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OK, so we are live now. Um Welcome everyone and thank you for joining the talk this evening. And we have Professor Graham Jackson talking for us this evening and he's a consultant hematologist, specialized in he malignancies. And it's just a reminder that all of us speak because of volunteering. And we're very grateful and lucky to have pro here with us this evening, giving us his time back out of almost retirement to talk for us this evening. So, um everyone, I without further ado I will hand over to Professor Jackson. Thank you Miranda. And it's a great pleasure to be here. And um I just said to Miranda that if anyone wants a PDF of these slides, I'm very happy to share them. I'm also very happy to answer any questions. I do have to be away by 10 to 8. Uh But people want to email me afterwards on my NHS email. I'm happy to answer questions. So I'm gonna talk about um myeloma and I think a lot of people find multiple myeloma a really difficult disease to understand. And, and actually I, when I was a medical student and through my medical training And before I became a hematologist. And even actually when I became a hematologist, at first, I really struggled to understand multiple myeloma. So I hope I can debunk some of the mystery around it and help people have a better understanding of this disease, which is one of the most common hematological cancers. Um And it is quite important for people who may not actually go into hematology because it is one of those cancers which are but against numerous medical teams, oncology, teams, cardiology teams. Uh So it is a disease where even if you're not a hematologist, you may well come across it. So this is my title slide and I've kind of shown you the enemy, this is the enemy. These arrows point to the malignant plasma cell living within a fairly normal looking bone marrow background. Uh and multiple myeloma is a disease that lives in the bone marrow and that actually provides a lot of diagnostic difficulty because as we will see, it rarely comes out of the bone marrow. So unlike say a breast cancer which might present with a lump or prostate cancer, which might present with urinary difficulties or a colon cancer that might present with bleeding or pain, multiple myeloma. If it does, when it does present, often presents with very nonspecific symptoms and does not present with a symptom that is characteristic in the way that many other cancers do. Ok. So let's just talk about it. It's a cancer of the plasma cell. As you will know, the plasma cell is the antibody producing cell, which is the final common pathway of the immune system, particularly the B cell immune system. And normally plasma cells will produce uh antibodies. So if for instance, we're all vaccinated, uh the end result of vaccination will be we produce lots and lots of plasma cells which will produce lots and lots of antibodies against the vaccine. But multiple myeloma is a cancer of the plasma cells. So the plasma cells in multiple myeloma do not produce a useful antibody. And all the antibody they produce is identical and useless. I'm also gonna touch on a a number of other disorders because actually multiple myeloma is part of a family of disorders. You'll know of monoclonal gammopathy of uncertain significance. It can present as a single lump uh in the bone marrow called a plasmacytoma myeloma. And its associated disorders are the commonest cause of amyloidosis in the form of al amyloidosis. And rarely, this disease can pre present as a very aggressive form of myeloma, namely plasma cell leukemia. So what else do we know about it? Well, multiple myeloma, as I say is a clonal plasma cell neoplasm. It produces a monoclonal antibody and it's twice as common in terms of epidemiology in populations of African descent. All patients have a preexisting monoclonal gammopathy and the way I kind of sometimes explain this is that the monoclonal gammopathy is a little bit like having an abnormal cervico smear. Many people can have an abnormal cervical smear but do not all go on to get cervical cancer. But all people who have cervical cancer will at some point have had an abnormal cervical smear. And as I said, in most cases, this disease is only found in the bone marrow. So more facts about multiple myeloma which are uh make it a difficult disease. Sometimes for us when we are meeting patients for the first time is there are a lot of delays in the diagnosis of multiple myeloma. And for the reasons that I stated before, they often present with very nonspecific symptoms. The commonest sy symptoms can be fatigue, back pain, general malaise uh and obviously GPS see lots of patients with back pain, lots of patients with general malaise, lots of patients with fatigue and there are no characteristic symptoms of multiple myeloma that makes the disease easy to spot. So for multiple myeloma patients, they have to make the most visits to a GP from the first symptoms to getting a diagnosis. And of all the