(Guest Lecture): Stem Cell Transplant | MCRT Webcast: Experts Discuss Newly Diagnosed Multiple Myeloma Issues

I'm trying to talk very briefly on the role of stem cell transplantation in multiple myeloma. I'm going to focus on autologous transplant because that is the standard of care for treatment for transplant eligible patients. As both of the speakers have mentioned briefly on the myeloma disease, it is about rare cancer, about 1% of all cancers and about 10% of all blood cancers. This is the estimate of the American Cancer Society for 2020, 32,270 new cases for 2020 and out of that about 13,000 expected deaths. The disease of the elderly, some median age is about 65 plus years, but having said that, all of us who are seeing myeloma patients in and out, we're seeing very young patients as well. The youngest patient I have is about 30 year old, very unfortunately patient. And it occurs in all races, but as Dr. Kalanir said, it is twice more common in African Americans than Caucasians and there might be some genetic influence there. The study is ongoing for that. So both of the speakers said beautifully about the milestones that we have achieved in the treatment paradigm in multiple myeloma leading to tripling of the survival than what it was about 20 years ago. So the first treatment, that systematic treatment started in 1960s with the introduction of oral melphalan and Pernishone. And you can see in the figure, the high dose therapy or high dose therapy, or high dose melphalan, which is a part of the autologous stem cell transplant started in 1980s. That time it was started without any stem cell support. And then later on the stem cell support was given. And the first randomized trial to establish the benefit of the high dose therapy followed by autologous stem cell rescue was done by a French group in 1996 leading that lead to a, that showed that the high dose therapy followed by transplant was associated with the progression for survival and oral survival than the conventional therapy. Now, as you all know, the novel agents that started in early 2000 with the introduction of a drug with halidomidin and its analogs. And since that time, we have achieved a lot of success in myeloma therapy with introduction of the code of individuals, second generation inmates, and in the last five years, the introduction of the monoclonal antibodies. So as you can see, this introduction several therapies have increased the survival quite a bit, but the role of stem cell transplant still remains very strong. Even with the introduction of all those therapies, the transplant still remains a very important therapy for the eligible patients. So what is stem cell transplant? Actually, when I tell my patients, it is not a transplant per se that you are getting transplant from somebody else when you're talking about autologous transplant. So it is nothing but it is basically stem cell rescue. So what we're doing, this is several steps involved in the process of stem cell transplant. The first step is the collection of the stem cells. These are the stem cells that go on and multiply to become a good cells like red blood cells, white blood cells, platelets that are needed for the survival of the body. So we take those stem cells and then we collect and process them and we put them in the freezer. So when you put them in the freezer, we can be used any point of time later on. And once after that process is done, we give a very high dose of chemotherapy and the standard of chemotherapy that is used in this process is melphalan. So that was introduced in 1980s. And the high dose melphalan will kill off all the good and bad cells and we hope that during the process it kills off the bad cells as well. And since you need those good cells for survival, we infuse those stem cells. So it's basically we're giving a high dose chemotherapy to clean off your bone marrow and then infusing those stem cells. This is basically in a nutshell, stem cell transplant, autologous stem cell transplant is. So when I tell my patients to understand them better, I tell them it is like a lawn care. So this is a lawn which has a lot of grants, which is the work you need, but they have a lot of weeds as well, which is like a cancer cells. And you want to kill the weeds off and use them with the initial chemotherapy to get the weeds off. But somehow or the other, the weeds are still there. So what do we do is you kill off those everything, including you clean your lawn. But you need the grass for a lawn. So you need to have the seeds at the store and that is something like the stem cells. So stem cells like nothing but the seeds. And then this, when you kill off this or clean the marrow, you give the high dose chemotherapy like cleaning your lawn. And since once that is done, you put the seeds back and wait for the counts to come up and same like growing your grass in the lawn, you have to maintain it properly, make sure that you water the lawn and then make sure that they are not infested by the other outside invaders and then make the lawn go completely as if, you know, and ultimately you want the clean lawn with the grass, a lot of good grass and no evidence of any other weeds. It's something like the conceptually it is something like that. So you are killing off your bone marrow cells and in the process you kill off your good cells and both bad cells and then you get the stem cells back and wait for the counts to come back and ultimately your good counts with the hope that there are no weeds left. Now, so if you look at the role of stem cell transplant, the autologous stem cell