(Guest Lecture): Why Consider Bone Marrow Transplant? | MCRT Webcast: Understanding Myeloma Stem Cell Transplantation

[Music] good morning i'm natalie callander from the university of wisconsin um i have a little bit of shield here here i've just been rounding on are actually our transplant ward so i'm going to talk to you a little bit today and i'm going to try to share my screen so what i'm going to do today and here's the outline of my talk is basically talk a little tiny bit about myeloma epidemiology because we're all here together as uh people interested or either having myeloma or caring for somebody with myeloma talk a little bit about that why do we do autologous stem cell transplants at all for myeloma and then the question that i think comes up is should everybody get a transplant and also what are some of the results with autologous stem cell transplantation and then i think a very pertinent question are we always going to do transplants so i think unfortunately i think there was some controversy earlier or some years ago about whether or not myeloma is becoming more common and i think most people think it probably is so these are the most recent data from the american cancer society showing that the incidence of myeloma in both men and women continues to be increasing and we think it's le not just a phenomenon of more cases being discovered because we're just better at diagnosing it as i think everyone here in the audience knows there are still unexplained differences in different types of populations for the incidence of myeloma with a lower rate seen in people of asian descent and of course a hot the highest rate at least in the us seen in black americans and again this is also unfortunately true carries over to death rates as well this is a an interesting map that was published this year looking at incidents of myeloma by state and you can see that there are some areas shown in the brown that seem to have a higher incidence of myeloma and again that may reflect some of the ethnicities of the populations who live there so to to clarify terminology just for the rest of the day an autologous stem cell transplant or an autologous bone marrow transplant refers to using your own cells and basically and i think sometimes there's some confusion about this what we're what we're doing with those cells is they're really sort of serving as an antidote for what we call the conditioning regimen which is basically chemotherapy or chemotherapy blood plus radiation that's used to kill off any remaining cancer cells and the in the the bone marrow or cells that are fused in are basically there to help your blood counts recover and that's opposed to an allergenic transplant where we're often still giving conditioning regimen to control the cancer but at the same time those cells that we're giving or or marrow it can be that as well are actually supposed to be fighting the cancer itself through some immune effects and for reasons that i'll just touch upon later allergenic transplants are done very infrequently in multiple myeloma and really i think are considered by most experts to be a research question so why do we do autologous transplants in the first place in myeloma and i think to frame this is a nice map this was actually published in circulation recently looking at the development of various drugs for the treatment of myeloma and i'd like you to focus here on this area going back to the 1960s so the average survival for a person diagnosed with myeloma in 1960 was six months which is obviously terrible and right at the end of that decade simultaneously in the soviet union in the uni uh the united kingdom melphilan or l-phenylalanine mustard was developed as an oral agent and was given with steroids and this increased survival in myeloma from six months to 18 months which was really a big deal but what then happened if you look um at this timeline here that nothing is happening in other words 25 years go by and there really isn't any improvement at all in myeloma treatment and really not many drugs so it's not surprising therefore and that's listed on the timeline here in 1983 a couple of investigators in the uk uh mcelwine and powell's basically said all right we've got one drug here we've got melflem why don't we do something different with the mouthland and what they ended up doing is treating nine people some with newly diagnosed but others with relapsed myeloma with one big slug of intravenous melflin and what they ended up publishing here was that something quite surprising that had really not been seen before that of these nine patients five of them responded so very high response rate and three of them appeared to go in remission it was really something that had never been seen before but what they did notice is that the time that these individuals had very low blood counts was for weeks and so of course the idea was all right there's dose intensity that seems to be helpful in myeloma but we're going to have to do something to help people improve their counts and so this started to be explored in the mid 1980s this was a paper published uh 40 years ago by bart barlogi and what they did in this particular study is take people with myeloma just a handful and actually do an autologous transplant in this case uh they were treated with melphilan and then they were able to show that they seemed to do a little bit better than than not doing a transplant but it was still uh the the take away message was maybe if you wait too long when a person's had myeloma for a while the transplant doesn't do much so fast forward another 10 years and