(Guest Lecture): Research Finding about Need and Effectiveness of ASCT | MCRT Webcast: Understanding Myeloma Stem Cell Transplantation

[Music] thank you very much jenny and i want to thank all the people from myeloma crowd for the kind invitation and let me share my screen now and put this in presentation mode and i hope you can all hear me well and see my slides so i think both dr schroeder and dr calendar did an excellent job in setting the stage and i want to kind of summarize some of the points they made and give you a vision of what we think may be happening in the future so these are my disclosures and i'm the first to admit my biggest conflict of interest i'm a transplant and i really believe that this technology has helped thousands and thousands of people with myeloma and yes there are many other medications coming through but i think tran high-dose melfin and autologous trap transplant is of still a platform for long-term disease control so let's talk a little bit about this early versus late transplant and what the evidence is and i'm going to advise you something i tell all my patients transplant's a choice it's not a necessity it's a choice you make based on the recommendations your physicians make based on what they think your disease is going to do with or without high-dose melflin you need water you need air you need food you need love nobody needs a transplant transplants a choice it just happens to be for our perception the best choice choice for most patients with myeloma because it is the single most effective way to get as you've already seen in the previous presentations long-term disease control so you've seen this study a couple of times already so these were patients were randomized to either get high dose therapy early versus high dose therapy late in the case of relapse and you've seen this again that yes for the patients who received an autologous transplant early they actually had better progression-free survival which means that the time of disease control was longer however there was no survival benefit as of yet partly because we have very effective salvage treatment so that once the disease comes back we have ways of treating them but what is the advantage for patients who got treated early with a transplant that in the end of time they really were exposed to less chemotherapy because they had a longer remission duration now it is true that we sometimes say that there was no survival benefit but however for patients with high-risk disease defined as stage 3 or abnormalities of chromosome 17 or with specific cytogenetic abnormalities i don't think that it was that you know these people actually lived longer if they had high-dose therapy and autologous transplant up front and it was a significant difference three years overall survival of 50 if you were randomized to the group that had late transplant versus 75 so there are groups of patients in which i strongly encourage them to undergo a transplant part of the fact is because they are likely to live longer if they do so and these are the groups of patients that is dr schroeder described have high-risk disease this is the other study that we have heard a lot about today again this is the french american study in the french study that has been published and you've seen these results yes there was a benefit for high-dose therapy in regards to progression-free survival but as of today there's yet no benefit in overall survival but what was that benefit due to that benefit was due to the fact that the patients who had the high-dose melflin had the deepest response and they were mrd negative as you just heard from dr schroeder and being mrd negative meaning in this study meant that if they counted a million cells they were unable to find one myeloma cell so a lot has been made about the fact well if you're mrd negative it doesn't matter if you had a transplant or not because as you can see patients who are mrd negative after two years of rev limit the risk of relapse seems to be only 20 over the next 18 months on the other hand if you're mrd positive the risk of relapse is extremely high 50 to 60 percent so a lot of our colleagues have used this as a rationale whereas a reason to say well if we can get patients to be mrd negative with treatments that do not include high-dose melflin why not we just avoid the high-dose malfunction and spare the patients that toxicity and we'll discuss that a little bit later on when we talk a little bit about that you know mrd to 10 to the minus six is not necessarily cure so there are now the four drug regimens and what i want to show you is with the four drug regimens again we don't get everybody into mrd negative states but we get to a large proportion of patients who are in complete remission and of those 50 percent of them get to an mrd negative state dr calendar spoke about this study and again what i want to show you is the importance of this study is that the patients who despite getting a very effective regimen of carfisma and a little my dexamethasone the patients who were assigned not to receive transplant during the first year those patients had a doubling of the risk of relapse as opposed to the patients who had their transplant during that first year of treatment so again i think as dr calendar alluded to there's still a role for high-dose melflin in the treatment of myeloma so this question of transplant becoming obsolete is again a little bit you know dismiss leading let's remember how does tr why do we talk about transplant as as dr calendar alluded to transplant is simply the vehicle that we use to deliver high-dose melflin an autologous transplant is not a treatment for myeloma the treatment for myeloma is the high-dose melflin what allows us to give the high-dose malfunction is the fact that we have your stem cells collected and stored and we can rescue