← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 148: Myeloma Series, Pt. 8- Transplant in Multiple Myeloma (2026)
Ronak Mistry, Vivek Patel, Dan Hausrath
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- [00:00]
A
Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call, the Hemong Podcast. We're coming at you from Brule University Medical Center. I'm Ronick, and in today's episode, we're super excited to have two very special guests with us. Dr. Amer Kelker and Dr. Shonali Mehta, both of whom are bone marrow transplant physicians at the Dana Farber Cancer Institute in Boston. Listeners, you'll recall in a prior episode, we talked all about the role of transplant in the treatment of multiple myeloma. We alluded to the fact that there is a changing landscape. And so we're so excited to have them with us to be able to talk about the nuances of transplant. And so, without further ado, let's roll that show. We are so excited to have two guests with us this week. In our episode talking about the role of transplant and myeloma. We have with us Amer Kelker, who is a physician at Dana Farber Cancer Institute and an instructor of medicine at the Harvard Medical School. Also from Dana Farber and Harvard is Shonali Mehda, who's also joining us from. They're both part of the division of hematology at the Farber. So, guys, thank you so much for being with us this evening.
- [01:25]
B
Thank you for having us.
- [01:26]
C
Yeah, we're so excited to be here.
- [01:28]
A
So in the usual spirit of our show, we love for you guys to tell us a little bit about yourselves, your background, kind of what your clinical interests are now. And we always love hearing one fun fact about you, so please be sure to include that as well.
- [01:41]
B
Sure. So I'm Sonali Mitta. I'm Jersey born and raised by way of Chicago, Boston, and finally training in Florida at Moffitt Cancer center and came right back to Boston after that. My clinical interests are early phase clinical research and myeloma bispecifics, immune therapy, as well as digital health. And in terms of a fun fact, I guess I love to bake. So if I weren't a physician, I'd have my own bakery.
- [02:08]
D
You know what I always wanted is to do a great British baking show thing in America where everyone's collegial, you know what I mean? But I don't think that's ever possible. That's my dream. My second job's Gonna be start a new show that's like a collegial American great British baking show or whatever. But it'll probably never happen. But if it does, I'll hit you up.
- [02:25]
B
Let me know when you pilot.
- [02:27]
D
Yeah, yeah, that's right.
- [02:29]
C
My name is Amar Kalkar. As you mentioned, I'm at Dana Farber as well. I'm one of the new transplant faculty here in Boston. I got here by way also of Chicago where I went to high school, Central Illinois, Florida, but in Gainesville rather than Tampa like Sonali and then up here to Boston as well to get started. My clinical interests are primarily in allogeneic transplant and GVHD as well as specifically transplant for non malignant conditions. And then on the research side, care delivery, health economics and bioethics. The fun fact about me is that I love to sing. I also actually enjoy baking as well, but not quite as talented at it. So I'll go with singing.
- [03:05]
D
Did you do like the a cappella thing in college or.
- [03:08]
C
Yeah, no, I did acapella, sang jazz, sang classical. It was definitely a fun thing to do before we all went to medical school and probably after. There's ever time.
- [03:17]
A
If you feel so inclined, feel free to sing any and all parts of your responses to any questions we ask you today. It'll be a nice new to our show.
- [03:27]
D
We'll do a fellow on call musical edition. Yeah, nice.
- [03:31]
C
It'll be like that episode of Scrubs.
- [03:33]
D
Yeah, yeah, exactly. That's one of the best episodes of Scrubs too. I love it.
- [03:36]
C
Totally agree.
- [03:38]
D
So I'm going to get us started with a case and then we'll all kind of round robin ask you some questions about this. So let's just start with a 55 year old male who has standard risk multiple myeloma. So let's just say IGG kappa multiple myeloma. We're in the new era of the world. So this guy got Dara VRD for his induction and he got a VGPR after four cycles. We collected his stem cells is kind of what we always talk about in our questions. But before we do that, let's do what is done in real life. So let's say that they come to our clinic and we started them on Dara VRD and we said hey, this 55 year old looks fit and we firm over to transplant to you guys and how exactly? The first question that always mind boggles me and makes no sense to me is what makes somebody transplant eligible? Is it an eyeball test? Is there some formal way of Assessing this. What goes through your head when you're seeing this? Consult from us with standard risk myeloma, let's say a couple cycles of DARA vrd in now he comes to your clinic. What do you guys do?
- [04:38]
B
Absolutely. So here we actually do our own transplant cases for a lot of our own myeloma patients. So it really ends up becoming an individualized question and is one that I think should be that way. A lot of the basic things that go into it are looking at age, looking at performance status, frailty. There's several different scoring systems you can use for frailty now and several that are specific to myeloma. And then I think importantly looking at cytogenetic risk factors, looking at clinical presentation and sometimes they don't always line up. So that's another thing to keep in mind. And then level of response with induction therapy. So it really is something you have to take into account several different patient factors. And then probably the most important is, you know, what does the patient want? What fits into their quality of life, into their lifestyle, their day to day? Do they have the ability to take some short term disability to be able to fit in transplant at this time? Do they not want to? What are their concerns and have a very honest conversation with them about what are the benefits and risks going into transplant, especially with the data that we know and which way do they feel that they would benefit most?