transplant, the molecular myeloma remains the most important indication for autologous stem cell transplant. This is the data from CIBMTR and this is from 2014 data as you can see on the left hand side. And the green is for the autologous transplant and the blue is for the allogenic transplant, so which is the transplant from the donor and multiple myeloma still remains number one indication even now as a call as a modality of the autologous stem cell transplant and there is after that is lymphoma. And the trends for the autologous transplant over the years is growing in the case of myeloma. Now, having said that, it still remains an underutilized modality of treatment despite being a very effective treatment. It still remains an underutilized modality, especially in the minorities. The rate of transplant license is about 30 percent, so that is the lot of work still has to be done because it is effective therapy and it still remains an underutilized. Now, the big question that comes to patients and to all of us is, is there still a role of autologous transplant in myeloma in the current era? So Dr. Costa showed a beautiful slide of the new drugs, the combinations and the good responses that we have seen with this introduction of these regimens. But now the question that comes up is, do we still need to go for a transplant? And my patients always ask me this question, that either can we avoid that or do we need to like that? Is it alternate treatment that we can do that would get the same benefit of the transplant? And the question, at this point of time, I can say that there is still a role and the transplant still has an important role in controlling a disease and to get the better outcome in the long term. Now, what is the evidence behind that? So this is the summary of the studies that have been done in the current era that try to establish the role of stem cell transplant in the context of novel agents. So there are a total of five studies. The first two studies are the studies that were done in 2014-15 that used a Revlimid dext induction, which is the one that we kind of don't use that frequently now because now as we all know, the triplet induction is the standard of care. And so in this group, the patients were randomized to two transplant back-to-back versus the conventional drug. And this is the data. So there are two important points that we have to look at. One is called progression-free survival, and the other one is over-re-survival. The progression-free survival means how long your disease remains in remission. And then over-re-survival is how long you live, which is the most important endpoint. And as you can see that in both the cases, the progression-free survival, the SDT stands for high-dose therapy or the transplant group, and the SDT stands for the standard of care non-transplant group. And as you can see, people who went to high-dose therapy group, their progression-free survival is 43 months and significantly much higher than the standard therapy group. And similarly for the overall survival, their overall survival is the four-year overall survival. The four-year overall survival was also significantly higher. Now, the study that is really relevant to our context in the context of the US is this study by Atal, which is the IFM 2009 study from the French group. They looked at the patients. Another question that came up was, can we delay the transplant and can do the transplant after a first relapse? So this study tried to answer the question in the context of the more on therapy. So in this study, the patients got hard VD induction, about three cycles, and they went to either transplant with Melflo and 200 single transplant, or they had just stem cell collected and they went to get the Edison cycles of VRE. And as you can see, the PFS, so this is for the early transplant group, the people who went to early transplant, their PFS benefit was 50 months versus 36 months. So significantly different. And the overall survival was about pretty much the same, about 80% in both arms at a four-year mark. Now, what important to realize is that in this group, the people who are relapsing at the first relapse, they were mandated to get the transplant at the first relapse. So these people who didn't get the transplant earlier, they went on to get the transplant later on. Now, this recently published is a study from the Italian group. They looked at three things. One, they looked at whether there is benefit of transplant, and also there is benefit of double transplant versus single transplant. Now, this is for the whole group. They are also the same thing. There was a progressive survival benefit. That means the disease remission, they're significantly longer time with the transplant group versus the non-transplant group, and the survival was pretty much the same. Now, if you look at this data a little bit more closely, when they looked at the double transplant versus single transplant, the overall, the people who really benefited are the patients who were in the high-risk group. Now, there is another trial that in the US that we did called Stamina trial, which I didn't show, which tried to answer the question of single transplant versus double transplant versus single transplant followed by consolidation with the VRD, and that didn't show any benefit in three groups. They are all same. So the question of tandem transplant or double transplant still remains an open question, and there are a lot of debate out there still, but it is different in the US study and the European study. And lastly, there is a study from the Spanish group