(Guest Lecture): The Process of ASCT | MCRT Webcast: Understanding Myeloma Stem Cell Transplantation

[Music] i'm gonna share my screen here that was a fantastic introduction and overview of why we consider stem cell transplant and i'm going to i'm going to take a little bit deeper dive my name is mark schroeder i'm an associate professor of medicine at washington university school of medicine in st louis and and my focus is in stem cell transplant so i'm going to discuss the process of high-dose chemotherapy and then using your own cells to rescue you from that high-dose chemotherapy i'm going to take a step back initially and i'm going to talk about the phases that we use to treat myeloma what does it mean to undergo induction consolidation and maintenance hopefully you'll have an understanding of the procedure its associated toxicities and we'll also discuss some of the points that the calendar discussed about tandem transplants and then i'll go into monitoring disease and effectiveness so we'll start by talking about induction consolidation and maintenance and this schematic is a general overview of how we approach the treatment of myeloma and i know that those listening are probably somewhere along this continuum you may have just been diagnosed with myeloma you may be managing relapse i'm going to take you through this treatment i'm going to focus on those that are stem cell transplant eligible that's measured by fitness not age and we're going to talk about initial treatment with induction we'll talk about consolidation which is treatment primarily after transplant and then after you get control of disease talk about maintenance throughout this process of treatment we're going from a high tumor burden initially and the goals of treatment is to reduce that amount of tumor we'll talk about how we measure the amount of tumor and where along this continuum that we're assessing response this flow diagram shows current dogma of how we approach myeloma as somebody who's initially diagnosed with multiple myeloma you've probably heard about crap criteria in addition to having crab criteria we also want to know about your risk we classify risk and myeloma to standard risk in high risk this is driven by some of the clinical signs of the myeloma as well as the cytogenetics of your disease or the genetic changes in the myeloma and depending on your risk of presentation your doctor may recommend a treatment usually with three drugs either velcade revlimid dexamethasone or perhaps chlorphyllum breath limit dexamethasone as dr calendar alluded to there's recent data that four drugs may have deeper responses and this initial treatment is called induction this is the way to get control of the disease prior to thinking about high-dose chemotherapy and stem cell transplant now high-dose chemotherapy and stem cell transplant is part of this initial process typically in the management of myeloma it can also potentially be delayed to later on but i'll focus on its initial use up front after this induction phase response is assessed throughout this treatment depend depending on response to the initial induction also depending on the risk that your myeloma falls into your doctor may consider consolidation therapy they may also consider as part of the consolidation a second transplant after achieving maximal response we go on to a phase of treatment called maintenance which is usually less intense than your initial treatment and your consolidation typically that maintenance is with a single dose of revlimid or perhaps a combination of velcading reflement and our goal throughout this treatment is to maximize the duration of your response and to improve your survival let's talk about the autologous stem cell transplant procedure the goals of an autologous stem cell transplant are to maximize the cider reduction of your tumor we're going to use your own cells to rescue you from high-dose chemotherapy which is toxic and will reduce the amount of cancer cells in you but without getting your own cells back you'll have profound low blood count so we use your own blood stem cells to rescue from this and there's also recent research evidence that performing autologous stem cell transplant may re-stimulate and reset your immune response against the cancer so how do we proceed on with stem cell transplant well number one as i talked about you have to undergo induction chemotherapy to control the growth of the cancer after induction chemotherapy we have controlled the growth of the cancer we want to collect stem cells we have to collect enough stem cells that's going to allow for adequate blood count recovery after chemotherapy in autologous stem cell transplant you are your own donor and this donation requires the release of stem cells from the factory that makes your blood that's the bones we're going to use growth factors now your body normally produces these growth factors called gcsf but we give them at higher doses and we give these growth factors typically for five days in a row at some centers an additional medicine is used to release the cells from the bone marrow called cleric sephora it is very unusual that we harvest stem cells directly from the bone or give you chemotherapy then followed by mobilization for multiple myeloma but we use these terms interchangeably bone marrow transplant it's not we're taking cells from the bone we're releasing those cells from the bone into the blood and collecting them ultimately using a catheter that's placed and we collect your blood through a priest procedure called apheresis after you've received this growth factor to release the cells from the blood this blood collection is called apheresis and it takes four to six hours it happens after you've been exposed to this growth factor to release the stem cells into the blood these cells are collected typically in one day for the majority of patients but some patients have to come back a couple more days we know that the longer you're on initial treatment or potential exposures to other chemotherapies makes it a little bit harder to collect these cells so we want to collect these cells early on in your treatment course those cells once collected can be frozen that's called cryopreservation and they're good for years after the cells are collected you will receive the dose of chemotherapy that chemotherapy is called melphalan typically it's given as a single dose sometimes a couple doses one factor as part of your support is that to prevent some of the mouth sores associated with this chemotherapy that develop later on after