this is really the study i think that sort of broke open uh transplants for myeloma as we know them today and this was a study of 200 newly diagnosed patients with multiple myeloma from france and they received either the best chemotherapy of the day a combination called vmc and vcmpb which we don't use anymore but they either got that chemotherapy or that chemo plus a transplant and what the investigators showed was really striking because the response rate was way higher but also in long-term follow-up the survival rate was uh literally almost five times better if a person had a transplant and one of the other things that they noted in a follow-up study is that the quality of life for people after they recovered from the transplant also seemed to be improving so right now uh autologous stem cell transfer from multiple myeloma is really the number one indication in the us for a transplant and we're going to talk the reasons why and many of us think that this number should actually be twice as high as it is because we really do think that there are measurable benefits from a transplant so to to talk a little bit about how we sequence in a transplant or make this decision um as many of you know if you're newly diagnosed with multiple myeloma the first thing we decide to do is how are we going to treat you initially now we never do a transplant as the first step so we always want to give a lead-in type of chemotherapy so how we pick that is also undergoing changes right now and and as opposed to the 1960s where the response rates were quite slow with drugs like melphalan we now know that we can use combinations that can give very quick response rates often in a month or two and we want to do that we want to get that deep response we want to improve the performance status that means how well somebody's functioning just in their daily role and we want to improve their quality of life of course we want to limit side effects but we also want to pick drugs that we think can help not interfere with stem cell mobilization and currently most of the research is looking at should we offer you four drugs or three drugs or maybe for less fit individuals two drugs and then how long are we going to do that for and then finally if we're going to offer a transplant when should we do that and by and large and i'm not going to touch upon this right now most of the transplants done in the u.s are done as part of initial therapy as part of an initial package of treatment now one of the things to keep in mind is that if you look at the average age of a person diagnosed with myeloma it's 69 and more than a quarter of people diagnosed with myeloma are over 75. so for a while it seemed like transplants were only something to consider in younger patients which was really initially defined years ago as less than 60. but more and more we believe that the the thing that we should be paying attention to is actually fitness now this is not a transplant study but what i'd like to focus on here is blue in the blue line are patients who are older but who are considered fit so they can do all of their normal activities they can manage their money they can handle transportation whether that's driving or getting on a bus and if you look at people who can do that regardless of their stage of myeloma they are going to live longer than frail individuals and they're also going to be more likely to adhere to treatment so we do now when we're recommending autologous stem cell transplant really look at fitness as a very important factor and there are people who are 50 years old who probably shouldn't get a transplant because they have too many other important medical problems that might cause some interference now very quickly i'm going to i know the other speakers are going to touch upon this most of the time you're going to be offered a stem cell collection if you are opting for treatment for a transplant after about two cycles of therapy you can do this later on at well there's various reasons why that sometimes it gets a little bit more difficult and typically you're going to receive what's called mobilization now more and more this is done with one or two drugs either just growth factor something called craniocyte colony stimul stimulating factor by itself or often now with a drug called pleuric sephora mobizole and then there are still some people who are receiving chemotherapy as part of their mobilization strategy and then anywhere from a few days later to several weeks later if it involves chemotherapy you're asked to come to get cells collected with an apheresis machine that's shown over here and either you'll have this done either through peripheral ivs or sometimes a central line will be placed and then your blood will be filtered to take out these stem cells and typically per transplant we're looking for a minimum of two million cells per kilogram of body weight and most transplant centers are looking to collect a minimum of five so that there could be enough for two transplants either done at the same time back to back or later on as a salvage therapy so this is very briefly again the time course of what to expect if you were having a transplant and so um this is uh showing uh a person you know getting that mobilization which bumps up their white count the cells are collected down here then they're coming in either the clinic uh in many places do this completely as an outpatient or some people are admitted getting this mouth land which has been really over the years compared to many many other drugs and still seems to be the winner in most studies uh the the melflin is