- [05:54]
D
And when you're having that conversation with the patient, what expectation do you give them about time away from work and proximity and all of those things?
- [06:02]
B
Yeah, so there's actually some really good quality of life data that's been published for several of the transplant trials, most recently being determination. And so the way I kind of tell patients is transplant is like getting hit by a truck. It will wipe out your immune system and also pretty much wipe out your energy, your ability to do a lot. Yes, there are a handful of patients that continue to work from home or part time through this process, but that's, that's the exception, not the rule. And so from the studies that we've done looking into transplant, it's about 90 to 100 days for that quality of life to return back to baseline or in some cases even above their prior baseline. So generally I give patients that expectation that It'll be about 90 days at the least off from work.
- [06:48]
C
I was going to jump in. I can't take a much more patient centered approach than Sonali just described. I think that's really even how we think about transplant, even on the allo side. And I love the way she described it, focusing on how patients have to think about this and what to expect going through the transplant. The other thing is just to throw in a couple other explicit factors that I usually think about that we kind of have to from a fact standpoint, meaning the accreditation standpoint. We also think about things like cardiac clearance, so we think about getting echocardiography or a MUGA looking at the left ventricular ejection fraction. We think about pulmonary function tests. So we're thinking about the FEV and the DLCO modified by hemoglobin level. And then other things like general life expectancy in myeloma, that's often less of an issue. But certainly when we're getting older patients that we're considering transplant, that is a major factor in whether or not their transplant elevated eligible. And then a couple other implicit factors beyond what Chanel described. Probably the other one I'd throw in there, which is probably a little controversial, is thinking a little bit about health literacy. So not so much that it's a barrier, but that you certainly want to think about things like caregiver availability when you're thinking about whether patients are fit to go through transplant, especially if they don't have a good understanding about what medications are important, when and how to take them, who to go to for medical issues when they come up. And some of these things may seem obvious to us, but if you're not generally hooked into the health system, these can be major barriers. And again, it's not so much to stop people from getting transplant, but to make sure that you are availing them of all the resources that your center has available.
- [08:18]
B
I would agree with that. And I think one thing to keep in mind as well is there are several centers that do auto transplant outpatient. Ours primarily does inpatient with the ability now to do outpatient. A lot of that is based on logistical factors. How large of a city do you have enough resources, et cetera? But especially for outpatient transplant, the caregiver health literacy is very important. So it's something that you definitely have to keep in mind.
- [08:47]
D
I love that we're talking about that because as we know and that we've talked to the data for IFM and the determination, we're talking about a PFS benefit and the way you sequence this is. We have room to sequence here. We have other therapies that we're going to get to in this conversation. We have these quadruplet induction regimens. So the game's a little bit changed now. And I Think that's really, really important because we want to set our patients up for success. Transplant has risk of mortality to it. It's not a benign procedure. You get hit by a truck. I love that analogy when we think about this.
- [09:17]
B
Absolutely.
- [09:17]
A
And just to explicitly, straightforwardly ask this question. So is there some sort of algorithm that you guys use that standardize? Is it just that you include these multiple factors, including some of these more objective data like Amar had mentioned, and collectively look in and try to see, do you plug that into something or is it still a little bit more of a subjective component of analyz? All that information?
- [09:42]
B
We definitely collect all the information. It's not any one factor necessarily that rules you out. I will say that most myeloma practitioners I know would try to avoid transplant above the age of 70 just given delayed count recovery and risk of infection and morbidity is much higher. And that's more specific to the US I believe in Europe they don't even really consider transplant above the age of 65 or it's much harder to consider there in certain areas. So that's one thing to keep in mind. But looking at comorbidity scoring, which takes into account ECOG as well as echo finding, lung function testing, renal function, which especially something of concern in our myeloma patients, and we'll go into that in a bit as well. But that does play a role in how you dose your conditioning as well. Along with these other things are definitely something that you take into account. We have certain hard and fast criteria to request exemptions first, those parameters that fall out of the normal range. So we do have a system by which we check, but again, it's on a case by case basis. So if you have a patient that you're considering transplant and you think they would be a good candidate or you believe that they are in need of it, even if they have one of these parameters that falls out of the range of normal or close to normal, you still have a system by way of completing transplant.
- [11:03]
C
Yeah, and there are. I mean, to bring it to a parallel with allogeneic transplant, we do use systems like HCTCI and the Soror score and things like that. But while those can be helpful tools in auto transplant, they haven't really been consistently validated in that group. So that's why it's a little bit more patient dependent, as Shonali said.
