Transplants for Older Adults: Who Is a Good Candidate?

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Transplants for Older Adults: Who Is a Good Candidate?

Tuesday, May 3, 2022

Presenter: Uday Popat MD, University of Texas MD Anderson Cancer Center

Presentation is 25 minutes long with 19 minutes of Q & A.

Summary: Stem cell transplants in older patients have, historically, had lower success rates than those in younger patients. This presentation describes several new promising strategies to improve transplant outcomes and survival rates in older patients.

Many thanks to Pharmacyclics, an AbbVie Company, and Janssen Biotech, Inc., Jazz Pharmaceuticals and Omeros Corporation, whose support, in part helped make this workshop possible.

Highlights:

• Older patients are most in need and are increasingly undergoing stem cell transplantation, but outcomes need to be improved.
• Giving older patients high-dose chemotherapy given in smaller dosages over two-three weeks, instead of higher dosages in one week can improve outcomes.
• A “pre-habilitation” program to improve older patients’ overall fitness and physiological reserve before transplant improves outcomes after transplant.

Key Points:

(04:10): How healthy a patient is – the physiological age - is more important than chronological age, when considering whether an older adult should consider a stem cell transplant.  

(05:45): Since the median age for blood cancers is 68, it’s important to find effective ways to transplant older patients.

(06:19): The number of stem cell transplants performed in older patients is increasing.

(09:35): Older patients are most in need of transplant, are getting them more frequently, and their outcomes are getting better

(10:54): Older patients who have other health concerns, are not active, are unable to perform tasks of daily living and/or are unable to process information well have a poorer outcome after transplant than those who are fit.

(12:13): A promising strategy to improve outcomes in older adults is to give them high intensity chemotherapy before transplant over a longer period of time, like two to three weeks, rather than the standard one week

(16:41): Outcomes in older patients can also be improved by providing better supportive care to address other health issues associated with advanced age.

(18:29): Improving the fitness and nutritional status of older patients – their physiological reserve – before transplant can improve the outcome after transplant.

(19:48): A “prehabilitation program” was initiated at MD Anderson Cancer Center to improve the physical and functional status of older patients prior to transplant that involved a physical medicine and rehab physician, physical therapist, occupational therapist, dietitian, clinical pharmacist, advanced practice providers, nurses and geriatric doctors.  

(22:42): Prehabilitation activities significantly improved survival rates in older patients.

Transcript of Presentation:

(00:02): [Lynne Spina]  Introduction. Hello. My name is Lynne Spina. Welcome to the workshop Transplants for Older Adults: Who is a Good Candidate?

(00:11): First, I'd like to thank Pharmacyclics, an AbbVie Company, and Janssen Biotech, Inc., Jazz Pharmaceuticals and Omeros Corporation, whose support helped make this workshop possible.

(00:26): It is now my pleasure to introduce to you our speaker, Dr. Uday Popat. Dr. Popat is a Professor in the Department of Stem Cell Transplantation at the University of Texas MD Anderson Cancer Center in Houston, Texas. He is also the Interim Deputy Chair of the Department of Stem Cell Transplantation. His research interests include reduced intensity allogeneic transplantation for patients with myelofibrosis, the use of stem cell transplantation to treat multiple sclerosis, and transplants for older adults and patients with other medical issues in addition to their primary diagnosis. Please join me in welcoming Dr. Popat.

(01:20): [Uday Popat]     Overview of Talk. Thank you, Lynne, for that kind introduction, and good morning, everybody. I guess it is morning here in Central time zone. I guess some of you are on the Eastern time zone. So very good afternoon to all of you. And it's a pleasure to give a talk about this. And what I'm going to do here is to share a few thoughts about stem cell transplantation in older adults. And hopefully after 30 or 35 minutes of the talk, I will have a chance to answer your questions. So without further ado, I'll go ahead.

(02:06): So here are the few key points I'd like to make. First, older patients are most in need of, and are increasingly undergoing, transplantation. However, we do need to improve the outcomes.

