(Guest Lecture): Discussion of Two Case Studies with Full Faculty | MCRT Webcast: Understanding Myeloma Stem Cell Transplantation

[Music] all right so again hello everyone and thank you for the opportunity to moderate this case discussion my name is zachary kris and i'm one of the hematology oncology fellows at washington university school of medicine here in st louis and i have the pleasure of presenting the following two cases to our distinguished discussants dr calendar dr schroeder and dr jarrell and as we make our way through each case i'll try to direct some targeted questions to each of our discussants and at the end of each case we'll also have the opportunity for the whole panel to be weighing in on these two cases so we'll go ahead and get started first we'll start with case number one a 62 year old female with osteoporosis who presented with five months of low back pain she initially saw care from a chiropractor as well as an orthopedist who ultimately treated her with steroid injections and offered no relief really for her back pain so she was seen by her primary care doctor who ordered mri with images here showing multiple level compression fractures and so with the history of osteoporosis the initial concern was she should be treated with a kyphoplasty unfortunately during a procedure she had a bone biopsy done and that was reported out of showing 60 plasma cells and so of course this prompted an additional myeloma workup and we can see some of her lab data here her hemoglobin creatinine calcium albumin beta 2 microglobulin and ldh were all within normal limits her serum protein electrophoresis showed a 1.5 gram per deciliter monoclonal protein her serum light chains were normal however the skeletal survey showed multiple lytic lesions in multiple areas here and under bone marrow biopsy it showed 50 cd 138 positive kappa restricted plasma cells with normal cytogenetics and so with these data the diagnosis of multiple myeloma was confirmed and the patient was categorized as having iss 1 or revised iss 1 staging and so with a patient like this presenting with low risk disease and minimal medical comorbidities there's obviously different options for induction regimens that we've already been discussing this morning some may favor morteza nib lenalidomide dexamethasone while others may favor carphylsemib and then as doctors are all alluded to there are four drug regimens and so maybe dr calendar if you wouldn't mind starting us out share with us what you might recommend for an induction regimen for this patient yeah i i just to just very quickly um for your audience i think this this kind of presentation actually is not uncommon when people are sort of thought to have osteoporosis for a while it turns out to be uh something else i think everybody here probably on the panel has probably seen this multiple multiple times so we always are on the lookout for people who just don't seem to fit that category but in terms of induction regimen i think that that there is pretty convincing evidence uh from uh the recent econ trial comparing vrd to krd that is velcade revlon and dexamethasone to carphylsumib that there's certainly for a person who would have what we would consider low-risk disease very better better safety and an equivalent result in terms of effectiveness with a vrd regimen so that's what i would pick for this patient otherwise if they wanted to go in a trial using a four drug combination that would be reasonable but but off of trial i would i would opt for vrd excellent thank you dr calendar and and that is exactly what this patient ended up getting vrd i ended up getting five cycles for logistical reasons and their response assessment showed that their steering fly chains remain normal their u-pep didn't show any monoclonal protein but their serum protein electrophoresis continued to show a 0.3 gram per deciliter monoclonal protein the bone marrow biopsy showed less than five percent plasma cells and so this patient was categorized as having achieved a partial response and so at this point some might favor more induction therapy and tell a maximum response while others may opt to just proceed with transplanting a you know pr where others may also favor a delayed auto transplant at first relapse so maybe dr schroeder would you mind um sharing what your next steps and management of this patient would be with somebody only achieving a pr after their induction regimen yep sure um so again again response in this setting when we talk about partial response that that means a change in your protein level from from the myeloma so it was a 50 reduction but didn't grit down to ninety percent we know deeper response associated with time until the myeloma progresses this is a patient that is standard risk in just to highlight how we would determine standard risk in this case this staging system has to do with the labs initially so they had a normal or range beta2 microglobulin they didn't have high risk genetic changes in the myeloma the problem with continuing on the current therapy until we achieve a complete response is that it's going to be harder to collect the stem cells so in this case i think it's reasonable they've had a partial response is to try and collect stem cells for a transplant the longer you're on revlimid the harder it is to mobilize those cells and collect those cells so i would focus in this case after five cycles of the initial induction collecting the stem cells and because they've had a partial response and they're in the standard risk category moving on to stem cell transplant after excellent thank you dr schroeder and again this is exactly kind of how things proceed the patient was mobilized and taken to an auto transplant and at their day 100 assessment of their disease status they were