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I am Claudio Shift Fiona. I currently working hematology unit of Visitor Manual Labor law studio, Takoradi to Meridian. Um Adoree located in the meld are not far from Bologna and another part of Italy. And I'm really glad to speak today about the treatment options for patients with myeloma renal failure. Uh The under title is uh no patient left behind. And this is uh a focus from Moscow 2023 educational sessions focusing on management of multiple myeloma, special patient's population. And this is a great recognize mint for the researchers in multiple myeloma because uh focusing on special populations means that uh we had the real revolution in therapeutic panorama with this disease. And that's why today we can think also to the subgroups of the special population which uh in the past that being left outside from clinical tires and from better therapeutic opportunities. How to define renal impairment in multiple myeloma is a correct question. And uh at first, we have to consider according to International Normal Working Group criteria that renal in pyramid could be based donator, elevated the serum creatinine more than 2 mg, the senators or reducing the creatinine clearance less than 40 mL from minutes, which must be the result of myeloma itself. At diagnosis of the incidents of renal in pyramid is about 20 to 40% with a slight area proportion over the course of the disease because of the worsening of renal function due to the natural history of multiple myeloma eats itself. And this is an important aspect to be considered. In particular, recruiter renal involvement is an independent adverse prognostic factor with a negative impact on overall survival and an overall response rate, especially in terms of increasing the risk of early deaths and infections. And that's why it's really important to know how to manage this important problem in multiple myeloma. We know more over that the average level of renal function among the general population, not myeloma patient, the general population more than 70 years is at or below the threshold used to define chronic kidney disease with an estimated the grow Meral glomerular filtration rate of less than 19 mL prom units. Therefore, since aging is associated with the gradual deterioration of renal function, the possibility of having it together multiple myeloma and also pre existing renal impairment is uh particularly consistent and notably Eiger in elderly population. And if we cause that the median age of myeloma diagnosis or over refractory nous and relapse of disease, we can imagine how many patient and that renal impairment together with multiple myeloma. In particular, latterly population with the chronic kidney disease is representative on a frail group more prone to develop a renal injury from moment treatments but to reverse a li this population is underrepresented in clinical trials, particularly some categories is really difficult to enroll patient with the Savella rental impairments in clinical trials. And that's why we want to focus on autumn manage this patient. Considering that a large observational course study demonstrated that patient with multiple myeloma chronicle kidney disease and an increased risk for mortality, delaying it. Setting the next line of therapy and incidents of anemia, hypercalcemia progression of chronic kidney disease itself. And that's why we have to carefully manage this popular and to know which are the best weapon steals with them. Uh What is the physiopathology of myeloma kid Annette? First, we have to consider that really an injury, multiple myeloma has been well described as a secondary event due to multiple Kiriko pathological mechanisms involving monoclonal free light chains, which lead to the damage of rental structure first renal tubules and subsequently in the interstitial space and grew merrily. The foremost final mechanism of kidney disease itself is the so called cosmic property where an overproduction of feel like change, the cause of direct proximal tubule injury and indirect the custom mediated the damage. We know that the interaction of light chain with the tubular cell leads to chronic tubulointerstitial inflammation triggered by light chains, endo citosis inducing the release of sit of interleukin six of interlochen eight and monocyte came attract a protein of one. Finally, resulting in F F could be intracellular pro flammatory pa pathway activation. These histological features in a typically are chronicle to burster sit still nephritis with diesel tubal metachromatic cast, frequently surrounded by syncytial jumped sells polymer for nuclear reactive infiltrate in there. You can see an image or what happens in chronic interstitial inflammation. What is that a great supportive care to perform in this patient? This is another really important point to focus the cornerstones of supportive care adrenal impairment in emergencies, I think are adequate did radiation and deeper calcemia control through the administration. In particular, true leaders Proscar monitor per day is essential to temporarily dilute corona corona light chains concentration in the tube decreasing in this way, their potential ruling in using cast formation, we have seen previously, moreover, we have absolutely to avoid or withdraw over potentially nephrotoxic agents such as the non steroidal anti inflammatory drugs, loop diuretics, aminoglycoside, it's angiotensin converting enzyme inhibitors, orange attention to receptor inhibitors. These are drugs to avoid in this category of patient's. Another important point is that in uh supportive care for multiple myeloma, we use really often bisphosphonate because we want to manage also the bone metabolism of this patient's. But we know that in this category of patient that this should be a little bit carefully use that particularly knowing that they have a well known potential nephrotoxicity. Particular for the possibility of in using a tubular necrosis and that's why zoledronic cases and pamidronate cases should be administered carefully in this setting. And only when the clearance is more than 30. Moreover, we have to consider that also crowed chronic acid should be used only when the clearance is more than 12 promi prominent any patient with then the stage renal disease. Then