 Vsrednji prezident NPE je zelo veliko prav, da imam hongerijskih hematologi, tako, da je to druga razdaj v istoriji NPE, mjesta, klasi, ki sem več prav. As a member of AGM program committee, I had the possibility to recommend a lecturer, and I recommended Dr. Otto Czočovski immediately. Dr. Czočovski is the hematologist of the Saint Laszlo Hospital in Budapest, which is the most excellent hematology and transplant center in Hungary. He is the representative of a new generation who understands exactly why patient education is so important. He had lectures to patients several times with great success, and now he will be talking about a difficult topic about the myeloma related diseases. After the lecture, you can ask questions, so please welcome Dr. Otto Czočovski from Hungary. Otto, the floor is yours. Hi, very thank you, the invitation in this congress. I have a very, very hard topic, the myeloma associated disease, so it's very strange and very rare in a hematology. Many times we have a very big problem, how to diagnose this disease and how to realize that the symptoms cause this rare disease. First time I would like to show my clinic. I'm working at South West, the South West Central Hospital. This is the national institute of hematology and infectology. It's a very old and traditional hospital. It was built in 1896, but the hematology department and the transplantation is a new one building. I would like to share some information about our clinical practice. We have a single myeloma department with 20 beds. All clinics have 120 beds. 10 autologu stem cell transplantation box, approximately 140 autologu transplantation per year. 80 myeloma transplantation per year, so we are the biggest center in Hungary. Approximately we take care of myeloma patients 250, and approximately we have 70 newly diagnosed myeloma patients a year. My topic is very hard for me, because all doctors who work in general practice can't realize the symptoms, the in-connection, the symptoms and the diagnosis. I would like to share the most favorable myeloma society disease, like MGAS, the solitaire plasma cytoma, the volentium maculoglobulinemia, the plasma cell leukemias, the amyloidosis and my favorite, the other rare disease. This is the we geoclassification of the plasma cell discrazor, have lots of diagnosis and lots of things. And I would like to share one slide from the other clinical complication, which associated with myeloma, but not a single diagnosis. The pathological vertebral compression, the high-level calcium, acute renal failure, several anemia and bone pain, but it's not a topic in my presentation. I plan my presentation that every, before every diagnosis, I would like to share patient, our clinic, one cases. And after it we discussed what is the most important information about the disease, what's the prognosis, what's the incidence, what's the pathological things and what's the symptoms. So, the first one, 62 years old woman. She was asymptomatic. She went to the house doctor, to the average blood test, which was normal, but the ESR, the erythrocytes sedimentary rate, more than 100. The immunological and rheumatical examination was negative, so she didn't suffer any problems, haven't got any symptoms, only the high ESR rate. What's the next examination step? It's every thinking in mind in Hungary that the hematology saw everything. So, when stop some doctor's minding, take the patient to our clinic. We made the bone marrow aspiration, which shown less than 5% plasma cells. We made the total body x-ray, which was negative, and the immunochemistry shown a monoclonal gamma party IgG kappa. Diagnosis was M gas, the monoclonal gamma party undetermined significance. What can the doctor do in this situation? Nothing special. We every two months have to check the symptoms and the immune profile, the IgG, IgA, IgM and the monoclonal antibodies. And if the doctor noticed some new symptoms or progress in an immune profile or appear enemy or any other symptoms of myeloma, we decided how to retreat this one. So, this is the situation when we have to start the anti myeloma therapy. What is the M gas? M gas is not exactly the malignant disease. This is the pre-malignant condition. The incidence, 3 between 4 per 100 person a year. Prevalence, you can check that increase by the year and increase, for example, in less than 50 age, less than 3 person, but in 85 age, it's more than 6 person. The median age is 72 years. Patemaharis is very complicated. The mechanism is anti against stimulation. It's very same in myeloma. So, the autoimmune disease, the chronic inflammatory and the other chronic inflammation made the plasma cell tunings and it's appear like a high gamma party. But, 90% have a genetic instability. This picture, but it's IgM, so it's a validation, but you can see that normal B cell metering in a lymph node and after it went to the blood. But, the M gas with the stimulation and IgM, and the water-shrom macroglobenemia is a problem in a maturing period of the plasma cells. The progression rate to other lymph operatives, this phase is very same. So, when