- [11:23]
E
Yeah. And you know, Sonali, I'm glad you brought up renal dysfunction. That's something that's really common in myeloma as we Know, especially when you're first meeting somebody, initial diagnosis oftentimes their renal function is well below, hopefully, where it can come back up to with induction therapy. Is there like a level of renal dysfunction where you're thinking, okay, this person's probably transplant's off the table, or do you really have to see how they end up responding to that initial therapy?
- [11:47]
B
Really, it depends on a couple factors. If their renal dysfunction is from their myeloma exclusively, they don't have several other comorbidities. Part or all of that function is recovered with induction therapy, which oftentimes is not the case because it takes time for that to recover, even past the first four to six months of therapy. Then you have to take it into consideration for how you dose consolidation and how you treat the patient. But it's not a factor that would limit you from going forward with malphalan consolidation and transplant if it's needed. It definitely plays a role in how you dose your mouthalan. It's something that you would want to keep in mind, especially in patients that have renal dysfunction for prolonged cytopenias because of the melphalan. So it's something that you, you know, have discussion with the patient that you may have a slower count recovery in those cases. That puts you at higher risk of infection and related complications. But it's not something that cannot be done.
- [12:44]
C
Absolutely. I think while I have not personally had the experience of this, I've even had colleagues who've had patients go through malphilan conditioning therapy before auto transplant in the setting of hemodialysis and things like that. Again, to the point of sonali, that it really depends on whether you believe it's reversible or not and then what the dose adjustments are, which usually for hemodialysis you can give about a 50% dose reduction. So instead of the 200 milligrams per meter squared, you'd give 100 milligrams per meter squared.
- [13:09]
D
Yeah, that's a huge, huge thing. Especially when we think about patients with amyloid and that we do have data that these patients can get a stem cell transplant and a renal transplant. These patients can get a stem cell transplant and a cardiac transplant. So it is good to know because I think a lot of, for me, at least, when I saw patients with myeloma, I just kind of assumed, well, transplant seems kind of intense with this high dose melphalan. I feel like there's probably some real cutoff. So it's just good to know that we have that option, especially if we can reverse Things in these patients who have hopefully years and years and years of life expectancy.
- [13:41]
B
Yeah. And there have been studies looking at different dosing of melphalan in myeloma, and for that, looking at 50% dose reduction with 100 versus 140 versus 200, which is what we typically use, 100 in the most cases, except obviously in those transplant or in the end stage renal disease, not very effective. But between 140 and 200, there's not a huge amount of difference actually in terms of efficacy. Granted, most of these are all retrospective collective studies and have to be taken with a grain of salt. They do have smaller sample sizes. But in most cases, if patients have achieved a VGPR between 140 and 200, there's not a huge amount of difference in their response with consolidation and transplant.
- [14:22]
C
One side benefit of the reduced doses in a lot of those studies is you'll end up having fewer side effects related to the melphalin, particularly mucositis, which is not to be trifled with.
- [14:31]
D
Yeah, I remember my first transplant rotation. It was the GI side effects of melphalan mucositis and diarrhea was just a big thing for those patients. And I'll never forget it. And anyone who hasn't seen it, you'll see it.
- [14:43]
B
Cryotherapy is your friend.
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C
Cryotherapy is our fancy way of saying, give them ice chips.
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D
Nice.
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C
I love it during the infusion.
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A
And popsicles, you said?
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B
Yeah, you can use popsicles. Some people love Italian ice. Whatever it takes.
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A
That's awesome. I love that.
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D
For them, I would go with a Haagen Dazs bar or something. I don't know, maybe that's just me.
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B
I think after a couple hours, you can only go through so many Haagen Dazzles.
- [15:10]
D
That's right.
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B
Popsicles. At least get some. A little bit more hydration in there too.
- [15:15]
A
One of the things that we don't get to see very often is this apheresis process. And so could you kind of talk us through that? What does that entail? What is that timeline? Like, how do you counsel your patients on what that preparation process looks like?