also ma'am the fully human monoclonal antibody against the rank ligand. This alternatively indicated that this is the bisphosphonate that we particularly wanted to suggest in this category, particularly considering that there are trials. And also real words, data that confirm that this drug is the best to manage bone disease in this category of patient. What about rental replacement therapy? We know that I cut off dialysis with the protein leaking dialyser can improve the clearance rate of re like Shane's particularly 35% to 70 in the first two hours following. Then by a gradual reduction in efficacy, medically physician effect because of the free like chain concentration rebound by their biological compartments. We know that there is a randomized trial that did not show any significant difference between conventional aid. I cut off dialysis causing the questions that currently remain on the optimal strategy. But we know that the efficacy of this method for renal recovery, multiple myeloma is the only thing that we can do at the moment waiting for solid at uh waiting, maybe also for a real world data arising from registries. And we know that in this moment. There are no consensus guidelines on the approach for rental represent mint therapy in multiple myeloma. But it's recommended that this should be initiated. In addition to difficulty myeloma treatment as soon as possible, the number of sessions are guided, always buy the goal of free light chains less than 500. This is a threshold for triggering tubular injury. Moreover, we know that there is a trend toward better and allow outcomes with the use of I cut off to dialysis even if nuclear data available on long term rental general outcomes because of the lack of renovance in the clinical trials, randomized clinical trials, as I was saying previously, like totally in this kind of population. That's why we have absolutely to focus on producing data in this subcategory of patient uh and regarded anim paloma treatment. We need a rental adjustment requirement and now to manage therapeutically, this patient, we know start from immunodoron modulatory drug in multiple myeloma renal impairment. The thalidomide, the first in class among the emits initially adopted the single agent and now part of a combining induction treatment uh is pharmaco kinetics are never affected by renal function impairment. Since the clearance parameters of this patient with renal failure are very similar to do one reported the normal renal function. And that's why in this drug, we have no need to modify its those during the dialysis. And during the general similar repairment. Lenalidomide is a second generation in in the moderate engagement and we know how much is widely adopted, the most transplant eligible, not eligible and also relapse that refracts three multiple myeloma. But it is a relevant to rental expression requiring those adjustment in relation to renal function as moderate severe or end stage renal disease in person is expression. And that's while in a little bit busy derangement have been documented as effective, impatient with renal impairment, but we should be really careful in clearance of creating in monitoring as the major toxicity. The mythological adverse events seems to be directly related with the Empire adrenally demined renal clearance. And we know that there is a really important and again, really actual consensus position paper statement which continue to be a guide regarding managing those independent of the combination adopted by creatinine clearance level. And this is the one published on leukemia Demopoulos is first out or optimizing the use of lenalidomide relapse. And the refractory multiple myeloma consensus statement. What about pomalidomide? The third generation immunomodulating agent? It is poorly x created by seed kidneys only about 2%. And that's why patient with also moderate or severe or advanced renal impairment should not modify. The 4 mg are recommended. The start and standard does uh a bird. Um It is a novel cell model that we are using inside the clinical trials, not currently FDA approve it, but we know from preliminary data, the its activity and safety profile are not uh modified in impair adrenal function even if it's profile is currently being explored. And we wait for more solid data to know if it should be adjusted or not in this category of patient. What about protests? Um inhibitors bortezomib as you know is the first in class is mainly a pathetic metabolism and particularly is is really active, impatient with the renal disease. And we know that rapid reduction of disease burden and no significant renal metabolism result in i overall response rate, adrenal response. Particularly many patient is a reversibility on injury or renal injury. Thanks to this agent and that that's why treatment is associated with the significant probability of a rapid Reynold response. Even inpatient under dialysis because of the kidney disease. And that's why improving survival of this patient could also be thanks to Burton's um in particularly in the ones who can became a dialysis independent. Bortezomib is the more important, the most important drug for this category of patient. Let's not forget about proteasome inhibitor, calf eats and which is a second generation protease inhibitor without any influence or renal function on pharmacokinetic parameters. That's why there is no need for those adjustment. Even if in advance that renal impairment, we have only a warning about rare and unpredictable normal um related renal injury, particularly traumatic microangiopathic with albuminuria more than one grand per day and at least a grade three ecotrin, a luxury. That's the only case reported. And we know that we should be careful about this. But at the moment, we don't consider any those those adjustment in this uh drug and indeed combination exact. So maybe is a new generation, the only one orally available protests of inhibitor. And we know that the incidence of a grade three and grade four adverse events in several uh severe renal impairment or impatient in the analysis. Uh Advocates the use of uh reducing the doors of the 3 mg instead. Oh before in these patient's and that's why disease together with lenalidomide, the only one in which we have to adjust the doors for the classical drugs