found to be in a complete response fortunately and so now it raises the question and one that um all of our speakers so far i've kind of touched on is maintenance therapy and so with the patient being in a complete response transplant dr geralt do you mind kind of sharing with us how you manage patients that you achieve a cr after transplant do you consider tandem transplants in some people do you favor alternative consolidation regimens or would you move to a more maintenance strategy so the standard of care this is a great case because it really is something that we have to address every day so the standard of care across the united states now is lynolitomide maintenance until progression based on the randomized trials performed both here and in europe and which you know linolitamide maintenance until progression was associated not only with a progression free survival benefit of almost two years but a survival benefit of you know of you know significant reduction in risks of dying at seven years from myeloma so i would advise the patient look the standard is maintenance at this time and you should be getting maintenance within a little my five to ten five to fifteen milligrams 21 days out of 28. i'm just going to many of your our audience may be hearing different things in different centers this is a patient with relatively low risk disease if the bone marrow showed mrd negativity you could actually make the case that this patient may actually benefit from just observation and not need to expose them to revlimid that is currently a question that is in the clinical trials whether we should be doing mrd directed treatment such as what dr schroeder was talking about but the standard and i would in this patient because of the fact that she failed to achieve a complete remission to induction which was you know the best drugs available at that time i think when a little mind maintenance would make sense with careful monitoring post transplant which is also essential patients have to be monitored you know at least every three months with blood and then maybe once a year with bone marrow to see what the status particular what the status of their measurable residual disease is excellent thank you dr all and i'll that segues actually very nicely into the kind of last point or last opportunity to answer some questions for everybody we hear so this patient was treated on a maintenance regimen on a clinical trial with lenolidomide plus daratumumab and they were randomized to the treatment arm which was comparing lenolitomide alone as dr geralt mentioned to this combination regimen and i'll just highlight the schematic for this study included mrd assessments following transplant while on maintenance and so i wanted to pose the question to everybody as dr geralt already kind of very well puts how are you guys using mrd-based treatment assessments or excuse memory based assessments to modulate or to inform your treatment recommendations for patients um i so this is natalie again i would just say that i think mrd is still a research question and and i am not sure that we know enough about mrd you know first of all mrd is not just a single thing there are different ways to measure it there are different depths that you can explore and i think studies like this swag study 1803 are really important to help us try to uniformly assess this and so outside of a clinical practice i am not sure that it is appropriate to use mrd for decision making but but that's my opinion so i'm going to echo natalie and with the one exception so the place where i use measurable residual disease to make a decision or to inform patients is patients who are having significant side effects on analytimide maintenance or who want to come off linolitamide maintenance i tell them let's do a bone marrow and measure measurable residual disease because what we do know is that in patients who are mrd positive stopping the analytimide those patients will tend to relapse within 24 months now mind you you can recontrol them later on so we have this is really an individual decision and i've had patients who simply say i can't stay on analytimide even if i'm mrd positive i'll just wait and when the disease comes back we'll retreat it and recontrol it and i i would uh try to add to this discussion that um i i agree completely that using mrd currently off of study um for this particular patient um may not be the best approach and this is one example of a clinical study this patient could have been considered for a clinical trial upfront in their treatment as well if if one was available and that would have been equally acceptable i just want to encourage all those listening that clinical trials like this or ones earlier on or at the time of relapse are always going to be active treatment and well-designed like this study to answer questions this study in particular is going to try to answer that at the two-year time point is it okay to stop maintenance if you're mrd negative or positive so somebody participating in in this study is going to you know have the advantage of having access to mrd testing which may not always be performed at our center we are testing for mrd primarily in patients that achieve a complete response and we're using it prognostically not to modify treatment but in this uh in this study you are actually going to be potentially randomized to the standard lenolidomide or you get the standard plus daratumumab so it's a really nice design study and then they're going to adapt the treatment afterwards based on your mrd status which is cutting edge novel therapy i think in in the realm of myeloma and i would i would sign any of my patients up for this for this study for sure thank you everybody so we'll go ahead and move on to case number two so case number two