cancers, multiple myeloma patients have to wait the longest time from first symptoms to a diagnosis. And again, for those of you online who may not be going on to be hematologist or even oncologist, multiple myeloma is the cancer that is most likely to present in the emergency room as a medical emergency. The good side of this is that multiple myeloma is the cancer with the most rapidly improving prognosis of all cancers over the last 10 years. So that's a little bit of an introduction. Here's just a few more details. There's around about 6000 new cases of myeloma annually. It forms 2% of all new cancer cases. Around 3000 patients die from multiple myeloma each year. And the peak rate is about 75 to 80 years, but it can occur at any age. And I've certainly seen 18 year olds and 21 year olds present with multiple myeloma. And as you see there, the 10 year survival rate has improved from 5% in the seventies to 33% about five or six years ago. So dramatic improvements in outcome, but still a lot of work to be done. This is the age distribution uh by age and sex, uh red male or orange color female. And you can see the peak incidence is around about 60 to 70 but with the most common in terms of percentages in the seventies and early eighties. So it is a disease of the older patient and it is slightly more common in males than female. We don't know the causes. I've mentioned the uh the impact of of racial origins on the epidemiology but otherwise causes remain uncertain. It probably may have some in relationship to radiation agriculture. It is more common in farmers, people who work in the petrochemical or metal industry. Or fuel industry. And it is more common in families where another family member has MGUS or multiple myeloma. So there is a familial or genetic factor. Although the, although the familial and genetic factor in multiple myeloma is relatively weak, it's not a strong factor uh for causation but it is there. So as I said, it's a neoplastic proliferation of bone marrow plasma cells. So it presents and it's actually easy to detect. And and so one of the frustrations is that although the symptoms are very nonspecific, the diagnostic test is very simple. It's a, it's a measuring the immunoglobulin levels in the serum or in the urine. And almost inevitably in multiple myeloma. In 99% of cases, you will find a paraprotein in the blood or the urine. So the actual test to give you the hint that the disease is there is incredibly simple. So one of the things that we try and encourage people to do is even if they multiple myeloma passes through your head as a vague differential diagnosis and just do the test because uh it can easily be missed. It presents with these proteins in the serum and urine. But more importantly, one of the things that multiple myeloma it does is it loves to live in the bone marrow. And as it sits in the bone marrow, it gradually destroys the bone structure around it and causes what we call lytic bone lesions. And we'll see some of those in a moment. And obviously, the characteristic final diagnostic test is to do a bone marrow. And on the bone marrow, you will see an excess of plasma cell. So these are plasma cells, they proliferate, they secrete immunoglobulins. And as I've said, they influence bone turnover and we're gonna come back to that. But basically multiple myeloma will cause osteoporosis, will cause lytic lesions and fractures. Uh And that is part of the symptomatology and the difficulty these patients have. So, just a brief reminder, I'm sure you don't need this. But this is an immunoglobulin molecule. You'll know that an immunoglobulin molecule has two heavy chains and two light chains. And the two ends of the Y are the variable regions that bind the antigen. And the FC tail is the signal to the rest of the immune system to coma and kill whatever the variable regions are targeting. Now, in multiple myeloma, because it's a tumor cell, the aerators for putting together immunoglobulin molecules isn't perfect. So, one of the important things that you have to think about multiple myeloma is that actually, although the tumor produces full immunoglobulin molecules, it is a poor manufacturer if you like. So, a normal plasma cell will produce intact immunoglobulin in large numbers. But a malignant plasma cell will often produce intact immunoglobulins w but will produce vast excesses of the light chain. So if you go back the light chains of these things, and if we go forward. You'll see here, this cartoon of a plasma cell shows it producing an excess of these light chains which see uh are excreted into the bloodstream. And you can measure both the full immunoglobulin protein and the light chains from blood tests. So I thought we would just before we go on to multiple myeloma talk about making sense of blood results. So let's say you've sent off a, a blood result to the laboratory. Uh and you've got a paraprotein result coming back. And I'm just gonna talk a little bit about how you might interpret this because not all paraproteins