we diagnose the M gas, we can decide in the future that how to progress. So, any other plasma cell disease can progress the M gas. What is the symptoms? Average asymptomatic. No abnormal physical findings. How to diagnose? It's same in myeloma. So, the blood sample, the immune chemistry and the bone marrow aspiration show that how many plasma cells are in the bone marrow. In a regio, the classification shows that less than 5% plasma cells have to in the bone marrow. Urine electrophoresis and the protein urea, the protein in the urine we can measure, and the total about the radiotherapy, radiology, the x-ray, the other things. So, how we treat? No treatment. Clinical and laboratory revelation every six months. In our hospital in our country is not six months, it's three months when we check the patient's blood chemistry. The second one case. 46-year-old businessman. Every second day after the work went to the gym. He was very, very good condition. But one day after approximately 60 kilogram weight lifting, felt destructive pain in his back. He went to the emergency room in a hospital and made the CT from the lumbar area, which saw the solider tissue, which compressed the spine and made the pathological compression in vertebra. What the doctor do? The first one, the pathological examination, the histological sampling. And the immunoglobulin level measuring, which was normal, and immunofixation was negative, so it's not a myeloma. The bone marrow was normal, too. The histological examination show this is a solider, extremidular plasma cytoma. In the image you can see in this area, the plasma cytoma, which compressed vertebra. And it's very important thing, but we discussed the other side, that the solider plasma cytoma is a solider, not a systemic. So we can find only one region in a body. And if we find any things in a blood, for example, the high level immunoglobulin and so on, it's not a solider plasma cytoma, it was the myeloma with a plasma cytoma. So how we treat antikompression therapy, we made dexamethasone, and after a local radiotherapy, it's enough anytime. So the solider plasma cytoma have two types, the bone-associated and the extremidular. The last slide showed the bone-associated type, which can move from vertebra. But in this picture, it's a sinusoidal region in a head. This is an extremidular, not a bone type. Solider area of leetic bone destruction due to plasma cells in the otherwise asymptomatic patient. Generally, no serum and urine paraproteins, so it's not a systemic, I repeat again. No myeloma-related organ tissue impartments, so note, not renal failure, not the hippocasemia, no, anemia, only the abnormal tissue in the other region in the body. What are the symptoms, the compression symptoms? The patient feel very big pain, for example, when grow up the tumor in the vertebra region or near the neurological side, and the neurological too, so it's very... If you found the plasma cytoma somewhere in the body, we have to treat it urgently for the neurological symptoms. So how we treat it? The fractionized radiotherapy, it's enough. 75% progress to myeloma conventional chemotherapy. So it's a big problem. And I shared two sub-types, the medular and exo-medular. The survival, it's very, very good. The median survival, for example, the medular type, more than 10 years, with the local radiotherapy and a salvage dexametazone. The astromedular type, it's very, very rare, but the survival is better. More than 70% in between 14 years. And it's very special because it occurs in the head and the neck region, upper areas and the tonsil and in the sinusoidal region. The other disease and other cases, which one? Yes. 52-year-old woman. The symptoms start two months ago. Typical back pain, fatigue, anemii, exchange of the bone lesion in a skull, the cost and pelvic region. So it's a general doctor's first thing that it's myeloma. Chemistry confirmed monocloma in our gamma party. It's a very, very simple diagnosis in myeloma. But we check the blood count. And the blood count shows that the total white blood cells, more than 55. So what is the diagnosis? So it's not a simple, like a leochemiac blood count. We made a special examination, the flow cytometry, and this is shown circulating plasma cell in her blood. It's a very, very big problem, because the diagnosis was primar-plasma cell leochemia. The primar-plasma cell leochemia is very, very rare. In my practice in the last six years, I found two cases, I think, the primer one. And it's a very, very bad prognosis. Have two types, the primer and the second one. The primer is the first diagnosed when we detect the plasma cell in the blood. The second one is myeloma, which progressed to the plasma cell leochemia. We found it after the autologous transplant relapsed. Myelomas, so it's absolutely the end-stage myelomas, can progress to the plasma cell leochemia. It's a very, very bad progression. High-grade malignancy can measure the plasma cell in her blood. This is the typical... And the genetic examination is important because this myeloma type and this plasma cell leochemias have