your bone marrow from those effects as dr macklewon and powell showed many years ago by increasing the dose of melflin we can actually kill more myeloma cells and more importantly we can kill myeloma cells that are resistant to conventional chemotherapy and this was the first treatment strategy that we could use to kill resistant myeloma cells so i have a lot of conversations and discussions and debates with many of my colleagues who believe that mrd negative negativity should be the surrogate and that a patient who's mrd negative with primary therapy should not undergo tridos melfonant transplant and what i remind everybody is mrd negative just means that you have less than one in a million myeloma cells in your bone marrow as we saw by dr schroeder this by no certain circumstance means a cure these patients continue to relapse and many of them die from their disease and although yes that if you're mrd negative at 10 years you're a have a 20 chance of still not relapsing that means that if you're that many patients have relapsed within two three four and five years so mrd negatives is not a surrogate for cure and 10 to the minus sig and our feeling is that particularly in patients with high-risk disease even if they're mrd negative high-dose melaflin may actually get them to even a lower level of disease and i think the lower the less myeloma you have the better it is and since your myeloma is not going to be nice to you we should not be nice to your myeloma so this is what's happening in the united states myeloma transplants that are about 9 000 a year have plateaued a lot of it because of the perception by many physicians and patients that you know with all these new drugs i don't won't need to get high-dose melflin but you know one what we have done we've broken the age barrier we transplant patients over the age of 70. two it's still unfortunate that the number of myeloma transplants that are being performed in the united states is less than 50 of the numbers that we think we should do if you're less than 65 and only 30 percent of the numbers we should be doing if you're over 65 and there's a significant racial difference so for patient for our african-american patients the access to transplant also seems to be hindered so let's go back from a patient's perspective what are the benefits of deciding to go to an early transplant well this is the youngest you're going to be this is the healthiest you're going to be and myeloma is going to be the least resistant at this time and it's your quickest return to new norm what's the benefits of delaying the transplant well you conserve your quality of life in the early part of your disease journey it does minimize the disruption of your lifestyle and you hedge your bets because actually we do know that 25 to 30 percent of patients who do not undergo a transplant up front can still be in remission seven to eight years down the road what are the disadvantages of an early transplant well again twenty percent of patients may not need it and we don't know whether it would have made a difference twenty percent of patients still relapse within the first two years so i said well why did i go through this if i'm dealing with this again there's a one percent chance of serious life-threatening complications a three-month recovery and no proven impact on survival what are the disadvantages of thinking about delaying your transplant two-thirds of the patients will eventually need it within two years so you do really are kicking that the can down the road not very long 20 of patients relapsing cannot go get their transplant as a delayed because the disease came back to aggressive they got too sick or they had not collected stem cells before and recovery is likely to be harder than if you had done your transplant up front so what are we doing and how you know what for those of you who are about thinking about am i going to do this am i not going to do this what can you do to make this journey as dr schroeder very clearly exposed easier so the first thing is you have to choose your transplant program carefully um it's you get to know the doctor get to know the nurses ask them do they do the transplant as an outpatient as an inpatient and see what what the team has to make your transplant journey easier so as dr schroeder alluded to the main and most important side effect that most people complain about is fatigue it is expected it can last one to three months you can do something about it you can try to get your rest address tell your doctors to address your insomnia if you're not sleeping well and balance activity with rest so every time you have activity you rest activity and rest nausea and vomiting were very good in controlling we have good medications but the important thing is to prevent nausea don't let it get ahead of you so take your anti-nausea medicine schedule diarrhea is a rare complication but it can happen you should avoid milk or milk products there are anti-diarrheals that again you should take regularly as instructed by your transplant team and it's better to take frequent meals than three large ones mucositis or mouth source is actually that something that now happens much less frequently than what would happen before because of the fact that we're not giving people uh the chemotherapy used for induction is much less toxic than now than what it was before but it still can happen pain control is essential most all transplant centers are very good in handling pain your counts will drop to zero you will be on prophylactic antibiotics it is essential that you follow the instructions of your transplant team and that you take your medications as required so i want to show you a couple of things that are being done at memorial about trying to make the transplant journey better and what you see here is a curve what we call a transplant symptom