called Forte study, which tried to answer the question with the KRD induction. And we know that KRD is a very powerful regimen and a new API, and they did the KRD induction transplant versus KRD 12 cycles. And what they found out is that for the KRD transplant group, what is significant to know is that the risk of early progression, means the people who are progressing in 18 months after transplant, the risk is significantly much lower in the transplant group, about 8% versus 17%. So what all this data suggests is that the early transplant or the transplant in myeloma helps you to achieve a longer and deeper remission. And if you want to achieve the first remission, which is the best remission, longer, then probably transplant is the best strategy. Now in all these studies, except for the Forte study, we don't have the data. All these studies, the patients who are not in the transplant group, when they relapse and the first time, most of them went to get a transplant as a salvage therapy. For example, in the ULTEL study, which is the IFM study that they mandated the patient who were going to relapse or the first relapse to get a transplant, 79% of the patients went to get the transplant. Now that's the reason probably the survival is sinking. But what it highlights most important point is that if you want to get a transplant at a later time or after first relapse, not all of the patients will be able to get a transplant. As you can see, they were mandated to get a transplant, all of them at the first relapse, but only 80%, less than 80% of them were able to get a transplant. And more than 20% of patients were not able to get a transplant because of a number of reasons. One could be the disease became very aggressive, more aggressive than when it came back. And what two is the patients probably were much older, the patients were sicker with other comorbidities. So it is important based on this data that even in the context of the modern therapy, I think to get a best remission and also longer remission probably transplant is the best strategy as a backbone in these eligible patients. Now, so Dr. Costa mentioned about the achievement of the minimal residual disease status, negative MRD status, and that translating into better outcomes with the therapy. Now all these studies, the recent studies, particularly the IFM study and the FOTA study looked at the MRD level after transplant. So this is the subset analysis of the IFM study where the people got the RVD arm and all the transplant arm. And this is the MRD level measured by the next-gen sequencing, which is the FDA approved assay. And you can see there is a significant difference in the level of MRD negativity achievement with the transplant modality about 30% versus 20%. So there is about 10% difference in the MRD difference, MRD negativity difference with the transplant arm. So that established that the transplant can achieve a deep responses. Now on the right-hand side of the curve, you can see that the people do the same, whether the standard risk or high risk, if they achieve the MRD negativity. So one of the questions that people sometimes ask me is that, do we really need to transplant MRD negativity? Now here the study is not designed to answer that, but more importantly, what we have to rely on is if you do a transplant, the chance of you actually MRD negativity is much higher than not doing a transplant. So based on that also, if you want to achieve deep and longer remission, at this point of time transplant still remains the important modality. Now what about the quality of life? People kind of worried about when you talk to them about post-transplant course, staying in the hospital for two weeks and then your immune system going down, people always ask about the quality of life. Unfortunately, there is no any prospective data looking at the quality of life in the current setting. So this is the study that was done before we had this novel agents and all those stuff in 1998. And they looked at one of the end point called TWIST. TWIST stands for treatment time without symptoms treatment and treatment toxicity. So if you look at this, the people who went early transplant, so this is the study that was designed to look at the benefit of early versus delayed transplant in the pre-noval agent era. And when they looked at that end point, they found that people went early transplant, that TWIST or the time without symptoms treatment and treatment toxic is much longer, significantly much longer than the people who went to delayed transplant. So if we extrapolate that data, I mean it is possible that the patients who are going to early transplant because they are younger, they're probably fitter and they have probably less comorbidities than delayed time, it is possible that they would have a better quality of life. And based on our clinical experience, I can tell you that the rough time is the first two weeks after the transplant, after the recover from the transplant, given the fact that they don't need to be a lot of treatment, just a little bit of maintenance treatment, their quality of life has, based on our experience, is much better than that. But if you look at the study, there is not much of a prospective study and that is needed at this time to answer that question. Now, who are the candidates for an autologous stem cell transplant? So the study that I showed to you, all the five studies, they are European studies and they looked at the patients, the age limit was about 65 years of age. As we know that myeloma is a disease made in ages over 65 plus, so about two to two-thirds