(02:23): Factors predicting success include other health concerns at the time of transplant, what we technically call comorbidities; geriatric assessment, that is assessment of whether you are able to do your activities independently, activities of daily living, and your ability to process information and cognitive status.

(02:53): Next I'll go over how to improve outcomes in older patients, and we'll share some exciting data we have had at our own center, both in improving the conditioning regimen, that is a treatment that we give before the transplant and improving our supportive care. And I'll talk a little bit about either of those.

(03:16): Older patients with acute myeloid leukemia are cured less often than younger patients. So without further ado, I'll proceed. So I'm going to show you some of the graphs, and this is probably the first one. And what you see here is the survival and cure rate of acute myeloid leukemia. This is data from England. And I would like you to focus on the blue line. And what you see in the top left curve is that this line is sloping up, and about 50% of the patients, younger patients, are cured. However, if you go at the bottom line bottom, right hand corner, this refers to older patient and only up to 20% of older patients are cured with this disease. And we hope to change that as you will see in some of the slides and data, I'll show you later.

(04:10): How healthy a patient is – the physiological age - is more important than chronological age, when considering whether an older adult should consider a stem cell transplant.  So, I think one of the first question people ask me is how old is old? Well, it changes as I get older. So, to my young daughter who is currently 17 or 18, her older sister, who is about 8 years older and who is a resident, she thinks she's too old and I, for her, am extra old.

(04:41): But coming back to it, if you look at it, in transplant literature, many a times, some people would consider old as older than 60, and the reason there is, when you use an intense myeloablative regimen, the outcome is not good for these patients. And therefore you consider old as older than 60.

(05:06): But these days we are using reduced intensity regimens in these patients. And we do transplant in older patients. And as a matter of fact, at the end of my slide, I'll show you that we even have a myeloablative regimen for older patients, which we can deliver safely.

(05:26):. One of the other definitions people use [for old] is when you are eligible for Medicare. That is older than 65. Again, I think what I would say is age is just a number. I think what is more important is how healthy you are, what is your physiological age?

(05:45): Since the median age for blood cancers is 68, it’s important to find effective ways to transplant older patients. And really, we do need therapy for older patients simply because the median age at which all blood cancers occur is about 68. So if we have a treatment that misses half the patients, I don't think it is worth it, which is why we really, really need to improve our treatment. And that is what we have been working on. Transplant can be curative in substantial number of patients.

(06:19): The number of stem cell transplants performed in older patients is increasing. Here, on this slide, you can see in the left panel, you see in the bar chart, over time, the number of older patients undergoing transplant is increasing. So in the green here is patients 60 to 69 years old. And in gray is patients who are older than 70. This is data from the Center for International Blood and Marrow Transplant.

(06:47): And on the right hand side, you can see our own data from MD Anderson Cancer Center. And this is data, number of patients older than 65 undergoing transplant. And as you can see ,in the early 2000s, only handful of patients were undergoing transplant, perhaps 15 to 16 per year. But last year we had about hundred patients older than 60 have allogeneic transplant. So things are changing.

(07:19): Historically, survival after a stem cell transplant using donor cells (allogeneic transplant) was lower in older patients, compared to younger patients. And so are the outcomes. And I think I'll show you several of this graph just so that you get aligned to it. On the X axis, it is time. Here the time is in months. And on the Y axis or the vertical axis, it is the probability of survival. And the top of the line it is one or a hundred percent. And as you go down, higher the line, the better is the outcome.

(07:48): So in the left part of the graph, what you see here is that the younger patients traditionally have a better outcome. So 68% survival in patients who are younger than 40, as opposed to, say, 48% in patients who are older than 60.

(08:09): However, on the right hand side, what you can see here is that the outcome [in patients] older than 65 is even worse than those who are between 60 and 64. And keep these numbers in mind when I show you the later slide, because we do plan and want to change this.

(08:33): One other thing I will mention. My talk mainly concerns allogeneic transplant, or transplant from somebody else, and not autologous transplant, or the transplant from yourself.