are multiple myeloma. So, first of all, the most common condition that is related to multiple myeloma is this condition called monoclonal gammopathy of uncertain significance. What does that mean? Well, it means patients have a paraprotein but they don't have multiple myeloma. And the uncertain significance is you do not know if that paraprotein heralds, a patient going to have multiple myeloma or not. And MGUS uh is defined as people who have low levels of plasmas cell in their bone marrow. The paraprotein levels are very low and they have no evidence of myeloma related damage and they have no symptoms. So this is monoclonal gammopathy of uncertain significance. They have a paraprotein but it's low. They may have plasma cells in the bone marrow, but they're not common and they have no evidence of myeloma related to damage. And just to show you how common MGUS is, this is a a age incidence from a population study. Uh that shows you that by the time you get to 73% of women and 5% of men will have MGUS. By the time you get to the age of you doing blood tests, 5% of women and 7% of men have a paraprotein. So these paraproteins are actually incredibly common. And as our population ages, we find more and more patients with MGA. So we have to work out which are patients who are going to go on and get myeloma and which are patients. We do not want to worry and we can leave well alone. So we do a number of tests just to show just to try and assess the risk. You don't need to know all of the details of this. But basically, if you have a low level of a band, it's an IgG MGUS and the light chain levels in the blood are very low then and this is most patients, then the chances of them getting multiple myeloma over the next 20 years is 5% or one in 20. And the chances of the patient dying of multiple myeloma in the next 20 years is one in 50. But if we then look at patients who got higher risk, these are patients who've got a bigger level of paraprotein in the blood, they've got more light chains in their blood and they've got IGA mgus, then you can see these patients have a 60% chance of going on to get multiple myeloma and a 25% chance of dying of this disease. So when we as hematologist come across a paraprotein, we want to know what level it is, what type it is and how much light chains there are in the blood. If the patient is low risk, we never see these patients again. Um And they probably will get annual blood tests with their general practitioner. However, as hematologist, if they have two or three risk factors for disease progression, we will hold on to these patients and monitor them because they have a significant risk of going on to get multiple myeloma and dying from multiple myeloma. And this just brings me on to uh the fact that all patients who have multiple myeloma will have had MGUS detectable prior to the diagnosis. Uh And this brings about some discussion about whether we should have a, a national screening study for multiple myeloma, particularly given how difficult it is to diagnose. And you'll see this was AAA study done by the US army where they basically bled 70,000 troops for many, many years. And when they found patients, uh the some of these troops went on to get multiple myeloma, they went back to look at their blood tests and you can see they could find MGUS detectable for up to eight years before they got their multiple myeloma. So we know all myeloma patients evolve from an MGUS state. Now, I'm not gonna go on about the genetics of the disease because that is, is can be regarded as quite complex. But actually, we know a lot about the genetics of multiple myeloma and it is a truism of all cancer care. Now that the genetics of the tumor, which obviously differ from the genetics of the normal cell. But the genetics of the tumor give us really important clues about prognosis. They give us really important clues about potential treatments and they also show us how tumors can develop. So we know it's multiple myeloma. There are a number of primary genetic abnormalities within the genetics of the tumor cells, usually involving a tumor promoter gene and a uh immunoglobulin molecule. So you'll see the 14 uh t 14. So 11, 14, 4, 14, 16, 14, 16, 14, 2014, these are all where tumor promoter genes are put against the promoters for immunoglobulin production. And this is what drives the initial tumors. But then as the tumors develop, they become more complicated with increasing numbers of genetic abnormalities and these increasing genetic abnormalities, fuel and more aggressive tumor phenotype as the patient goes through their treatments. Um And for those of you who want to be hematologists, um this is something that is endlessly fascinating. And as I say, one of the great developments in all oncology, but particularly in hematology is understanding the genetics of a disease has massively increased our ability to successfully treat this disease. And I've seen a question from Doctor Aie, who's uh, who's listening, who's asked about, will it be