receiving it we always advise patients to ice their mouth before during and after chemotherapy now this chemotherapy infusion is a one-time infusion but it damages the myeloma it also damages your normal blood producing stem cells so that's why we have to use these cells that we collected the week or two before to rescue from this chemotherapy those cells are infused after they're thawed at your bedside this infusion of the cells usually takes in a matter of minutes 15 minutes it may take longer depending on how many days or how many bags you had to collect of stem cells some common side effects that can be seen in somebody undergoing the infusion of the cells there's an alteration in taste maybe garlic tastes tickling the back of the throat flushing associated with the preservative in the cell very rarely there can be allergic type reactions to the infusion but that's unusual now in this slide i highlighted what i've seen as the typical side effect profile of stem cell transplant and this is the peri transplant period so around the time of transplant you may describe it as a roller coaster the chemotherapy initial infusion there's good medicines to prevent nausea right at the time of infusion and even on the transplant day patients feel pretty good what you can expect in the first few days is nausea as the blood counts drop you'll feel more tired and fatigued what counts are highlighted with the declining arrow in this figure most people have other gi toxicity of diarrhea and when your white count or the good infection fighting neutrophils fall less than 200 you typically have fevers and those fevers are caused by infection or bugs that are normally on your skin or lining your gut and you don't have a good white count to fight those infections this period of feeling you're most fatigued you're most ill lasts for less than a week in most cases and by the 10th to 14th day we start to see recovery the white count and that's when people start to climb out of this this hole for some people it's an easy climb for others it's like climbing inverted on this uh this mountain top but once the neutrophils recover your strength improves the swords in the mouth if you develop them get better diarrhea subsides and you're able to leave the hospital in about two to three weeks from the admission to the hospital and i can see that uh there are a number of you probably asking but why would you do this why would you put me through all of these toxicities and dr calendar alluded to some of the data i will just touch on one study that she discussed and this was a study that took half of people who were candidates for transplant and said okay half of you you continue on this original induction regimen the other half we're going to give you the transplant and after transplant will put you on maintenance therapy with lenolidomide and these are the results of this study this study along with others have found that autologous stem cell transplant using your own cells to rescue from high-dose chemo results in a longer time before the myeloma progresses that's shown in these curves progression-free survival so each of these dips down in the curve mean that somebody in this study progressed with the myeloma and this is time on the x-axis so progression-free survival shown in the gray curve is improved by transplant that means it takes longer for your myeloma to progress and on average it's anywhere between one to two years longer than somebody who just continues on that three drug induction now let's say you get through transplant what do we do after transplant well that management after transplant again that's included in the induction depends on your myeloma risk typically are you standard risk are you high risk also what was your response after transplant we assess response before and after transplant and look at how well you responded to treatment some patients might be considered for consolidation consolidation means let's give you some more of the treatment that you have before transplant or maybe we should do another transplant you had such a great response or your high risk should we consider another transplant after that consolidation then we go on to maintenance that means low dose of treatment to continue to see a response again our goal is to maximize the duration of this first response and hopefully improve your survival i'll highlight one study this is dr gerald's study again this asks the question what's the best treatment after you undergo a stem cell transplant all of the patients enrolled in this study had to be 70 years or less that may not directly apply to you but they all underwent high-dose chemotherapy and transplant and after transplant they agreed to be randomized to either just going right on maintenance lenolidomide more of the drugs that they had before transplant with consolidation with velcade revlimid dexamethasone or they agreed to undergo a second transplant now one of the problems with this study is that in the group that underwent the second transplant because of the toxicities i talked about 30 percent of those patients were unable to undergo the second transplant all patients in the study underwent lenoletta my maintenance and this maintenance was continued initially for planned three years and then they subsequently evaluated well what if we continue this maintenance treatment longer and these are the updated results that were presented at the american society of clinical oncology what they found in the group that was high risk myeloma that underwent a tandem transplant that actually succeeded in getting there remember 30 percent of people didn't get there that this high risk group had a longer time before their myeloma progressive progressed that's shown in the table 43 percent who had an auto followed by an auto compared to those that just went on maintenance with revlimid 32 so it increased the chance that at five years you have not progressed with your myeloma by 10 percent so would increase the odds that you live longer before the myeloma progresses if perhaps you have high risk myeloma in addition they looked at the question should we stop the revlimid at three years or should we continue it and in this study as well as others it's been found that those that continue rev limit are shown in this orange dotted line they have an increased probability that the myeloma does not progress compared to those that stop it at three years and just are observed this applies to both standard risk and high risk patients what they concluded from this study is that as dr calendar alluded