(08:52): When I use the word myeloablative transplant, what it means is very high dose of chemotherapy that is given to the patient, which is what you we use in younger patients. Whereas reduced intensity is the lower intensity of the conditioning regimen that we use, or the chemotherapy regimen we use. And really what I'm, again, going to reiterate and show you is that we do have a way of delivering very intense conditioning to older patient. And the reason we want to do this is to reduce the relapse rate or cure the cancer.

(09:35): Older patients are most in need of transplant, are getting them more frequently, and their outcomes are getting better. So key point of these many slides is that older patients are most in need, they are increasingly undergoing allogeneic transplant, as I showed you. And again, outcomes are getting better, but we need to get them even better or improve them even further.

(09:53): Likelihood of a successful outcome in older adults undergoing transplant depends onSo what determines the outcomes? What determine the likelihood of success? So it's a balance. The benefit of transplant is long term disease-free survival or cure, on your left, whereas the risk is treatment related complications, treatment related morbidity, and mortality. And that depends on several things. So whether a patient should undergo a transplant or not would depend on treatment related morbidity and mortality. What the alternatives are available? What is the prognosis or what is the likely outcome? Again, age and other illnesses or other comorbid illnesses. They also make a difference. And of course, at the end of the day, as a patient, what your thoughts are, what your viewpoint is. That's again, very important.

(10:54): Older patients who have other health concerns, are not active, are unable to perform tasks of daily living and/or are unable to process information well have a poorer outcome after transplant than those who are fit. Here is a graph showing that if you have more comorbidities or other illnesses, the transplant related outcome is worse. So the higher the number was the outcome here.

(11:09): On the left scale here is treatment related mortality.

(11:14): There are some other factors that predict for transplant related mortality. And that is if you're not fit, you are unable to do your activities of daily living, as it can be seen in this red curve, that matters. If you are not very healthy and not active, you walk slowly, you have low mental health. And there are some lab measures that we look at. Some of those also predict for transplant outcomes.

(11:46): So factors predicting likelihood of success are whether you have any health concerns at the time of transplant, or comorbidity, whether you have other problems related to aging, whether you are able to do your activities of daily living normally, and what is your ability to process information or your cognitive status.

(12:13): A promising strategy to improve outcomes in older adults is to give them high intensity chemotherapy before transplant over a longer period of time, like two to three weeks, rather than the standard one week. Next, I will talk about how do we improve outcomes in older patients? And here is a cartoon that shows that what we do. So if, for example, you have acute leukemia, the first thing we do is give induction therapy, or this is a non-transplant therapy. And then we give transplant therapy.

(12:37): Now in transplant, really the important part is played by the pre-transplant chemotherapy conditioning. And what we are trying to do is to intensify or improve this, to improve the outcomes.

(12:56): So, with that, we said, "Can we give an intense conditioning regimen to older patients?" And the idea, we really thought, it took a very simple approach. So traditionally we give pre transplant chemotherapy over a week period. We said, "Can we do it over a longer, two or three week period?" And the main idea underlying this is you can reduce toxicity and treatment related mortality of an intense myeloablative regimen by simply giving it over a longer period of time. So instead of doing it traditionally over a week period, we do this over a three week period.

(13:41): So here is traditional way of doing it. So you are admitted in the hospital, you get four or five days or six days of chemotherapy, and on day zero, we give you cells, which is in the green arrow over here. What we did was, we just separated out the treatment. So we have outpatient chemotherapy two weeks starting on day -20, and also on day -13. So we split the full dose of chemotherapy, and instead of giving it over a one week period, we gave it over a three week period.

(14:28): And here was a study, which included all patients with hematological malignancies. We had patients having related and unrelated donor as well. Median age was 61, as you can see in the top left table. So these are older patients. The age range was 39 to 70, and many of these patients had comorbidity, as you can see in the red on the right hand side. Any score more than one or two, it reflects more comorbidity.