detected on the gallery test? And yes, we have had some patients come through uh to our new patient clinic where their myeloma has been detected on the gallery trial. Also. What sometimes confuses us is that some patients can have the tumor i multiple myeloma, but the tumor is sitting in the patient's bone marrow but not causing any problems or damage. And this is called asymptomatic multiple myeloma. And actually, this is a benign form of the disease and this actual form of multiple myeloma can be watched without needing treatment. So we do have some patients and it's quite difficult sometimes to explain to them. But we do have some patients where we say, well, we've diagnosed multiple myeloma in you, but we can find no evidence, it's causing any problems. And for these patients watching and waiting is actually a very reasonable treatment option. Although it's difficult sometimes for a patient to get the head round that concept. Um And we've had patients who've lived with multiple myeloma without treatment for 568, 10 years and longer. And the disease has never evolved into a more aggressive form of the disease. So, one of the interesting things about multiple myeloma is it can behave in a relatively benign fashion. That's not the case for most patients. But there is a small subgroup of about 10% of patients where myeloma itself behaves in a very benign fashion to be diagnosing multiple myeloma. You have to have more than 10% plasma cells in the bone marrow and, and or the paraprotein level has to be above 30 g. Or you're producing a lot of light chains which are appearing in the urine. But importantly, these patients don't have any evidence of bone damage, any anemia or crab criteria, which I'll come back to in a moment on myeloma defining event. And these patients can be watched. This graft just shows the probability of MGUS patients presenting over 20 years to multiple myeloma and the possibility of myeloma smoldering myeloma or asymptomatic myeloma progressing to active disease over 20 years as well. And you can see we diagnose smoldering myeloma. 50% of patients will need treatment within the next five years. But that means that 50% of patients won't need treatment over the next five years. If you look at 10 years, it will show you that 66% of these smoldering patients have gone on to need treatment. But again, if you look at that the other way, 33% of patients do not or have not had any treatment. And again, it's 15 years, there's still 25% of patients who remain untreated. So again, it's a truism of oncology, but particularly for multiple myeloma that you can isolate patients who do not require therapy and clearly the best and safest treatment is no treatment at all. So this just sums it up. But so multiple myeloma itself often can present with high calcium. We're gonna come back to that in a moment, renal problems, which we're going to come back to anemia because the patients, uh bone marrow is not functioning properly. So they often have a very low hemoglobin at presentation uh and bone disease, which we're going to come back to as well. The other frequent abnormality with multiple myeloma patients is although they produce lots of paraprotein, the immunoglobulin that the tumor produces is functionally useless but suppresses the immune system in a way that makes these patients very open to infection. And you have to think of these patients as being fairly significantly immunosuppressed. Ok. So let's talk about symptomatic myeloma. What do patients with multiple myeloma present with? Well, they can certainly present as me medical emergencies. I'm just going to talk about the medical emergency present with, they can present with acute renal failure. They can present with high calciums and hypercalcemia. And I'm sure some of you have dealt with patients with high calcium, they can be very difficult patients to deal with until the calcium is corrected. They can very importantly present with spinal cord compression and actually multiple myeloma is the commonest cause of malignant spinal cord compression. And they can present to orthopedics with pathological fractures So the important thing about these medical emergencies is that if you treat the patients promptly, if the emergency is recognized very quickly, then actually these problems can be reversed. And particularly the renal failure is a huge emergency. And if you treat it promptly, you can make the difference between someone with myeloma living a fairly normal life, albeit on treatment and someone with multiple myeloma facing treatment and being on dialysis. So there is uh a very important important lesson around treating patients with multiple myeloma who present with renal failure as an absolute emergency. And we would almost start their treatment on the day. The diagnosis was suspected. Now, why do myeloma patients get renal failure? Well, it's quite uh a lot to do with this excess of light chains that are produced. And I'm just gonna go back to just reminding you that these light chains