of the patients are not represented in that group. But we have a lot of real old evidence that patients, 65 plus and even older patients can derive the benefit of the stem cell transplant. So I can tell you from our experience, we have transplanted patients up to 80 years of age as well. So age is not a limitation. What is important is how functional and how fit the patient is. As long as there is no prohibitive comorbidities, that means if the lung and heart is doing okay, the patient is fit enough that the performing status is good enough to allow them, we will usually take them to transplant. And the patients should have adequate stem cell collection, minimum is around two million in most of the centers. And in general, it's a very safe modality. And the data that I showed to you, and there are a few of the two of the studies reported the transplant related mortality, or the risk of dying just because you went to transplant, the risk was less than one percent. So this is the national average. But if you look at the center specific, that is much less than that. So it's much safer modality, and then it's pretty effective modality. So that's why we kind of encourage the patients who are transplant eligible to go to this treatment process. Now, what are the complications? Some of the complications that I think were worth knowing is that divided into two, one is immediate and early complications, and the other one is late complications. Most of the complications that patients usually face is the immediate and early complications. The immediate complications could be related to the stem cell infusion, reaction to the stem cell, to the preservative or sometime flushing, and all that kind of thing can happen. They're very rare. Mainly the complications happen during the early period when the patient don't have enough blood cells that can result in the mucositis, result in potential infections, though we do all the preventive antibiotics, prophylactic antibiotics for doing the time. And sometimes during the time when the counts are coming up, we can also see some of the symptoms, patient experience with the diarrhea and fever, we call this engraftment syndrome, but it's very easily treatable with the steroids. And the late complications are sometimes some of the patients may not get engraftment or especially the predatory engraftment can be late. Infections can still be a risk because your immune system may not have mature right away. And so we put them in some prophylactic antibacterial and antiviral medications. And the late complications include the risk of second cancers. So the risk of second cancers in people who went to transplant versus those who didn't go to transplant is slightly higher. And also sometimes the infection risk can be there because of the hypogammaglobulinemia or the low immunoglobulin level. But if you look at all this risk and the benefits, the benefits definitely outweigh the risk. And so it's better, we kind of recommend going for this morality for this disease. And one of the questions that always come to in the last two months and now is do we do transplant in the current setting when the COVID-19 outbreak? Now, as I said before, in our central, we didn't do a transplant in the month of April, but now we have started that. So this is some of the guidelines that is out there. And I just got it, it was probably applicable in most of the setting. The standard risk myeloma, you might consider by delaying the transplant, especially in the outbreak depending on the center and depending on the reason and how much surge is there and all those stuff. You might consider delaying the transplant by adding one or two cycles of induction treatment. And also you can delay the collection. But in high risk myeloma, I think, because a lot of studies have shown that there's a benefit of the transplant in a high risk setting, particularly somebody with the 7-pt deletion. So I think it is recommended to proceed with the transplant and we make sure that we test for the SARS-CoV-2 infection before the transplant and make sure they are not infected and take them to transplant. This probably would change even for the standard risk setting and going forward because now we know how to do the appropriate precautions and then we are more experienced in managing these patients now. So in conclusion, despite the development of a lot of effective therapies and regimens, auto transplant remains the preferred therapy for eligible patients. It is associated with significant PFS benefit or progressive survival benefit. And if you definitely associate with OS benefit if you don't do transplant, even for the early versus delayed transplant, maybe associate with the OS benefit if you follow them up longer time because we have a lot of effective therapies once the patient relapses and that might have kind of negated the benefit of the overall survival benefit of the transplant. But we for sure know that it is associated with deeper responses including the MRD negativity and we all know the achievement of the first remission and the long remission is the best remission and then also the long remission with the first remission is always important. So for that, transplant remains an important modality. Toxicity and the death associated with the procedure are very minimal. The overall mortality rate with the transplant is less than 1% and it may also be associated with quality of five, though we still don't have the data in the current setting. But based on our clinical experience, I can tell you that this may be actually the improved quality of life.