(15:04): And here was the outcome. Again, here on the X axis or horizontal axis, it is time in months. And on the Y axis, it is a probability of the survival. And even in this older age group, a one year survival here was quite encouraging over 80%.

(15:28): And this was quite good, whether patients were older than 60 or younger than 60. So even the green and red curve, green curve refers to patients who are older than 60 and they are similar. And this was because the treatment related mortality was quite low in both age groups, less than 10%. Again, this was very tolerable, even in patients who had some comorbidities or other illnesses. And again, whether you had no comorbidities or low number of other illnesses versus higher number of other illnesses, the outcomes were similar.

(16:22): So again, to reiterate the point, we can improve outcomes in older patients simply by giving the treatment differently. And this is what we have been doing with our fractionated busulfan regimen at MD Anderson Cancer Center.

(16:41): Outcomes in older patients can also be improved by providing better supportive care to address other health issues associated with advanced age. The other part of improving outcome is improving the supportive care, as it's seen in the red block over here. So can we redesign a transplant program for older patients rather than modify what we do for younger patients? As most of you know, transplant was discovered and designed for younger patients. So can we redesign it for older patients? And really what we need to consider is physical functional involvement.

(17:21): With aging, we do get frailty or weakness and muscle loss, and there are multiple other issues which are listed here. So older patients have declining organ functions, other illnesses or comorbid illnesses, they are on multiple medications, which may interact with transplant medication, they've diminished psychological and nutritional reserve, they have diminished physical function and functional status, and of course, there may be social issues as well.

(17:57): Considering all this, we decided to initiate a supportive care program called Enhance Recovery. Now, the idea here is simple. As you can see in this graph over here, as demonstrated by the arrows, you see the normal functional status, and after the procedure, the functional status goes down and eventually it recovers over a time.

(18:29): Improving the fitness and nutritional status of older patients – their physiological reserve – before transplant can improve the outcome after transplant. So can you change this red curve to the brown curve on the top wherein you improve the functional status of the patients before the procedure, and can you improve therefore, the outcomes? So if you will, it makes you physically even more fit than you are, and you can even fatten you up more than what you are before the procedure, which we know even eventually results in nutritional and functional decline. And by doing that, can we improve our transplant outcomes?

(19:14): This strategy enhances physiological reserve before transplant. So, here is again, stated in somewhat of a cartoon shape, as age increases, the physiological reserve that is available keeps declining, and any stress can result in further decline resulting in morbidity and mortality. The idea is to improve that physiological reserve.

(19:48): A “prehabilitation program” was initiated at MD Anderson Cancer Center to improve the physical and functional status of older patients prior to transplant that involved a physical medicine and rehab physician, physical therapist, occupational therapist, dietitian, clinical pharmacist, advanced practice providers, nurses and geriatric doctors.  So, we initiated a multimodal care in patients who are 65 or older to improve that physiological reserve. And we wanted to empower the patients to participate in their own care and wellbeing. We wanted to diagnose and optimize chronic medical conditions and thereby we wanted to improve transplant outcomes. We rolled out this program starting October 1st. This was a multidisciplinary effort where our patients see a physical medicine and rehab physician, physical therapist, occupational therapist, a dietitian, a clinical pharmacist, our advanced practice providers, and of course our nurses are also very actively involved. So are the geriatric doctors.

(20:37): And here is a complicated thing, but essentially each discipline, as you can see in the top block, is trying to improve the functional status. So with the prehabilitation, we prescribe the exercise program to make you fitter and make sure that you are optimal strength and optimal fitness. We identify any illnesses related to older age. Next, the nutritionist optimizes the nutrition or make sure that you have adequate nutrition. So on and so forth.

(21:23): Again, during the inpatient stay, our nurses motivate and encourage patients to exercise and perform activities of daily living. So we don't want you to lying down all the time. We want you to be active.