- [15:31]
B
Absolutely. So usually I tell my patients that with induction therapy, we plan to do anywhere from four to six cycles up to front. And the reason for that is we know that if we continue particularly IMIDs, but among that, including CD38 antibody treatments as well, the more therapy a patient's exposed to, the harder it is to collect your goal range of stem cells. So generally about six months of therapy has been the historic cutoff. And then prior to that, you want to let patients know that when you're planning on holding therapy, you do have to hold therapy for anywhere from three to four weeks prior to your planned collection. That's usually the time point in which we repe a bone marrow biopsy. We complete all the vital organ pre transplant testing that includes the echo, the lung function testing, ekg. In most centers, by default, we do a skeletal survey, although more sensitive imaging probably would be better in a lot of cases. And then repeating the marrow to see your level of response at that time and if possible, MRD status at that time. Then in terms of the apheresis process, we tell patients that mostly here we mobilize with GCSF and chlorexophore. We'll touch on other ways of mobilizing, I'm sure, but the majority use GCSF and paraxophore now. So you administer GCSF for the five days prior to the planned apheresis. Generally, what we do is the day prior to planned apheresis is when the patient comes in, has labs drawn to see what their peripheral CD34 count is as well as their other counts, and then has their tunneled line placed for apheresis, which is essentially like a dialysis catheter. And then I tell them that the following day when they come for their apheresis, they'll again have labs drawn the day prior if their cd34 count was kind of below or at our threshold. That's when we administer Pleuroxy 4 as well. It does require at least 12 hours to really kind of take effect. So you generally want to administer in the evening prior to the apheresis if it's needed. And then at the time of apheresis you have your patient's. In most cases, this is outpatient, so they go to. In our location, it's a blood center or a transfusion center where they're hooked up to an apheresis machine that looks a lot like a dialysis machine. So the process in terms of how it looks is very similar to that. They're normally told to hold any blood pressure medications that day just because there is a certain amount of blood volume that's in the unit at the time. So you want to avoid any hypotension at that time. But then they kind of just sit in the recliner all day with breaks and snacks in between when you continue collecting. So your blood goes through the apheresis unit, it's spun down, obviously, CD34 stem cells are larger, they fall to the bottom, easier to collect, and the rest of the blood returns to them, and that process continues all day. We then count the CD34 cells that have been collected. And our goal for at least for our institution is 4 million CD34 cells per kilo. You theoretically need anywhere over 2 million, but we tend to collect anywhere from 4 to 6 million as much as possible to be able to perform either a transplant at that time or a delayed transplant if you plan on it. But you can achieve transplant with a smaller number. If you can't attain that with the knowledge that count, recovery might take a little bit longer with the lower amounts that you collect. And then based on how much you've collected, it could be anywhere from one to three days of collection. There are some places that even do an inpatient collection. They're concerned, they need more days of collection. It's not very commonly done because it tends not to be very fruitful, but it is possible. And then the patient goes home and we quite literally keep them in dmso in the freezer.
- [19:11]
D
Yeah. That's insane. That's so fascinating to me. And there's a couple things I really want to touch on with that, and I think all of us really are interested in. So I'll ask the first question. I'll let the other guys ask some of the other questions. So my first question, we do that bone marrow biopsy. I've heard a lot less than 10% is a good goal to get to. So I want you to touch on that very briefly. But the second big question that I have, at least when we talk about mobilization, I've heard psi mobilization and GCSF makes intuitive sense to me. You're giving gcsf, that makes sense. But what is pleurexophore? And it's always on the ite and I always miss it and I just guess randomly and I'm like, what's going on here?
- [19:47]
B
Absolutely. So we'll touch on the mobilization first. So prior to pleurxophore, we used to do high dose cycloposified mobilization. This is actually what was done for the majority of the patients on the determination trial, which actually started back in 2010. And GCF for mobilization wasn't really used across the board until probably closer to 2014, 2015. But the idea behind using the cytoxin is that along with GCs, the GCFF in some cases can cleave Cxcr4, which is on stem cells. Cxcr4 is something that binds to adhesion molecules on stromal cells, which is what keeps stem cells in the marrow. And when you're cleaving that, then you have more stem cells that can then leave the marrow. Basically, cytoxin amplifies that process, and so it releases proteases that can also cleave Cxcr4, among other adhesion molecules, and aids the process along. So it's pretty synergistic. Along with gcf, you generally don't combine it with Plexifor, but in rare cases can be done. So that's the thought process behind why we used to use cyclophosphamide. Then Plexifor came along, which was actually a drug studied initially for HIV, as we know the involvement of Cxcr4 in HIV treatments. And so it is basically a selective inhibitor of CXCR4. And so it works in a similar fashion, just instead of being a protease cleaving, it's actually just inhibiting. And again, the same process by which it allows for the stem cells to leave the marrow and detach from the stromal cells into the peripheral bloodstream. So I know that question came up on its. It came up on my boards as well. So they just both have functions on CXCR4. One is to enhance protease activation to cleave. The other is as a selective inhibitor. So in terms of response going into marrow, into consolidation. So one thing I should have clarified earlier, the way I term it to most of my patients is we call it an autologous stem cell transplant. It's really an autologous stem cell rescue. What you're doing is using melphalan to wipe out your marrow. You're really just using the autologous stem cells to repopulate your marrow with as many normal stem cells as possible. And so it's not the stem cells that are the active component, it's the malfaline that's the active component here. So that being said, what you're trying to achieve is as deep a level of response as possible. So that's what we try to do with induction therapy. And we know that the deeper the response upfront, the better the outcomes in terms of pfs and os. So if it's a VGPR or better, we know that tends to correlate to better survival outcomes after transplant. Determination has also showed us that achieving MRD negative disease pre transplant is pretty much as good as transplant itself in those cases. So we have these arbitrary cutoffs for what our response is. We probably just aren't detecting the right amount. And so that's, I think what it really shows us is the deeper level of response that we can detect and get to the better off the outcomes are for the patient.