is about a 62 year old male with hypertension sleep apnea a history of papillary thyroid cancer that's been completely treated who's presenting with two months of weakness and left jaw numbness so the patient underwent a ct scan of their head which was read as unremarkable but then they had a brain mri to follow up the ct scan that showed what the radiologist characterized as a quote marrow replacing process so the patient underwent a bone marrow biopsy and from the outside hospital report we were informed that it should increase plasma cells and not uh additional information otherwise so this patient then got an additional myeloma workup and i've highlighted and bolded the abnormal values for all of our viewers so the hemoglobin was low at 9.7 creatinine mildly elevated at 1.31 calcium was elevated at 11.7 and was even higher when corrected for the low albumin of 2.6 and they had an elevated beta 2 microglobulin and ldh their serum protein electrophoresis showed a 5.4 gram per deciliter iga lambda monoclonal protein and they had a concomitant elevation in their lambda light chains with an abnormal kappalanda ratio skeletal survey was actually without lytic lesions and on bone marrow biopsy which demonstrated 20 cd-138 positive lambda lambda restricted plasma cells and normal cytogenetics on this patient and so for this patient they arrived at a diagnosis of multiple myeloma with iss stage three disease and revised iss stage three and they underwent an induction regimen that included carphylsemitamide and dexamethasone unfortunately the first cycle is complicated by a rash which was attributed to lenolitomine and therefore the patient was transitioned to carfilzone cyclophosphamide dexamethasone for two cycles and had persistent disease on their surveillance assessments and so with persistent disease after three cycles dr callender would you mind sharing with us how you might proceed for example would you continue with kcd or would you change to something else in this setting right i think this this actually points out an area where we have a great lack of knowledge and a lot of this is driven more by opinion than than what what what we know we should do i think given this scenario and given the fact that the person has revised iss stage three disease i think most people would be uncomfortable leaving on that current regimen and that is particularly as i mentioned that forte trial carfism of cyclophosphamy dexamethasone did not perform as well in the long run as carfilson revlimid and dexamethasone but what we really don't know yet is should you change all of the drugs or just start thinking about adding in or changing or a different class and by that i mean many people in this situation would probably go to a cd38 antibody inhibitor such as daratumumab or isotoxumab in combination and then this is where it gets tricky some people would say well it seemed like carpalsimov should be better but maybe i should go back to velcade or they didn't tolerate lenolidomine so i'm going to put pomalidomide in with that um i think almost everybody would be uncomfortable now in reality there is an older retrospective study from the um centers for international bone marrow transplant research that actually showed patients who go into a transplant in this situation didn't actually benefit from having a switch up of their therapy that they still seem to benefit as much as a patient who did have a change in therapy albeit that study included an era where we don't have nearly the drug choices but i think most people would probably bring in a cd38 antibody at this point and probably try to challenge them as well with pomalidomide but i'll be interested to see what so it's interesting that and also i'm the oldest one of the panels so i can say history here um initially before all these drugs when people were resistance to vad it was demonstrated that the best way to get a partial response was actually expose them to high-dose melflin so and this was a series of studies that were performed at md anderson with dr alexanian and what he demonstrated is is that you know high-dose melflin can overcome the resistance of uh you know can really get rid of a significant amount of resistant myeloma cells so in somebody like this we would do dsap collects times two collect stem cells take the high dose melflin and then post-transplant we would we would have a series of what we call you know maintenance trials for people with high-risk disease that he would qualify for i do think that that's a reasonable option but i also agree with natalie that with the advent of cd 38 monoclonal antibodies i mean it makes sense to to as you is prepare that is try try those agents now and if they get a response then proceed to transplant but if they don't get a response i think the most important thing is that patients with primary refractory disease should probably at least try to get exposure to high-dose malfunction these are very rare patients now by the way excellent thank you dr charlton thank you dr calendar and as both of you i don't know what i'd like to hear what mark thinks oh mark thank you thank you dr gerald uh yeah so i mean it um just just to highlight again this this is a high rate high risk case of myeloma because it's iga myeloma because it had elevated beta 2 microglia and elevated ldh that's why they got the revised iss stage 3. this is a similar approach for the initial treatment that we would have taken and i think that using daratumumab or cd38 [Music] targeted agent to try and get at least a response prior to collecting stem cells is what we would uh do here and zach has already moved on and and show me that my choice is wrong you may have persistent disease okay thanks zach no no no i so i i think that all of you guys were thinking the same thing