(21:40): Prehabilitation activities significantly improved survival rates in older patients.  The question is, after doing this program, did it make a difference? What was the evidence? So we compared our outcome for a one year period compared to a historic controls, that is patients who were treated two and three quarters of a year before that. So between 1/1/2015 to 9/30/2017, we compared that group to the group that was treated one year after this program was initiated. And of course there were 64 patients in our treatment or our supportive group and 140 patients in the control group.

(22:25): And again, these are the details. I don't want to go into the details of it, but our median age was 68 and about 20% of the patients were older than 70.

(22:42):. We showed that the survival was significantly improved from 53% to 74%. Here on the horizontal axis, the numbers are in months after transplant, and vertical axis, as I said, proportion surviving. And this is after our supportive care program in green, which is ER-SCT. And on the bottom, is it is our controlled patient. And that was mainly as a result of reduction in transplant related or treatment related mortality, which is seen in the right panel, where you see the transplant related mortality did come down.

(23:26): Summary: So again, key points to reiterate. Older patients are most in need and are increasingly undergoing stem cell transplantations, but outcomes need to be improved. Factors predicting likelihood of success include your underlying health prior to transplant, your functional status prior to transplant, and other comorbidities or other illnesses, coexisting illnesses, that you may have.

(24:01): How do you improve the outcomes in the older patients? You can modify your treatment regimen, design it for older patients, and more importantly, you modify the supportive care, essentially improve the physiological reserve prior to treatment.

(24:23): With that, this is our transplant team. This is our Enhanced Recovery team. So we celebrated our one year of program and I'll end my talk. Thank you. And I'll take questions.

Question and Answer Session

(24:40): [Lynne Spina] Thank you, Dr. Popat, for your excellent informative presentation. And we'll now take questions. Our first question is kind of a two part. Is high blood pressure considered a comorbidity, and how about blood pressure that is treated and under control?

(25:15): [Uday Popat] So, yes, a blood pressure is a comorbidity because it is co-existing illness, but if it is controlled well, it should not preclude transplant. The point is it needs to be controlled well. And if you think about it, in one in four Americans, the blood pressure is high after a certain age. So really it is not an exclusion for transplant. It just needs to be controlled well.

(25:47): [Lynne Spina] Thank you. Thanks for clearing that up. The next question. Is there longer remission if maintenance is given, rituximab, compared to no maintenance for mantle cell lymphoma? Also, is there a reason that maintenance therapy might not be recommended?

(26:11): [Uday Popat] So this is, again, we do autologous or self-transplant for mantle cell lymphoma, and there is a clinical trial that has shown benefit of maintenance retuximab, which is why I think most of us would recommend it because it improves survival.

(26:38): [Lynne Spina] Okay, thank you. Next question. Do older patients have a greater likelihood of getting GVHD compared to younger patients?

(26:49): [Uday Popat] That is correct. Older patients and even older donors do increase, theoretically, higher risk, but you can ameliorate by changing the graft versus host disease prophylaxis. So really we try and use post-transplant cyclophosphamide, which some of you may have heard of. So the answer is, yes, there is a higher risk, but then you can mitigate it.

(27:16): [Lynne Spina] Okay, next question. I am 60 year old, an HL survivor, non-Hodgkins, five years post-transplant. Do I have a higher risk of the disease coming back as I get older? [

(27:38): [Uday Popat] So actually the highest risk for relapse after non-Hodgkin's lymphoma transplant is in the first year and maybe first two years. So as you go further away from it, the risk goes down. It doesn't get to zero, but pretty close to it with Non-Hodgkins lymphoma.

(27:59): [Lynne Spina] Okay. What are your thoughts on clinical trials? When should I look for one?

(28:09): [Uday Popat] I think when you go to your doctor and if they have a clinical trial available, I think you should choose it. And let me clarify that. So most clinical trials will not be approved if they did not offer a potential for benefit to the patient. And that is usually clarified in the consent form. However, they are a clinical trial, and they may have unknown risk. So that will also be clarified in the consent form as to what potential risk that are trial entails.