burden curve and what universally happens is that most of the symptoms that happen happen at the time that your white count is zero this is the time when you're most tired this is the time when you have least appetite this is the time when your sleep is most disturbed it is interesting that at the same time a cytokine called interleukin-6 is at its highest level so we postulated that maybe if we could block interleukin 6 we would be able to improve your transplant journey and prevent the symptom burden and what you see here in this heat map is we ask the patients at the time they start then on the day of the transplant and then 30 at the end 30 days later how are they feeling and the greener it is the greener it is the better they feel the redder it is the worse they feel and as you can see as dr schroeder alluded to people towards the middle of the transplant when their accounts are low feel the worst and then 30 days later some people have recovered to normal but still there are some people who still are not feeling their best so we just finished the trial looking at celtuximab so tuxedo map inhibits interleukin-6 it's an interleukin-6 antibody so it basically blocks the activity of interleukin-6 and look at what those patients have described these patients really they they went through it and we're now planning a larger study to confirm this preliminary results that siltuximab can reduce symptom burden after transplant we actually have strategies that we have been uh explored and we've published so acupuncture actually has shown that you can reduce symptom burden in blue is our historical controls in red this was a randomized trial which means that people were randomly assigned to get sham acupuncture where the needle is placed on the skin but it's not put into the site and in green is true acupuncture and these symptoms are and here what you see is what we want we want to be able to do your transplant journey and you will not notice the difference you will feel as good on day 30 as you did before you got the mouth line so these are the strategies that are commonly used so we use anti-nausea i mean these are the current uh strategies that we're exploring there's trials on microbiota we'll talk about pk direct and melflin in a minute dr schroeder talk about ice chips and cryotherapy there are other strategies that we're using to prevent mouth source so interesting we give all patients currently the standard is you get 140 to 200 milligrams per meter square patients who are over the age of 70 get 140 milligrams per meter squared patients who are less than 70 get 200 milligrams per meter square but when i do that and i look at all the patients that we treat there's a significant variability of exposure because not all patients handle melflin the same way and there's actually a five-fold there can be actually a five-fold difference between one patient and the other on how much malfund they get exposed to so you have a patient who rapidly gets rid of melflin they have a low melt line exposure that patient would have with a low melt flat exposure we postulate that they might have a higher risk of relapse because they literally even though we thought we gave them the same melphilim they were exposed to a lot less mouth length likewise the patient who got exposed to a lot of melflin because they didn't metabolize it very quickly that patient could have a lot of side effects particularly a lot of nausea and diarrhea so this is what we call pk directed melflin we just finished a study showing that we can get everybody to a sweet spot the australians had shown that there is an optimal amount of mouthful and exposure but it was very difficult to get everybody into that sweet spot because of the drugs because of the melflin formulation that was available there's a new melphalan formulation called evomela that's much more stable that allows us to do pk direct and melflin and we're now preparing a second generation of studies where we are going to get everybody to that optimal mouthful and exposure and show that it may make a difference so in general the other thing is and many of you have alluded to the chat well the disease continues to come back what can you do to prevent it so one of the things is bring you into the transplant in a better shape with a deeper response the four drug regimens promise to do that the next thing is we are working with the graph source many of you asked are you getting rid of the myeloma cells no we do not purge partly because of the fact that none of the purging mechanisms that exist have been very good but we do know that there are graph characteristics that enhance your immune recovery after transplant and the group at menu and others have shown that the quicker your immune system recovers after transplant the less your likelihood of relapse so we're now working on strategies to see if we can identify what cells need to be in that graph to guarantee a quick recovery dr calendar has talked about that you know we continue to use melflin and we've been using it for more than 20 years there are new conditioning regimens that are being explored some of that with radio immunotherapies some of that with novel drugs and there will be a new melflin a new melflin-like drug called malfluffen that seems to be more active against myeloma cells for which a clinical trial is now being planned i think most importantly is what happens after the transplant and we're now very excited with all these new immunotherapies such as those by specifics and the car t cells we think that post-transplant we can get these remissions to last now they last an average of four years with lenolitomine maintenance alone we think we can get them to last even longer and hopefully without need of any treatment and i want to thank you very much for your attention and are now ready for questions you