- [22:59]
C
Yeah, and I actually wanted to jump off one point you were making there about deeper remissions and responses. But one of the thoughts behind why cyclophosphamide was popular, in addition to providing a boost in terms of the protease cleaving of Cxcr4 and Vcan1 is that the thought was that it would also provide additional cytoreduction, but this didn't actually end up bearing out. There are several different studies that actually shown that there's no difference in outcomes by using Cytoxan. And when I say outcomes, I mean in terms of pfs, time to next therapy and CR as well as overall survival. So there's very little difference in that perspective. So it's kind of interesting. Whereas Cytoxan is a very active agent in myeloma when it's used later.
- [23:39]
D
Line, that is fascinating to me that you use this high dose. That makes so much sense that you're having a twofold process there. We're going to maybe hit some of those plasma cells. We've talked about the role of Cytoxan in our previous episodes, but that makes so much sense why some people are like, oh, we might consider high dose PSI mobilization because then you're hitting the plasma cells and mobilizing the stem cells. So really fascinating.
- [24:01]
E
And so earlier I think we had referenced that a certain number of cycles of therapy is obviously needed before somebody can get to transplant. But I want to move from minimums to maximums. Is there a certain number of. Is there a certain amount of exposure to IMID drugs in particular that you worry about not being able to collect enough stem cells? Or is it also more of a case by case thing?
- [24:22]
B
Definitely it can be case by case if you have certain situations where a patient needed more therapy upfront or needed intensification of therapy. And that's not common, but it does happen. That being said, of the classes of drugs that we use primarily, we know that it's IMIDs that can limit our ability to mobilize and collect enough stem cells, especially if it's given, generally speaking, again, this is based on mostly retrospective data, but more than six months of therapy. And so we know that in those cases, in some cases, when you combine with alkylator as well. But again, those were smaller studies. The majority of them looked at either proteasome inhibitors, looking at pad versus bad, looking at imid therapies with RD versus vd. And so in the more recent data sets, there's a couple from some of the larger academic institutions that include over 300 or 400 patients each. Patients that received more than six months of immun therapy had a higher rate of failure to mobilize and collect. There are other things that go into that. So patients that had higher comorbidity scores, I believe over three, they also had more difficulty collecting. So it's not the only factor that goes into it, but it definitely does. Just given the amount of myelosuppression, specifically with revlimid, I don't believe the same has actually been seen with thalidomide. And it hasn't really been well described with pomalidomide either. But because we more commonly use revlimid as part of induction and upfront therapy, that's the one that's been studied the most. And that's why we see that now there are studies looking at whether daratumumab or isatuximab used in that front setting can affect stem cell collection immobilization. There was some concern about that with daratumumab, and they actually had. There was a abstract at ASH last year that looked at a possible decrease, although it was not significant. And that was based on patients from the Griffin trial. The same is being looked at in the GMMG concept of ISA rvd. I can tell you from my experience, I've had patients on that trial and we have not yet seen a high rate of failure of stem cell collection and mobilization. So it's been reassuring to see that on our end because we all were concerned about it. But again, it's on a clinical trial, they're getting a fixed four cycles upfront before they're moving on to stem cell collection and mobilization. So we are limiting that therapy to the first four to six months.
- [26:44]
A
That's really interesting and something that I want to jump off of based on what you just said, is this mention about new therapies. And I mean, in a prior episode, we kind of talked about how the landscape of myeloma treatment has really evolved over time. And it almost seems that there's drugs coming out faster than there are these major studies that are able to keep up with this. And so I think it naturally begs the question of what is the continued role of transplant in the present day, knowing that there are so many treatment options. And so specifically, so far we've already mentioned the IFM trial, we've mentioned determination to My understanding and my knowledge these trials are older trials, relatively speaking, before the advent, a lot of the newer drugs that are currently available on the market. So with that in mind, what do you think is the true role of transplant in the role of management of myeloma in the present day? And also I'm hoping that maybe you guys can include things about cost benefit of the transplant upfront in this setting.