(29:01): Now, there are some trials which are minor changes to what you would traditionally get anyway. It's not a big deal. There are some trials, which we don't know very much about and may entail some risk. So you have to weigh these, but really the reason to choose clinical trial is if it offers you any benefit over and above the standard therapy. I think that's the way I would look at it. Is there any extra benefit to me as a patient over the standard treatment? That's what you should ask.

(29:47): [Lynne Spina] Thank you, Doctor. It's always good to understand more about clinical trials. The next question is, how do you handle older patients with kidney involvement from going onto dialysis?

(30:00): [Uday Popat] So unfortunately for allogeneic transplant, we don't do allogeneic transplant in patients on dialysis. For autologous or self-transplant, and this usually is in patients with multiple myeloma or amyloidosis, we do do transplant in patients on dialysis, and obviously they continue their regular dialysis, and we adjust their medication dose and timing based on their dialysis, or provide them dialysis appropriate to when the treatment is given. And most patients do well after autologous transplant for myeloma, even despite their kidney failure and dialysis requirement.

(30:50): [Lynne Spina] Thank you. Can you comment on this? How do doctors specifically assess one's functional status in older people? And relating to that, is afib considered a comorbidity? So how do you actually assess somebody whether or not they're fit at their age?

(31:19): [Uday Popat] So some of it is up to the doctor, and as we are getting more and more sophisticated, we are using more and more specific measures. But really it is your interview with your doctor and evaluation by your doctor that determines how fit you are.

(31:45): So as a doctor, if I have a patient who comes to me, what do I look at? I look at his history. I talk to him and see what other illnesses he has. And somebody asked about hypertension, diabetes, are these well controlled? If they're well controlled, they may not be a problem. What about atrial fibrillation as the question alluded to? If the atrial fibrillation is controlled, and patient is on treatment, that is great and we would proceed. Obviously, any comorbidity, including atrial fibrillation, does entail additional risk of treatment related complication.

(32:32): At the end of the day, it boils down to the risk of treatment or transplant, as opposed to the benefit of transplant. And more often than not, the functional status, if I had to evaluate somebody, whether somebody is fit for the transplant, I look at the disease history. But then I look at what activities they're able to do. What is their activity of daily living normally? How much do they walk? Do they run? Do they use a bike or do they go for a walk every day? How easy is it for them to get from exam chair to the table? And then of course we have some formal methods where we can do some of the tests to assess this. So that's sort of a long winded answer to your question.

(33:25): [Lynne Spina] What effect do genetic and chromosome characteristics affect outcome?

(33:35): [Uday Popat] So any outcome of any disease depends on how aggressive it is, how responsive to treatment it is. And that is where genetic and chromosomal factors come in. So some chromosomal and genetic factors would suggest that the patient would respond to treatment well. Nowadays some genetic factors would suggest that we should use X treatment versus something else. So yes, they do indicate good or bad outcome to the current therapy and may even help us choose the right therapy.

(34:20): [Lynne Spina] What is the most common reason for death in transplant patients over the age of 70?

(34:28): [Uday Popat] I think the most common reason, usually, still is the recurrence of the original disease. But having said that, there are treatment related complications that may also cause death, and one of the ones we worry significantly about is graft-versus-host disease and resulting immunosuppressed state, or immunocompromised trait, or weakened immune system, probably that's a better word to use, that may result in risk for infection. So infections, graft-versus-host disease, and of course the original disease. Those are the major reasons for death for any patient and more so for older patients as well.

(35:19): [Lynne Spina] After a stem cell transplant, 100 days at MDA, is isolation from relatives required for longer periods due to being immunocompromised?

(35:39): [Uday Popat] So I personally do not recommend it for my patients except to say that if somebody in the family is sick, stay away from them. Sometimes even with the little children, if they are going to daycare, and if they get sniffles and all, we would suggest that you stay away from that and isolate from that, if you will. But otherwise, really, if somebody is healthy, your relatives are healthy, we wouldn't recommend isolation.

(36:13): [Lynne Spina] Is 78 too old for autologous transplant for someone with recurrent lymphoma?