a high-grade genetics disorders. What is the therapy? It's a very aggressive chemotherapy. Urgently, we have to start the chemotherapy with anthracicline, well-kid, dexamethasone, and so on. And the endpoint of the therapy, the autologous bone marrow transplantation in the first remission, if we can make the patient to the remission. Other cases, 67-year-old men, no comorbidity. The ESR-100. The symptoms is fatigued anemia. In the last three months, 20 kilogram weight loss and lymphodenomegali. The neurological analysis shown the polyneuropathy on the low extremity. So it's... The diagnosis may be myeloma, but the lymphodenomegali is rare in this situation. The blood has shown the very low hemoglobin and the very high plasma protein. And the immune chemists show the EGM, which was very, very high, and the EGM copper is very high, too. The beta-2 microglobin is high, too. So we made the bone marrow biopsy, which shown the plasma cells, the plasma cells like cells, the lymphoplasma cells, which is confirmed, diagnosed, that the Vardantium macroglobulinemia. What can the doctor do in this situation? The first one is a plasmatheresis. You know the very, very high complication of the Vardantium macroglobulinemia that the plasma cells product the very high EGM. The EGM causes the hyperviscosity and any other symptoms, this and so on. So the first time, when we start the chemotherapy, we have to make the plasmatheresis. And the combination therapy, you know the Vardantium is very, very different from the myeloma. The myeloma cells, the plasma cells, which can appear in a bone marrow, it's stopped in a maturing procedure after the B cell. The plasma cell is the last step before the maturing plasma cells. So after four-psychotherapy, the control bone marrow biopsy confirmed a complex remission, the next step was the stem cell collection and the successful autologous bone marrow transplantation. It's a very rare disease. The incidence is less than one per 100 person. The median age is 63, between 68 age. The generally cause, we unknown, is the main risk factor for VM, the pre-exist EGM-M gas. So when we detect the EGM-M gas sensation, we have to plan the mind in our head that it will be progressed to the EGM-M gas to the Vardantium macroglobulinemia. Prognosis, the median time to progress to asymptomatic approximately seven years. We take care of approximately 40 mile valenšom patient in our clinic and approximately 22 who haven't got any asymptomatic. In this situation you have to watching and waiting, not the therapy. The median survival five years, 10% alive approximately 10 years. 20% dead unrelated cause and 33% died in any other infection. What is the patomehanism? The somatic hypermutilation, so the genetics factors and the genetic profile, it's very important in this disease too. The last step to differentation to maturing plasma cells, very high EGM production, crealglobulinemia is a side effect and the side things which appear in valenšom macroglobulinemia and hyperviscosity syndrome, the disne fatigue and limb discoloration. The symptoms is very average. Recurrent infection, because you know the plasma cells which can produce normally the immunoglobulin for the bacterial infection. It's not normal in diseases. So the infection rate is very high because the patient suffers from the immunoparesis. Bleeding nose, disnoe, breathing lose, neuropati syndroms are very common in valenšom macroglobulinemia, the neurological disorders, the headache, the dizziness, the visual upset and the impotency. Hemorrhegic disorders, thrombosis and bleeding it's very average too. Autoimmune disorders, the utekaria, the fever and rush. I have two picture which is very typical. The upper one, it's like a reino syndrome, like a autoimmune disease, the discoloration of the hand. The cause, the circulation, IgM and circulation, creoglobulin, which can stop the normal blood circulation in the head. Sometimes we found the white fingers like gangrena. Then the other one in the leg is a typical bleeding disorders. How we diagnose, it's very same, the other plasma cell disease, the blood sample, the parapatase levels, the urine examination, immunoglobulin levels and alpha. So it's very same to the myeloma. The bone marrow biopsy, it's very important because the typical Valdemstr cells appearing only in a bone marrow. The plasma cell viscosity is a very, very big problem. The first symptoms, which appear in a patient, the plasma cell high viscosity. And the beta 2 microglobulin level it's very, very important because the Vigio prognostic score have the beta 2 microglobulin level. So it's changed the classification when the beta 2 is higher or lower. Treatment, the first one, the plasma pharesis, the symptomatic ones are shown, and the retoxemab, the anti-CD20 antibodies, because it's not a typical plasma cell. This is a plasma cell between the maturing and healthy cells, so it's a lymphoid cell. So product the CD20 antibody in the survey of the cells, which combine the clastical chemotherapy, cyclophysomid, fluidorabin, bandermostin, and steroid. In which patient, who