that we use in multiple myeloma. What about immunotherapy? Immunotherapy is the revolution in multiple myeloma. And we know that uh today we have a significant advantage thanks to the response rate and presently survival for patient. Uh We, we seem not to be affected by in periadrenal faction from multiple myeloma, but we know that they're automobile is a toxin member. Uh Aunt is the 38 directed humanize it in, you know, globally monoclonal antibodies with the remarkable efficacy, newly diagnosis, a relapse refractory multiple moment. We use these drugs in many combinations and many of them we will see in next future. Uh It's an administration leads to rapid the manama sell debt by several mechanisms such as a complement mediated ct toxicity, antibody dependency to toxicity and so on about teratoma. But we have a rapid drop and feel like chains after its administration with the non negative impact on safety, even in severe renal injury. Moreover, about safety and maintaining the figures of Daratumumab. But we know that in term of uh efficacy of older response rates, rest of visible but MRD negativity from both patient with the normal, any periadrenal faction we don't see from clinical trials, any difference. And that's why we need absolutely not loss adjustment with this drug also with the PSA too maximum. Another E G one monocle antibody with a different target tippett tope very active anti um Aloma agent which can be combined at the moment with the pomalidomide on capitol. But we will see also that in front line multiple myeloma and also in high risk smoldering myeloma. We hope according to the clinical trials, there is no need for those adjustments. Also in patient with severe renal impairment. Uh We have also ultra novalee monotherapy in particular Bellantoni Amatfau dotan, we know which is a first in class and B cell maturation vantage and and it's a single urgent activity for the one is currently approved is not influenced by mild to moderate renal impairment, even if not, that are available for several impairment and clinical trials are underway for single agent and combination. And that's why we will see more in the next future. What about the the specific antibodies we know that list some of these be specific directed against B C M N C D three T cell engage with binds be semi on plasma cell C D three until lymphocyte. And we know that there is a currently no indication to reduce the schedule. It does over 1.5 mg per kilogram weekly of checklists, um veronal faction even if we wait for prospective confirmatory that and we wait also for combination trials. Many clinical trials such as Majestic Tree are developing tech list um of being combination with the monopoly all antibodies and the many other combination. And we will see in the next future if in the combination, we should not just something but the impression is that it is absolutely not a nephrotoxic. What about carty engineering T cells against B semi or myeloma cells? We know that they will be an option that in next future will be also proven in our daily clinical practice which provide deep responses or longer term treatment intervals free. And that's why similar to the other drugs, we have explored the potential role in renal insufficiency and multiple myeloma. But even if we need the prospective studies uh confirming the safety and efficacy at the moment, it seems that they are not deaf, a toxic but a solid that at the moment is not yet available. So which are the take home message of this panoramic about multiple myeloma renal impairment particularly we have two concert that according to International Manama Working Group criteria, renal impairment is based on elevated. The second, the creatinine in particular creatinine more than 2 mg or reduce the creatinine clearance, less than 40 which must be the result of the myeloma itself. In the elderly population with the chronic kidney disease could be a representative of a frail group which universal is under represented in clinical trials. And that's why we need the more solid concrete evaluation, solid data, particularly from registries and from real world. And I hope that we will evaluate more as soon as possible. What is the etiology of myeloma kidney? It has been well described as a second event due to multiple clinical pathology mechanism involving the monoclonal free like chain leading to damage of the rental structure. The supportive care, the corner stones in the emergency setting are add a weighted rotation and hypercalcemia control about to be phosphonate were able to avoid when possible solidary Cassie, the pamidronate Kassid, the if the clearance of the creatinine is not more than 30 but particularly platonic cast in the, we have to use only when it is more than 12. However, in end Reynold uh stage, we consider the nose um um as the best show indicated from all of the availabilities from clinical trials um from real world population rental replacement therapy should be exited as soon as possible together with anti myeloma treatment, even if at the moment, no consensus guidelines we have available. And there is a strong need of randomizing the trials about that uh anti myeloma treatment. We know that the rental adjustment required should be performed only for lenalidomide end ixazomib knowing any other drugs in mono modulating agents for some inhibitor, ultra novel agents. And we will see for the specific and carty also new combination. If something should be adjusted at the moment, we don't have any evidence about that. It's really important to concentrate our a force or send the management of a special patient population and particularly to live no patient behind. This could be the only way that we have in the road to cure multiple myeloma for all population. And this is the best way that we give to our patient to their caregivers and to all the myeloma researchers then every day dedicate their if force to cure multiple myeloma. And I hope that as soon as possible, we can write the word cure to every the myeloma population. I conclude. Thanking my colleagues from MS Sidhu Toto Martello Romania, particularly the scientific director, Professor Giovanni Martorell, the pathology division led by Girardeau Mo Saraki. All my colleagues from med alleges and divisions and all of you for the attention. Thank you.