are very toxic to the kidney. Why are they toxic to the kidney? Now, you never thought tonight you'd be getting a picture of a glomerulus in an oncology talk. But here's the glomerulus. And you can see that although proteins don't get filtered out into the urine, and we know that the glomerulus is very good at making sure we don't lose protein into the urine. The light chains that myeloma produces are so small that they escape through the pores of the glomerulus into the urine and the collecting ducts. And if we look further, you'll see that you get lots of light chains going into the urine, they go down through the proximal convoluted tubule into the distal tube into the loop of Henle. And this is where urine is concentrated and water is extracted. Now, if you have a lot of protein in a water solution, and you gradually take the water out. What happens is the protein solution becomes a gel and the gel absolutely bungs up the nephron. And each time that happens, the patient loses a nephron. And the end result of that is you get these casts forming in the kidneys. And once they form, there is an inflammatory condition that set up against the cast and the kidney is gradually destroyed. So all of the problems are because if a patient has very high levels of light chains, that means high levels of protein are delivered to the kidney, the kidney isn't used to dealing with lots of protein. And if the urine needs to be concentrated, you get gel forming and you lose nephrons very quickly. This can be exacerbated by hypercalcemia. We're gonna come back to multiple myeloma being a destroyer of bones and it produces very high calcium levels. In some patients. It can be made worse by dehydration. So often the first treatment we give these patients is very high fluid loads that dilutes the light chains in the urine and stops them forming the gels. We have to stop nephrotoxic drugs, particularly nonsteroidals. Often patients with myeloma are on nonsteroidals because they present with bone pain. We have to treat any infection, particularly urinary tract infection. And we have to be watching out for gout as you will all know that many malignancies, particularly hematological malignancies can be associated with very high urate levels and the potential to get gout. So we treat as an emergency. High levels of fluid are very important. You have to bring down the ca calcium, avoid the minor glycosides, ace inhibitors and nonsteroidals monitor for infection. Keep the calcium coming down with bisphosphonates. Watch the urate and check for amyloidosis. Now, I just wanted to mention briefly about amyloidosis. Again, it's a subject that is much beloved of medical exams. It is more common than you might imagine. And you have to think of amyloidosis in patients who might have macroglossia, cardiomyopathy, nephrotic syndrome, or kidney disease, malabsorption and also neuropathy and amyloidosis is most commonly associated with paraproteins. And it's the A L A form of amyloidosis. So, in our myeloma clinics, we always will deal with amyloidosis patient as well because it is treated in the same way as multiple myeloma if it is A L amyloidosis. So for amyloidosis, if you've got un unexplained nephrotic syndrome, unexplained neuropathy, macroglossia or congestive cardiac failure with an abnormal echo and no other cause, think of amyloidosis. And if you think of it, then you need to arrange a biopsy and the biopsy is very distinctive. So that is a little bit about multiple myeloma and renal failure. And I would say that now one would regard a multiple myeloma patient ending up in m on dialysis as a failure somewhere along the line of medical management. And certainly we would be very upset if we got a multiple myeloma patient, even one presenting with very significant renal impairment if that patient didn't escape dialysis. So the other medical emergency, myeloma can present with is the consequences of bone problems. So, hypercalcemia, you you know the symptoms of hypercalcemia. So myeloma presents, patients can present with hypercalcemia, confusion, abdominal pain, dehydration, vomiting, they can be very poorly and very difficult to deal with cause they're often incredibly confused and it's very important to bring down the calcium very quickly. And obviously, the bone disease can cause fractures and importantly, spinal cord compression. The key thing with spinal cord compression for any budding oncologist and indeed any physician is that spinal cord compression. If you ever think of it, you must make sure the patient gets an MRI scan that day and as quickly as possible, you should never let the sun set on a patient where they might have spinal cord compression without getting an MRI and preventing further cord compression. So, myeloma bone disease, myeloma loves to live in bone. It only lives in bone really. And you know, these are old x-rays just showing how the bone gets thinned. And this is a patient who eventually uh fractured their femur. And you can see how the bone is whittled