have the ability to transplantation in Hungary, the age stop at 65 years, we have to mind to the autologous bone marrow transplantation in a complete remission. And we have some new agent for the genetics disorder, so in a 21 century the diagnostic procedure is very, very well. And in the last five years we find a lot of typical genetics abnormalities and we have a lot of target therapy. For example, the Ibrutinib. It's very good for this disease. This is a plasma pharesis product in Valdašem. You can see in this area, so this is the monoplonal antibodies, the RGM. It's very important for the symptoms that the high level IGM which cause the symptoms are very changed to the hot and cold. So if the patient went to the winter, for example, in a cold weather, the symptoms are progressed. Case 5. This is... Oh, it's very interesting and it's very, very good things which was in my clinic the last five years. Forty-two years old woman. She was so healthy, but she felt disnoe when she goes up to the second floor, the last two weeks or three weeks. And it was so progressive. So if you went to the road ten meter, you have to stand and sit down because you can't breathe. She went to the cardiac clinic and made the cardiac examination which was... appeared a very severe cardiac failure. Erocardiografi šeoče, da je hodnje, vrste vrste vrste. Vrste, kaj je taj symptoms? Intermedical history, no other comorbidities, no familiar history. Hematologic examination šeoče v normal blood count, but the cup of light changed more than 8,000. The next step, the bone marrow aspiration and the bone marrow biopsy and the histology was the amyloidosis. The heart MR, it's a very good staging procedure before we start chemotherapy in amyloidosis, show the typical amyloidosis in the heart and the septum. What can the doctor do in this situation? The first one, the chemotherapy. Taki, talidomidin, dexamethazin combination. It's very, very good, and this is the new combination about the national literature. We have four psychotherapy and the second one, the heart transplantation, which was successful. After six months, the heart transplantation, the controlled bone marrow biopsy didn't find any amyloid in plasma cell and so on, and we made a successful autologous stem cell transplantation. And now, she worked in her office. The myeloma associated amyloidosis is a complete remission, so we can't find any light change in the plasma cell in the bone marrow and her new heart worked very, very good. So the next topic is amyloidosis. It's a very rare disease. In my practice... I'm sorry. In my practice, I found approximately ten patient who suffered from the amyloidosis. The incidence is one per 100 person. The most cases, between 50 and 70 years, more than 10 person. And it's very important that 15% myeloma develop amyloidosis. But what the pathomehanism is? The amyloidosis has two parts. The isle amyloidosis is a primer. It's a genetic disorders, which appear in a very early year, in a younger patient. The plasma cell product, the fibriela deposit, which involves a lot of organs. But the second one, which is important for us, the myeloma-associated amyloidosis, because the myeloma cells, the plasma cells, product the abnormal immunoglobulins. EGA, EG and EGM, or EGM. But sometimes, product this myeloma plasma cells, the fibriela deposit, the amyloid proteins, which can involve the kidney first, the heart, the liver, in the peripheral nervous system. Without treatment, the amyloid deposit progressively accumulates in the visceral organ, made increasingly several organs dysfunction. What are the symptoms? The renal involvement caused the renal failure. The cardiac symptoms, remember the cases, made the restrictive cardiomyopathy, the right side features and any other cardiac problems and complication. The neurological, the peripheral neuropathy, more than 20%, the painful sensory disorders, the autonomic neuropathy, so the patient suffer from the lower blood pressure and the gastrointestinal involvement disturbed the gastrointestinal motility. And it's very real, but the amyloid deposit can appear in a pulmal involvement and cause any other pulmal disease. Any other complication, the bleeding disorders, it's very common, the vocal cord involvement and dysphonia, it's very rare. The endocrine dysfunction, for example, the diabetes mellitus because the same mechanism because the amyloid involves the pancreax or the thyroid glands and it causes the secondary endocrine dysfunction. And the macroglossia, the tongue enlargement, it's very typical. It's a very, very big problem and the many doctors can't find and can't see the patient who suffer from the amyloidosis. So the first time when we diagnosed and when we found this patient suffer from this several multi-organ dysfunction. How we diagnose, it's very same to myeloma about the symptoms and the histological examination, the blood chemistry, the immunochemisty, the urine examination, the bone marrow biocet, it's very same to other plasma cell disease. But have a special histological examination, the congo red painting in a