and this is exactly how this patient was managed that we favored a c38 monoclonal antibody with some changes in the induction regimen with the hope that we might be able to induce a remission and fortunately the patient proved us wrong and continue to have persistent disease and so that brings up then the follow-up question of again next steps and treatment and as dr geralt and everyone has already kind of started to allude to there are other options that one might consider to patients who are for not responding to multiple lines of up front therapy so interest of time i'll kind of let the cat out of the bag so this patient got one of the regimens that was already recommended or actually both of the regimens that was already discussed they first were treated with dsap for two cycles unfortunately as dr geralt alluded to did have a partial response so they were chemosensitive and then were taken to an autologous stem cell transplant and at their day 100 response assessment their s peps still showed a small detectable iga lambda monoclonal protein on immune fixation that was not quantifiable their bone marrow biopsy was read by our various dude pathologists showing no overt disease by immunohistochemistry but when they looked at the plasma cells they thought that they looked morphologically suspicious for still low level plasma cell neoplasm persisting in the bone marrow and so this patient based on their month their m protein was characterized as having a very good partial response and so after treatment they were started on maintenance daratumumab pomalidomide and dexamethasone and unfortunately relapsed six months after their auto transplant with a rising m protein and so this then brings up the challenging clinical cases where fortunately they're less frequent but we still see patients with aggressive high-risk disease who are just not achieving optimal responses on treatment and um so i open this up to the panel and just for the sake of discussion i included the iss and some cytogenetic abnormalities for our patients to look at these are the things that we're looking at i wanted to hear from the panel how do you guys define high-risk disease do you focus on these scoring systems that we have are there other things you take into account and what are what's your approach for these sorts of patients that are really the most challenging well i think i think one thing that everybody will probably agree about uh we use these these staging systems and they're helpful but i think we also run across the patients who start off looking like they should have you know standard risk myeloma and should do well but after an auto transplant like this particular case um six months later their disease is back so i think you you look at both some of these initial characteristics of diagnosis but the behavior after you start treatment i think is also something that you have to take into account and so this patient would qualify for a series of high-risk trials that we're organizing and one is one that dr calendar is um is is going to be doing through the bmt ctn for the high-risk patients so when after the transplant the patient would be getting a bcma-directed car t in a way that uh to try to reduce tumor burden and prevent the disease from coming back the patient were younger or fit we would we would think that this patient might qualify for an allogeneic transplant also on a clinical trial looking at novel maintenance strategies with bcma targeted therapies so i think yeah yeah if mark mark is there i think i think we would all agree that boy we'd be looking for a clinical trial for somebody in this particular situation yeah i i completely agree i mean and to highlight in all these cases these are yeah these are potentially real examples of of patients everybody is individual how they respond to treatment so just because you do have and and to come back to that the high risk versus standard risk myeloma by these staging systems i think your response to therapy also is important in determining what to what to do next and we know if you go on to auto transplant and you have the disease progress early after auto transplant that's associated with a worse outcome and and those are the patients really to focus on uh novel therapies especially this patient that's progressed on some of our best agents looking into a clinical trial is completely acceptable looking into immunotherapies like car t cells or the antibody studies is completely acceptable in my opinion for for a patient like this this patient could be potentially considered based on long-term follow-up of the ctn study for second auto as well but potentially tandem auto and i guess an important for the audience to know that if the patient did not want to proceed to clinical trial or i mean there is now a drug commercially available for these patients which is valentime which has ocular toxicities requires an ophthalmologist to see the patient before getting the drug every month but it is indicated in this situation thank you all for your excellent discussion points and i want to thank all of our myeloma patients really and their families and their caregivers for all of the incredible stories that you all have and and for allowing us to participate in your care i want to thank the participants and the attendees of this case discussion in this first session of the presentation today i want to focus some thanks to dr dr calendar dr schroeder and dr gerald all for really an excellent discussion and sharing their expert opinion on how they would manage these patients and how they approach multiple myeloma i think the myeloma crowds and the crowdcare foundation as well as health free for helping to organize this and thank you again to all of the sponsors who helped make this possible you