sat there perfectly fine and she was married, she hadn't had a child and when she realized that it was three or four years into her treatment and that she hadn't progressed she said, well, I've always wanted to have a child. I'm going to have a child. So she's the only patient I know who has gotten pregnant on my time. I had nothing to do with the pregnancy. But she decided to get pregnant and as soon as she got pregnant her myeloma exploded. I mean, I introduced her to Peter before. And she went from an M spike of like 0.5 to 2.5 during the pregnancy. And as soon as she gave birth and she was no longer immunosuppressed the myeloma took a right hand turn. So progressed, gave birth, stopped where it was, didn't go back to where it was but the point is that what turned her from a smoldering myeloma into an active myeloma and then back to a smoldering myeloma again was a host thing. It wasn't a cancer thing. So I think the difference between the overwhelming majority of patients who have smoldering myeloma and those who ultimately evolve into symptomatic myeloma has relatively little to do with the cancer but much more to do with the host. I mean, obviously it's a combination of both of those things. Similarly in young women we see a lot of the myeloma while they become pregnant. Yeah. Well, we see, switch to why I tell everybody who works for me not to get pregnant because it's so, I mean, from an oncologic perspective it's a dangerous environment besides the fact that they then take time off and they do.