pathologist made this one in the picture. So the congo red paint only deposit and if we checked in a microscope, this picture, the dianoz, we're sending the dianoz that this is amyloidosis. And I spoke about the primary and secondary and the myeloma associated, it's more than 50% of myeloma. What is the therapy? It's complicated too because the first big problem is the multi-organ failure. So, ok, we know that he or she suffer from the amyloid, but when appear in our clinic suffer from the heart dysfunction, the G dysfunction, the neurological dysfunction. So it is very, very hard. The chemotherapy, the first one, what we can choose, the cyclophasmid, the dexamethasomalphalan, thalidomid valkid, so we can treat the myeloma. And the endpoint of the therapy, the autologous bone marrow transplantation too, for the eligibility patient. Prognosis, it's very bad if the patient not eligibility to the chemotherapy or ASCT, and cause of death, the organ involvement and disorder. So not the primal disease, the complication of the disease because there is a lot of patient. Finally, I would like to show very special and rare disease, which we take care in our hospital. So the case, 61 years old woman. Four symptoms, tumor in a gingiva and acute renal failure. It's very simple for the hematologist and it's a myeloma associated disease. The histology was the plasma cytoma. We made a bone marrow aspiration, which shown the typical plasma cells, but some not typical plasma cells appear in a bone marrow. The question was, what kind of cells were there? We made the immunochemistry, which detect the elevated level of cupolite change of IgG. Immun fixation was positive, so the diagnosis was very simple. It's a multiply myeloma. But after one years, the myeloma that I diagnosed and after the first chemotherapy period appeared a new symptom, the splenomagalli. The question was, which subtype of myeloma caused the splenomagalli, because it's very, very rare. And we know that the plasma cells and the abnormal immunoglobulin, not involved the solider tissue and the spleen too. We revelated the first histological result and we checked that these strange cells, which can appear in a bone marrow, which was not the myeloma cells, was the goshi-like cells. So the diagnosis was the goshi disease associated with myeloma. We measured the glycocelebrosis enzyme level, which was very low. Indication of enzyme replacement therapy was followed by the rapid response. Size of the spleen was dramatic reduce. Although the myeloma was non-responding to chemotherapy, and we have to use the other therapy protocol, after the salvage protocol, we call the stem cells and we made the stem cell transplantation in this patient. So the goshi disease. Incidents in Ashkenazi and Jews in 5000 person and the other population is less than one in one 100,000 person. What the pattern mechanism? This is a very, very rare genetics disease, disorders, which is a special enzyme defect, which breaks down the cell wall in the spleen. In defected, the incomplete metabolic are accumulating the organ, the spleen, bone marrow, and bovas. So this caused the symptoms, the thrombocytopenia, the anemia, the spenomegaly, the bone pain, fat tissue, joint pain. It caused this metabolism accumulation in this organ. Treatment is very simple, enzyme therapy in infusion or tablets. The prognosis is very well, the quality of life improves. OK. It's interesting, but how is connected to the myeloma cells? First one, the most common malignant comorbidity in Goshi disease is a myeloma. More than two percent. Why? In 2017 in January the new announcement was published which studied the mechanism of myeloma genesis. And find a new evidence to the theory, the inflammatory modulation of plasma cells. So this incomplete products, this metabolism involved the bone marrow and the spleen and made the plasma cells and made the immune system to fight in this in this product. And after it in all time fighting caused the genetics disorders and caused the plasma cells plasma cells tumor evaluation. And finally I would like to show my city Budapest, the house of parliament and the city at night near the Danube and thank you for your attention. Lecture We have the chance to ask Dr. Tchačovski We hope that this quite difficult topic has become more understandable. What is your access to new drugs in Hungary? I am very interested what is your access to new drugs in Hungary because I was a little bit afraid when I read that Talidomite is a new agent. Talidomite is not a new agent so I know we used the Talidomite the last 10 years but the guidelines see that the new agent we use because after it we use only the dexameters on the cyclophisomid and the old conventional chemotherapy. So the Talidomite using this Talidomite in this disease is a new, not the agent. Exactly, the Ibručenib is a new agent. I have access to new drugs for myaloma treatment like monoclonal antibodies. Yeah, we use the Dr. Tchačomimab, yes and Isotoximimab so we use everything. And this is reimbursed by the government? Yes. We have a big health system. So the government