away within this femur. And here's a skull which deposits a multiple myeloma. And you can see how the bone has dissolved around the tumor. And just to show that a little bit more graphically, here is the x-ray of the pelvis of the patient of ours. Uh And all the patients who've shown these x-rays have given us permission. This is a normal pelvis and this is the pelvis. And once you get your eye, and you can see that the ossification of this side of the pelvis is much reduced compared to this side. And if you then do further imaging with the CT scan, you can see that this patient has a huge tumor which is a myeloma tumor in that wing of the pelvis. And you can see the tumor is infiltrated through the acetabulum into the left hip joint. So you can really get a feel from these pictures of the level of bone destruction that goes on with the patient with multiple myeloma that can lead to fractures and particularly vertebral fractures. We've got better at imaging this disease. So here's a plasmacytoma coming out of the rib cage, there's a tumor coming uh out of the vertebral area. Occasionally you can get disease within the brain and very, very rarely the disease emerges out of the bone marrow into the, the liver. But then you can see some great hot spots of uh bone disease on this pet CT scan. Why do we get this situation? Well, there is a, a very important mismatch. So normally our bone uh our bones are very, very active tissue. Uh And it is it like a a kind of mad diy uh person who is constantly knocking down walls and rebuilding them to make them stronger. And our bone is very active. It's been set out, we replace our skeleton every 3 to 5 years, which gives you a sense of how active bone normally is. And normally there are two sets of cells, the osteoclasts destroy the bone and then the osteoblasts come and remineralize the bone and make it stronger. So, in multiple myeloma, the tumor produces osteoclast, activating sets uh proteins which basically make the osteoclasts go into hyperdrive and they destroy lots and lots of bone. And on the other hand, they produce sedatives for the osteoblasts. So, instead of the osteoblasts and osteoclasts working in perfect harmony, you get the osteoblasts, uh the osteoclasts working really, really hard and destroying the bone, but the osteoblasts go to sleep and this allows the bone around the tumor to be destroyed. And this is probably part of the interaction between myeloma and the bone, which makes the bone area a very nice place for multiple myeloma to live and survive. Uh So these are the osteoclast activating factors. TNF beta il one il six. So that produces the hypercalcemia and all of the bone problems. And we can this again, this just shows you the sort of symptoms that multiple myeloma presents with. So 70% of them will have anemia. I mentioned that they're immunosuppressed. They have a massive increased risk of infection. 20% of them present with CK KD. Five renal failure. 40% CK KD four bone disease, lytic lesions are found in 80 to 90% of patients with 80% of patients having bone pain, 50 to 60% of patients presenting with fractures and around 15% presenting with high calcium levels. So you really get the feeling. Where is the myeloma patient gonna present with the fatigue anemia, infection, renal impairment and the consequences of bone destruction. How do we treat the bone disease? Well, in the first instance, hypercalcemia, we treat you with IV fluids, steroids and bisphosphonates. But bisphosphonates were then shown to actually improve the patient's bone pain and used long term, improve the patient's quality of life. And if we look at some, just some graphs showing that zoledronate, the most powerful bisphosphonate massively reduces the amount of bone disease that myeloma patients get. And now with modern therapy, although we can't reverse the bone disease, that's often happened before presentation with active treatment and with an active bisphosphonate regime, we can prevent further bone disease from happening. Uh And this just shows if you've got bone disease at presentation, you, you can stop it from happening with alendronate and most importantly, if you get a patient without much bone disease, you can see that they are not gonna have bone problems in the future. So again, a common theme, if myeloma was diagnosed earlier, the patients are less likely to have renal impairment, less likely to have hypercalcemia, they would have healthier bones, uh and they could even have an even better quality of life and and enjoy the ongoing benefits of the improvements in treatment. And just for a final few minutes, just to talk about how this improvement is going. So this is, this is survival causes from multiple myeloma from 1960 through to 2010. And you can see that there was very little improvement through to about 1995. And then we started to get some new and more effective therapies. And you can see that the improvement in overall survival is dramatically improving. Although there's still patients