infused and then you are either monitored or as an outpatient or followed for uh in the hospital usually about two weeks for the very severest side effects usually can be some nausea vomiting diarrhea you're given a cocktail of antibacterial antifungal antiviral medications and then in about two weeks your counts recover and you're either at home or you're sent home and in reality it takes several more months after that for people to feel like they're back doing most of their normal activities and it takes about 60 days to see somebody's hair regrow okay so if we can give you kind of a laundry list or what are the pros and cons of autologous stem cell transplantation i think definitely in terms of advantages and many of us who've treated patients still believe this is that that one time therapy yes you are you are making this is a project to do this this is several months in the making but it has a lot of advantages in terms of being over with and so instead of coming in weekly uh for repetitive cycles of chemotherapy we can say let's focus on getting this done and then you get back to living there is a track record of effectiveness of this intervention that i'll show you shortly you can do this twice which is wonderful or some people have had even three transplants um and then even adding in another piece to this package the induction the transplant and now maintenance we really hope that in the majority of people we can control their myeloma for years before they're even going to need to consider another intervention on the disadvantaged side clearly there are side effects um as i mentioned during that little schema and there's also a death rate that's measurable it's less than one percent in most transplant centers in the country but it is still there and it is a risk and which is one of the reasons we look at that frailty uh equation there is the confinement in the hospital or clinic and of course you've got time away from home uh and a family and work and then there are rarely some long-term side effects that are associated with transplant probably the most serious of which can be blood disorders related to the transplant uh and potentially maintenance that happens maybe one to two percent of patients that can really be life-threatening but but let's move on again to the results and why we keep recommending transplants so um so you saw the results from you know almost 25 years ago what about more recent results and so this is a study from italy where they compared transplantation to the combination of melphalan uh revlimid and dexamethasone and as you can see in the blue lines the patients who got transplant and particularly maintenance ended up having a much better control of their myeloma and actually compared to those patients getting oral chemotherapy and no maintenance the survival was enhanced by the transplant here's another study from europe where instead of melphalan prednisone and revlimid they gave oral cyclophosimide revlimid and dexamethasone and compared that to a transplant and again you see the same type of results where patients receiving the transplant had better control of their myeloma but they also have better survival as well now studies like these have been criticized saying well that's not what the that's not the chemotherapy that we give in the u.s so of course it didn't do as well as transplants so what if you gave what is considered right now really the gold standard and that brings us to the ifm 2009 dana-farber cancer institute study in which a large number of newly diagnosed myeloma patients less than 65 were randomized to receive again best chemo that we believe velcade revlimid and dexamethasone either that as chemo alone for eight cycles or that chemotherapy with a stem cell transplant followed by vrd for two more cycles and then a year of lenoletamide maintenance and what this study has showed and it continues to be reported upon is that significant difference in control of myeloma what we call progression-free survival no particular difference right now in overall survival but a lot of people think that's related to the fact that by design people in the chemo only arm were salvaged with an autologous stem cell transplant if they progressed there also does seem to be an advantage if you were looking at mrd as we call it minimal residual disease for the transplant arm um so so these study this study is still being uh analyzed from the u.s component and we'll be very interested to see if this is uh their that data holds up as well and that'll probably come out i believe sometime next year how about two transplants so so this is a study that was recently updated again from europe where patients with newly diagnosed myeloma received velcade cyclophosamide and dexamethasone or cybor d and then they were randomized to receive velcade melphalan and prednisone or a single or double transplant and that was assigned based on what those transplant centers normally do and then they were randomized again to receive more consolidation with vrd or no consolidation at all so what i want to focus on here is basically what happened after that second transplant so does the data support doing two so they did show that a number of patients had a significant improvement in their response after the second transplant and particularly people with high risk myeloma were teased out and they did look like they benefited from that second autologous transplant what should be kept in mind is there were some patients who actually didn't look like they responded to that second transplant and then one of the other criticisms of this study