- [27:47]
B
Absolutely. So that's basically the million dollar or actually billion dollar question right there. Right. That's something that I think we need formalized trials to look into in terms of the role of transplant in the era of immune therapies and myeloma. We don't yet have a study that really looks at that. We have several that are trying. There are studies that are building off of MRD adapted or response adapted trial designs like the master trial. There will be other upcoming trials that will look at response adapted approaches to transplant. And I think that's going to be what we see moving forward. The amount of data that we know about mrd, yes, it's not something that we use on an FDA approved level yet, but we have enough data to say that MRD negativity, at least to 1 in 10 to the minus 5 or 10 to the minus 6 does have implications for progression free and overall survival. Especially when it's MRD, that's MRD negativity that's sustained, ideally for 12 months or more. But I think that's something that we're going to see moving forward to help us answer that question that should every patient that's achieving a deep level of response with novel therapies up front, do they actually need transplant? And the main question for that then also brings up who else should be getting transplant versus those that shouldn't. When we look at patients that have chip, should we be transplanting them? When we look at patients that have other malignancies, I've had a couple patients that have a prior DCIS or pre malignant conditions, should we be transplanting them? We know that melphalan can increase the mutational burden up front. We know that in patients that may have a risk factor, revlimid maintenance can create a proleukemic state. So which patients should we be putting through that and are we increasing their rate of possible MDS or AML or other dangerous secondary hemelignancies in the future? So there's a lot yet to be learned. My best answer is stay tuned. But I think we'll have those answers in the next, hopefully five to six years as those Studies are designed and accrued, hopefully maybe less time, just given the pace of research, but I think it'll take at least that amount of time up front.
- [30:02]
E
Yeah.
- [30:02]
C
And actually, Chanel, I had a question for you just related to that, because I have a patient right now, actually in my clinic who I'm seeing who had an auto and allotransplant for myeloma, had a heavy amount of alkylator exposure, even post allotransplant, and now it's come back to me with a very complex AML condition. And so we're taking him back for more aloe transplant. But in terms of the where CHIP testing is happening, are you guys doing extensive chip testing right now or at least some kind of molecular testing in your patients going through autos?
- [30:31]
B
That's a great question. So we're not doing it across the board. I think that is something that probably will change in the future, especially if you have a concern. So I am making sure to do it in patients that I know have a family history, just because there's a concern that there might be some underlying risk factor in patients, especially that I'm concerned about, that are presenting with other cytopenias beyond just anemia up front. We try to get some other molecular testing or a rapid heme panel, which is our version of a simplified panel for heme malignancies across the board, including CHIP mutations. And so it's something that I think as we learn more, it'll help us understand what we need to do going forward. There's a lot of great studies being done by our colleagues. I know Sperling's lab looks at this, Dr. Ebert's lab, I believe, Ben diamond as well, looking at the role of TP53 mutations and whether we should be using revlimid maintenance in those cases, or does that enhance that proleukemic state in patients that have an underlying p53 mutation? So it's definitely something that I think we will be doing moving forward more. So we don't do it across the board as a rule.
- [31:41]
D
Yeah. And I really like this discussion about chip. And just to remind our listeners, CHIP is clonal hematopoiesis of indeterminate potential. What we're talking about here is that a patient has some mutation in their stem cells that we can identify with next generation sequencing. So, for example, they might have an ASXL1 mutation, but they actually it's indeterminate potential because they're not having bad cytopenias. For example, some of these patients progress to things like MDS and aml. But if we have more hits to their system, then we say, hey, this is a risk factor, the protoplasm that might set them up. Right. And we know that with Revlimid that we talked about in our prior episodes, you have that risk of secondary malignancy. So this is really interesting for me to hear that. Yeah, that's something that could be coming down the pipeline is that should we use that as maybe, hey, we've got good overall survival without doing this transplant right now we have all of these other things that we can possibly do for this patient. Maybe we should. Maybe we should think about this differently. Maybe we should do a fixed duration of revlimid maintenance. Maybe we should do DARA maintenance instead. And there's a lot discussed about the issues in many of these trials with is DARA better or revlimid or DARA plus Revlimid? And we may not have all of the answers, but maybe this does help us. Right. Maybe we say, hey, let's give this patient DARA maintenance instead of revlimid maintenance if we think they're at a little bit higher risk. So maybe I'm off base by that, but that, at least to me, seems like where things are heading.
- [33:00]
B
Absolutely. I think the question of what maintenance to give is going to be one that's hotly debated going forward as well. The question of single agent versus multi agent maintenance and whether we should be using immune therapy and the duration of that. Similarly with patients that may have an underlying chip mutation, should we be using Revlimid or other IMID safe? Is our celmod safe in that space? Is pomalyst more or pomalidomide safer than Revlimid in those cases. So that's something that I think it'll be hard to accrue to something that looks specifically at that just because it's a very subspecialized population. So a lot of this will have to be to some extent subgroup analysis in the future, but definitely is something that we can look into a little bit deeper.
- [33:42]
E
We mentioned things that are coming down the pipeline in the future, and one thing I think is pretty exciting in the myeloma space is the role of MRD measurement looking for measurable residual disease. What do you see as the role for that going forward? There was a, I think a publication in blood pretty recently about using an MRD sensitive approach in terms of how to think about somebody's maintenance therapy. What's your understanding of how that is going to be used in the future?