pay everything for the health system and for the hospital. So exactly the hospital is not in a good condition but the orphan drugs for example in a Gaucher disease it's a very, very expensive treatment too and Ibručenib and Dr. Tchačomimab and so other new agent in myaloma and other hematological disease can pay. So everybody surprised and we surprised when I were in other country and other conference and showed for example the myaloma and how we treat other lymphomas I very surprised that it's very same in our country so it's good. Very good, thank you. But sometimes they have to prepare lots of paper Yeah, and exactly the... Yeah, and it's very I work in a national institute so everything is available for us. But the little centrum is less available for this agent and exactly the studies so the clinical trials which can... we can give this new agent for the patient. So it's very, very good things that we have lots of clinical trials. In introduction you made the distinction between autolog stem cell transplantation and myaloma transplantation and what's the reason of the last one. I don't understand why you mention it apart. Myaloma stem cell transplantation. Not myaloma, the autolog stem cell transplantation in myaloma. So I'm sorry it's not clear for me why you decide these two forms of transplantation. That why? Yes. Between autolog and myaloma. Misunderstanding, yes. Because... So the autolog... So every patient made autolog stem cell transplantation. So in my mind that the patient who before 65 years old we made the induction therapy in myaloma and the endpoint of the therapy the autolog stem cell transplantation in myaloma and this is all. Ok, so... Ok, it's clear. Thank you. My name is Roman, probably I'm the only one who can pronounce your surname correctly. Dr. Čachovski. You distinguish several examples. I will be fit in the second position. But as I know as I wrote read the proverb that each myaloma is separate. I mean, you cannot distinguish even main reasons to distinguish several types of myaloma. And myaloma is plasma ozitoma which behave like singular but I have several singular places. And if you would like to explain how you use the knowledge medicine knowledge to help those cases when you have clean blood clean bone marrow but several singular places. So what scheme do you apply in that moments? Difficult, yeah. Do you know what I mean? You can find several patients which you can distinguish like cars, CUV, limuzine and so on. But sometimes myaloma is a mixture of all. So it's difficult. I haven't got any chemistry medicine. I had only x-rays in pelvis and spine and I have still bone clean, bone marrow clean and blood clean. With plasma ozitoma after it. And you get the chemotherapy or only x-rays. Only radiotherapy. And when were the disease? When were the plasma ozitoma? In the spine. In the spine and pelvis. Six places. Six points. But no chemotherapy. No chemotherapy. I think it's very different doctor to doctor how you treat this one. So my professor use only the x-ray if have a solitor therapy. You know that it's very, very good imaging the PET city which can show the plasma ozitoma. It's a local disease only the pelvis or only other side. And in our doctor's mind that if the multiplex plasma ozitoma appear in a body but haven't got evaluated or increase immunoglobulin we use chemotherapy. The combination chemotherapy in this situation. We use only x-ray and dexametazone if have only one solitor things. Not the general. It's the same in my country. We will use chemo in your case. Because it's six places where plasma ozitoma is cured. So we will determine that like a pre-stage of mutiband myeloma. So we will go for chemo and for auto. So it's absolutely the progressive disease. So in my mind that if the patient have only one single disease in a spine for example I think it's enough the x-ray. But the many area of the body appear the plasma ozitoma we have to use the chemotherapy because in the future two years, three years it will be progress. Six years ago. This is great thing because we must consider tailor-made approach. Every patient is a unique one. So in your case that shows that ozitoma was unnecessary at this stage but in other the progression is very rapid. So it's very difficult because you are deciding when you are doing cohort studies so you are taking a lot of patients so you are deciding what is the best case scenario for all. But in your case that's not the situation. So the plasma ozitoma is very strange disease I think. Yes the protocol said that enough the x-ray and enough dexamethasom for example, first time. But in my practice it's very, very, very able. So I have a patient who suffer from the myeloma after the bone marrow transplantation the ologenic transplantation autologous after ologenic because he was very, very young. The relapse in the myeloma relapse was only the plasma ozitoma without the systemic disorder. So in a bone marrow and in a chemistry we couldn't find the typical myeloma disease only the plasma ozitoma. So it's very, very strange I think the solitare plasma ozitoma.