dying early and we haven't yet reached a plateau which suggests we're curing any of these patients. This is uh stats from England and Wales just looking at that uh five year survival rate, 11% in the seventies, maybe 15% in the eighties, 20% in the nineties up to 25% in the two thousands, 2005, you're up to 33% and now 47% 5 year survival, 33% 10 year survival. So dramatic improvement in prognosis. And that's just shown a different way here with the one year survival rate, the five year survival rate and the 10 year survival rate. And you can just get a sense of how tough things were back in the seventies when only 37% of patients survived one year and only 10% survived five years. Whereas in 2010 76% were surviving first year, 47% and 32%. So, a dramatic improvement. One of the reasons we haven't seen better improvements is that the most of the improvements we've seen are in our younger and fitter patients and people in all walks of oncology will tell you that actually the the hardest group of patients to treat are the older and frailer patients where they often bring frailty under the comorbidities which make it difficult for them to benefit with the from the treatments that really helped the younger fitter patients. And again, this is just data from the uh cancer Research UK showing the five year survival for uh younger patients, five year survival for 50 to 60 patients, five year survival for six year olds. And look at the difference once you get to over seventies and over eighties. So we still haven't made a huge or major impact in older patients, which is something we're working hard to change. It's a disease that goes through a number of periods of relapse and remission. We don't cure it eventually, it does become a refractory disease, but we definitely can offer 1st, 2nd, 3rd, 4th and 5th lines of therapy. So we are trying to make it a chronic disease, if not a curable disease. I've hi hinted at this. There are many ways in which we can assess prognosis. All of these factors can herald very poor prognosis. A high PT two micro, a low albumin adverse cyto genetics. L DH age peripheral blood plasma cells, frailty and extra medullary disease. All herald patients who might do very, very badly and we can put these together into risk groups. I'm not going to go into all of the details of this. But needless to say we can isolate patients who are gonna do well in blue and patients who are not gonna do so well in gray and sometimes we can treat these patients more aggressively. But also this will color some of the conversations that we have with some of our patients uh in terms of their prognosis. And also the final factor that defines risk is that if they are resistant to some of the chemotherapies that we have, uh then they also do very, very badly. So I'm going to stop there. Um I hope I've helped you understand myeloma a little bit better. I think the two key take home messages are there has been dramatic improvements in outcome, but importantly, multiple myeloma is not seen universally just by hematologists, it can easily present as a medical emergency, hypercalcemia or renal failure or as amyloidosis to cardiologists or as a fracture to orthopedic surgeons. And it can present as an oncology emergency with spinal cord compression. So it is one disease to think about. Even if you're not going to go into hematology as a career. Now I'll stop there. I see there are a couple of questions just coming through, so I'll acknowledge them whilst I'm finishing talking. So, for Doctor Roy, what is Walden Stones, macroglobulinemia? This is a type of lymphoma. It is not the same as multiple myeloma and it is treated as a lymphoma. What marks it out as being similar is that it produces a paraprotein, but in this case, it's an itm paraprotein. So an itm paraprotein usually goes with Waldenstrom, which is a type of lymphoma and is not myeloma and take taking Doctor Addie's question about is denosumab safer than bisphosphonates in patients with nephropathy, potentially. Yes. And denosumab is something we will use uh in patients with very severe renal impairment if we can't use bisphosphonates safely and with that, I will stop. Thank you. Thank you so much, Prof Jackson. I'm sure you'll all agree. That was a very clear and um helpful talk to listen to. Um I'm gonna drop the feedback link in the chat. Now, if everyone could give feedback, you'll get a certificate as well for attending. Um I know you have to be off track and so thank you very much for your time this evening. Well, um Miranda, I say two things. Firstly, um, if anyone wants a PDF of the slides that they find helpful for their personal use, I'm very happy for you to share them if I email them to you. And I would also be very happy if people wanted to ask questions via my NHS email address. If they wanted to with that, I'll say good night. And thank you very much for listening. I hope you all have a safe journey home if you're not at home or a wonderful ongoing evening. Thank you. Thank you very much. Bye.