- [34:08]
B
Absolutely. I Think there's multiple ways to look at it. One is our goal of getting to cure in myeloma and that's not a term that most myeloma physicians use very commonly. I almost off the bat tell my patients I don't use that word at all because we haven't achieved it. We haven't gotten to a point where patients are without detectable disease and not on therapy at the same time. So whether you call it cure or functional cure, I think that's something that our field has to aim to, but we're not quite there yet. That being said, MRD I think is a great tool to possibly get us there. So we know that sustained MRD negativity, so having less than one in 100,000 or less than one in a million myeloma cells that you can detect in the marrow after treatment, ideally sustained for six months or more, does correlate to better progression free survival and better overall survival. So now putting that into practice in clinical trial design is the next step. And so there are a couple studies that are looking at that like we discussed, there are several more in the future that are also looking at that ones that are accruing currently in addition to the MASTER trial and other concepts. And I think as we have those outcomes which we had some back at Ash21 from Master, it's definitely something we can consider probably more heavily in those that are standard risk cytogenetics than those that are high risk or quote unquote double hit myeloma. So I think we still have a little bit to learn there. Keep in mind, all of these cutoffs are very arbitrary. Right. So what we use for level of disease detection in myeloma, what we use for response criteria, yes, it's been decided on by the myeloma working group and consensus, but it still is an arbitrary number. The same way that the cutoff for plasma cell leukemia and having detectable myeloma cells in the periphery, it's an arbitrary number. There is not a significant amount of data to say that somebody with 4% peripheral plasma cells is any better off than somebody with 8 or 10 or 15%. So we do have to keep these things in mind with a grain of salt that as our level of detection gets better, our ability to get to a deeper level and understand what that level needs to be to achieve a functional cure has to be. We're not quite there yet, but we're getting there.
- [36:29]
D
So jumping off this MRD point, I want to get both of your the allotransplant person's thought and the auto transplant person's thought here. So, so let's say we had our patient standard risks, multiple myeloma, 55 years old, young guy, he wants to do everything he can to have a longest time off treatment. That's his main goal. And so we gave him Dara rvd and let's say that we went in six cycles of treatments. Five, six cycles of treatment. And this guy was an astringent cr. We tested him for MRD and he was MRD negative. Do you transplant him? And I know that's a controversial question, but how would you approach that? Let's say this guy was like, I really don't. I can't take off that 90 days. You had that conversation with him. So 90 days is a long time for me. What are your guys thoughts on that? And is that a patient that you would feel comfortable saying, hey, let's delay this transplant?
- [37:15]
C
Yeah, yeah, I think so.
- [37:16]
B
If you're MRD negative and you know you cannot take that time off or reluctant to, I would collect the stem cells and have you go on your merry way in this scenario. Yes, I would still use maintenance because we don't have enough data to say we can base our treatment decisions off of MRD negativity. But on the flip side of that, I've had some patients that we've either gone through or not gone through transplant and are MRD negative and for some reason or another maintenance has to be held or stopped, whether it's toxicity or other conditions, other health issues that come up in that time point. And so you do sometimes have to take patients off of maintenance and wash them. And I'd be more comfortable doing it if they're MRD negative than I would if they had detectable disease.
- [38:00]
C
I would agree with that approach. I think definitely this is one of those areas right now where determination and IFM give us that comfort that we can take a very patient centered approach in this. Thinking about this more from the perspective of what Sonali is doing, we would definitely want to approach this from talking to the patient, seeing what their lifestyle is. In this patient's case that you described, it sounds like it's not going to fit their lifestyle. We have data that shows that they could have this delayed transplant and still have very similar outcomes. And even within that study there was, as Shonali said, there's a variable amount of maintenance therapy lengths and patients still had similar outcomes. It was not a fixed period of time which gives you some comfort and flexibility. And as Sonali Said I think that MRD negativity, while we still have the jury is out in terms of how much we can use it for a risk stratified approach. There's a lot more comfort in making those decisions when you know, there's just less active disease at that particular time.
- [38:52]
B
And the flip side of that is also cost. And that's something that I think we're going to get to here as well. But things like lenolidomide among other drugs that we use, including Daratumab or others, if we consider a more intensified maintenance, unfortunately they're not cheap, they're expensive medications, some of the most expensive that Medicare covers at this time point. And so that's something to keep in mind from a healthcare utility standpoint is what is this doing to the patient's wallet, their stress level of their financial burden moving forward, seeing themselves on a drug for several years that costs co pays that go into the thousands sometimes versus being able to come off of that and save that money. So it's definitely something that needs to be taken into account from a systems wide perspective.