of recommending autologous stem cell transplant for everyone is that the induction was not velcade repliment and dexamethasone and some people think that makes a really big difference so that brings us to uh actually dr gerald's study the stamina trial this is a u.s trial where patients could have any kind of induction for up to 12 months and then had a stem cell transplant and then one of three types of maintenance or consolidation and a third of these patients were randomized to two transplants one third had v or d consolidation for four cycles and the other just went straight on to lenolitomide maintenance and what this study has reported out and shown is that if you look at the entire groups based on intent to treat that means everybody gets assigned to their group and you analyze it that way there didn't appear to be any advantage for any of these treatments over lenolitomine maintenance with a stem cell transplant in terms of both progression-free survival and overall survival and also there seem to be no difference in the arms in terms of what we call secondary malignancies now more recently there has been an attempt to say okay if you look at high-risk myeloma were there any differences seen between these interventions and at least it looked like on a raw numbers based on that intent to treat basis no however if you break it down to look at particularly in the second auto transplant the double autologous stem cell transplant it does appear that people who got that second transplant particularly if they had higher risk disease may have benefited from that and so that is something that i think is going to be focused upon but again statistically it's a little bit squishy to say you know only look at people who got the treatment usually we believe it's more important to look at the whole group one of the other factors that came out from this longer term analysis was that still that that lengthier time on lenolitamide maintenance seems to be helpful now let's go quickly to allogeneic transplant here and i mentioned that there really hasn't been a lot of data that supports the routine use of an algenic transplant for myeloma as opposed to other blood disorders and this is very long-term data just published by dr jurash this year looking at a study that compared a large number of patients who are randomized to receive either tandem autologous stem cell transplants or an autologous transplant followed by a low intensity allergenic transplant and even after 10 years of follow-up if you look at these graphs they still were unable to show an advantage for an allergenic transplant there was a suggestion that in high-risk patients it might be better but this is not considered statistically significant so in my opinion allergenic transplants why they continue to be very tantalizing as perhaps offering a cure are still something that that are largely a research question and something that we hope that we continue to try to craft studies that can answer that question uh more more effectively so how about will transplants become obsolete and this is something called the forte trial looking at what was considered best chemotherapy this these are all carphilsome based treatments again i won't go into all the details but the but the idea here is if you give people enough carfilzomib uh based regimens like essentially a year of therapy could you just stamp out the transplant and so in terms of things like progression free survival they were able to show that there was they were equivalent in terms of of uh looking at their responses to a year of carphylsemit revlimid and dexamethasone versus some months of that with a stem cell transplant but one thing that does appear to be different is obtaining minimal residual disease so here in the orange people receiving the transplant look to have a higher rate of mrd negativity and those who could be evaluated for it and one of the other factors that was found is the patients who had an autologous transplant had a lower rate of early relapse so everybody is looking forward to seeing whether or not this holds out but i think in my opinion this still shows that there is benefit for an autologous stem cell transplant so are we going to be doing stem cell transplants 20 years from now and i think really the big challenger is going to be the immunotherapies and this is just a slide to remind everybody if you look at only one target that is under investigation in myeloma b-cell maturation antigen there's all sorts of ways to exploit this and if we just look briefly at car t so there's drug antibody conjugates there's bi-specific engagers but just looking at car t responses very high responses in a very heavily pre-treated myeloma population so the questions out there if we start moving a car t transplant maybe to front-line therapy is this going to essentially knock myeloma off the off the pedestal so i think we're we're very interested to see what the results of trials like this that are coming out soon are going to show us so uh that is the end of my talk and in conclusion i think autologous stem cell transplants really are a very important part of myeloma treatment they do offer excellent control of myeloma it does offer time off of more intensive therapies and time away from the clinic i think in many cases people do come back and say you know my quality of life in the short one was harder but in the long run is better even transplants still remain important with the best drugs that we have it is possible however that newer therapies in the future are going to dethrone transplantation so thank you very much [Music]