(36:22): [Uday Popat] If you're healthy, no. Let me clarify. Yeah. So if you're healthy, no, it is not too old.

(36:38): [Lynne Spina] What is the data to support the use of maintenance therapy in MDS post-transplant?

(36:49): [Uday Popat] So typically, when doctors talk about data, the gold standard is a randomized trial, where we compare one treatment to the other or one treatment to no treatment. So if that is the gold standard you use, the question is, are there any randomized trials of maintenance therapy.

(37:18): Now maintenance therapy, for those of you don't know, means that treatment that is given after transplant to prevent a disease from coming back or to prevent relapse. So is there any data for maintenance therapy in MDS? There is no randomized trial data. That said, some doctors would use maintenance therapy in the hope that it would reduce the risk of relapse when they know the patient is at very high risk of relapse. So, say, for example, the patient has a Tp53 mutation, the risk of relapse is very high. So some doctor would argue, should we use some maintenance to keep the disease under check? That's the rationale currently. There is no randomized trial. Thank you.

(38:13): [Lynne Spina] This attendee asks, is stem cell transplant really the only potential cure for AML?

(38:26): [Uday Popat] The answer is, it depends. So if you have what we call a good risk acute myeloid leukemia, which is characterized by certain genetic changes, it can be cured with standard therapy and you don't need transplant. On the other hand, if you have high risk acute myeloid leukemia, based on certain genetic characteristic, then transplant may be the only curative option. And there are gray areas in between depending on the genetic characteristics.

(39:07): [Lynne Spina] I was transplanted for AML. How often do I need bone marrow biopsy? Is it more often because I'm older?

(39:20): [Uday Popat] No, it is not going to be different because you're older. It really depends on your doctor and the center which you are at. So I stop doing bone marrow biopsy after one year. But again, it boils down to your physician and the center at which you are.

(39:43): [Lynne Spina] Thank you. The next question is a little specific, but I'm going to ask it anyway, Dr. Popat, because maybe you can answer it with some generalities that could be helpful. This patient has multiple myeloma and amyloidosis and wants to know, would you recommend a stem cell transplant for a 73 year old that is MRD negative after induction therapy. This person has kidney and heart involvement and was cleared for transplant at Mayo and had cells harvested, but the risk of kidney failure was too great. So I guess he's looking for what advice would you give as far as moving forward, and also does longer pre-treatment protect your kidneys?

(40:41): [Uday Popat] So, I think this is, as you mentioned, is too specific a question and it's difficult for me to answer the specific question about this patient, but you always weigh the risk and the benefit. And with multiple myeloma and amyloidosis, we sometimes do transplant in patients who have kidney failure or even heart involvement. Now, sometimes there is always a risk that, if you have kidney involvement, it can get worse. And that is one thing that we would always talk to our patients. But I have to say that you have to weigh the benefit as opposed to risk and make a decision. And I think your doctor can give you the best advice on this. So maybe have a frank discussion. What if I do this? And what if I don't do this?

(41:51): [Lynne Spina] Do you use hypomethylating agents prophylactically after transplant, or only after you see evidence of MRD?

(42:09): [Uday Popat] We have several research protocols where we do use prophylactically after transplant. And sometimes when a patient is at high risk of relapse, we do use it even off protocol, but again, it's weighing risk versus benefit, and we hope that the data will come through that will answer this question for good in future.

(42:42): [Lynne Spina] This person wants to add to one of the other questions. Does the longer pretreatment help protect the kidneys?

(43:00): [Uday Popat] I don't think there is any relationship of pretreatment. The only way I can think of it is, pretreatment may reduce the protein that is damaging the kidney. So in that sense, yes, it helps, but I'm not sure giving it longer will make a difference as opposed to giving it until the protein goes away or until you get the best response.

(43:36): [Lynne Spina] Closing. Thank you very much. This does end our session and we have completed all the questions. And thank you on behalf of BMT InfoNet and our partners. Thank you, Dr. Popat, for your very insightful remarks, and thank you, audience, for your excellent questions.