to looking at just all comers there didn't seem to be across those three groups a difference in progression-free survival or overall survival but if we look at what rece treatment they actually receive the high-risk group may benefit from a second transplant i didn't mention in the discussion but they also found that second malignancies or development of other cancers was not different between the groups in that was your respective whether you stopped revlimid or you continued it that's been one of the concerns about continuing revlimid indefinitely is what if it increases your risk for other cancers that was not seen in this study to highlight the importance of continuing maintenance therapy i want to point out one other study the standard based on the stamina study as well as this other study is that lenolitomide or revlimid after transplant if that's what your doctor decides to put you on for maintenance should be continued after transplant because there's an improvement in progression-free survival shown in the blue curve those on let alone amide versus those on observation have a longer time before the myeloma comes back now this applies also whether your standard risk or whether your high-risk myeloma lenolenamide improves outcomes in studies that i am not going to show because of time in particular in high risk groups of myeloma there is also perceived benefit of adding proteasome inhibitors to that group in addition to lenolinamide to prolong the time before myeloma progresses so let's recap we've talked about when you're initially diagnosed we want to know whether your myeloma is standard risk or high risk that should be a factor that your doc focuses on before deciding on treatment induction is typically three drugs of induction given for four cycles if you are fit we should consider transplant because it improves progression the time before the myeloma progresses by one to two years enlarged meta-analyses also improve survival in patients up front depending on your response after transplant and your risk group whether you're high risk or not we could potentially consider consolidating this initial response with another transplant or further therapy in all patients after transplant should be offered maintenance therapy or low doses of treatment whether it's revlimid alone or revlimid plus a proteasome inhibitor depending on their risk group again gold maximize the duration of your response that will improve survival how do we monitor and measure effectiveness we've talked about measuring your myeloma throughout treatment well we assess response through blood work this includes the serum protein electrophoresis measuring serum free light chains we monitor for worsening kidney disease calcium problems or anemia we also check urine studies throughout your treatment bone marrow biopsies may also be performed and for some patients imaging such as pet scans or cts or x-rays might be performed to monitor bone disease now recent studies have focused also on a test called minimal residual disease testing or you might also hear referred to as measurable residual disease testing this is a very sensitive way to measure for leftover myeloma in the bones in fact there are studies focused on this to help to adjust treatment based on mrd positivity or negativity for maintenance treatment and to modify treatment up front based on how well a patient responds what you should know though is that currently there is no data to suggest that we should alter treatment of myeloma based on mrd testing this is a research test and it has very promising potential implications to be able to adjust your treatment based on this very sensitive test but currently there's not enough evidence to use that so along this continuum we're assessing response we want to stage the myeloma and assess it before treatment during the induction prior to transplant in prior to any consolidation or maintenance therapy and we're going to measure response based on how well the myeloma is reduced 50 percent reduction partial response less than 90 percent we are less than 90 over 90 reduction a very good partial response if we do a bone marrow biopsy and we can't detect any protein being produced from the myeloma that's considered a complete response and even a lower uh amount of detection is mrd negativity that's even more sensitive test and that's a complete response mrd negative and this is what a report looks like when we're measuring mrd somebody prior to transplant had one in 100 cells or myeloma after transplant this report shows at day 100 after transplant that had eight cells out of a million cells positive that look like the myeloma so it's a very sensitive test we're talking eight in one million cells and why does this matter for testing mrd because mrd status is associated with time to progression and overall survival shown in the blue curve those that become mrd negative have a longer time before the myeloma progresses and have improved overall survival this applies also to those that have a complete response to treatment mrd negative shows improved progression-free survival improved overall survival so that's the basis of why modern treatment trials for myeloma are using mrd testing to drive therapy so let me recap we've talked about up front for your treatment of myeloma we want to stratify your disease we want to base it on risk also throughout your treatment for the myeloma we want to assess your response and we may recommend treatments or increasing the intensity treatments based on the response the standard initial treatment or induction is three drugs this is based on your risk vrd for standard risk krd often for high risk four drugging regimens with daratumumab can also be considered we talked about the toxicities of stem cell transplant but this is associated with improved progression-free survival and in large cumulative data improved overall survival we want to re-stage the disease after transplant we want to consider consolidation therapies or even a second auto potentially in patients that have really high risk disease and all patients after transplant should be on maintenance therapy and this maintenance therapy should be continued indefinitely based on available therapy because it improves regression free survival and overall survival maintenance therapy can be adapted based on whether your standard risk or high risk after transplant that's the conclusion of my talk again like to thank the organizers for letting me talk i look forward to the uh discussion after dr drewell's presentation next thank you