- [39:40]
C
Yeah. And this is actually an area that Shonali and I have together been working on in terms of analysis. We put together cost effectiveness analysis looking at the determination study as a model. We were presenting these findings in a couple weeks in Paris at the EBMT conference. So looking forward to sharing that. But the bottom line approach, not to spoil too much, is that auto transplant is actually not cost effective in almost any scenario here because of the current standard where patients are getting maintenance therapy on either end. And so by adding that auto transplant fixed cost of a couple, you know, somewhere between 100,000 and $200,000 in most cases. There's just no way to make those ends meet even if you have a slightly overall higher quality of life post auto transplant in the short term. Now again, that is very much going to the data on quality of life with MRD negativity may also need to be factored in. So there's a lot more work to be done here as Shonali said. But that was one of our early findings that we thought was very interesting. And then we'll go through the whole model validation steps to really confirm and develop a little more nuance in terms of what we found there.
- [40:42]
D
I think that makes 100% sense. And in my head I'm like, well, the Dara, it goes down into the vein really easy. We have very little side effects. But the gold that it costs to get that DARA into the vein is insane. And we don't think about that a lot. And right now it's Dara with, I think Dan said in our, in one of our episodes, we gotta try Dara with everything and keep on taking Dara forever. But we really do need to do these MRD adaptive approaches and we really wanted to get our listeners to understand and I think you guys are really articulating this well. Is that sustained. MRD is going to be a very important tool. It's going to be impossible for us to get the perfect data. We'll have bias in our studies. There is no doubt about it. There's no way of pushing the needle forward without having some bias. And we have to do it the best we can. But this idea is really important and talking to the patient is incredibly important. And taking this patient centered approach, you don't necessarily need to do a transplant and absolutely everybody is. I think one of the biggest takeaways, at least that I'm taking from the conversation we've had so far.
- [41:38]
C
I'm sure Shonali will probably say something similar, but I think that's really what we hope to get across that it's not definitely do or don't do transplant at this point. I don't think that there's evidence strongly to push you in one direction or another, but rather meet the patient's needs and interests when you're making that decision. One other point to come back just in terms of two other cost points is just the nuance of the difference between. Chanel is mentioning how expensive Revlimid is, for instance. And one of the interesting side points of that is that Revlimid, even as it's gone generic, is still exceedingly expensive. And there's a huge out of pocket component that doesn't get factored into a lot of these cost analyses that are performed. We think about health system costs and the impact on the patient shouldn't be minimized. And so that's where more data on mrd, as you mentioned, is going to be really important. Daratumumab will be going generic in the near future as well. And so the question of where it falls in terms of because it's an IV or subcutaneous therapy, it's going to really make a big difference how much that cost comes down and how much that falls in the patient when you're making those decisions.
- [42:36]
A
Are you guys having these discussions about financial toxicity with your patients? I'm, I'm curious because we talked about your normal counseling, but this is important. And quite frankly, as fellows, we're so far removed from all of that and all of the financial aspect of healthcare. So definitely curious to hear your thoughts on that.
- [42:54]
B
Absolutely. It's something that we do prep the patient for because sometimes they get a call that, you know, your copay is several thousand dollars all of a sudden. And we are very lucky to be in an institution that we have a lot of support staff that can help patients find grant programs or other support programs and ways for the cost or the copay to be reduced. And in most cases those can be applied. It's very rare cases where you can't prove need or you know, the appropriate factors. But definitely is something that we do prepare the patient for that. If you get the call, let us know. We will find ways and programs to help you bring that cost down to something that is at least more palatable or at least sustainable for them. Because that's really the goal here is you don't want to add to the stress of an already stressful situation. Does it add to their stress? I'm sure I'm not the one that's in their shoes at that moment. And how much it factors into that is hard to tell. But it's definitely something that plays a role into it. It also in those moments helps to let your patients know what other support systems are there. Whether it's support groups through the institution, through online forums, reaching out to social work for even the little things. We live in an expensive city in Boston, so even finding payment programs for parking when they come for their visits or hotel stays because many come from a distance. So the little list of things can help. It's definitely something that stresses them out.
- [44:19]
C
There's just so many hidden costs that I certainly similarly end up doing a lot of counseling, not so much in the upfront part because I think think you guys will find this as well that in most places, maybe outside of the VA where things are also covered, but much more onerous to get to getting transplant paid for actually ends up being much more easy and provides less burden onto patients than all the drugs related to transplant that patients get outpatient. A lot of the patients are on Medicare. So issues with like Part D, Medicare or other insurance situations end up creating more issues for patients. So those conversations definitely have to be had. And thinking back to that patient centered example around determination and using when to time transplant or delayed or upfront, the factor of having a lot of upfront costs of maintenance Revlimid vs maybe be able to defer that or offer a shorter period of time of maintenance therapy in the setting of getting a transplant has to be considered too.
- [45:11]
D
Yeah, it makes so much, so much sense.
- [45:13]
B
All right.
- [45:14]
E
And so especially in light of what you said about cost effectiveness analysis of a transplant. I think I may know what you think about this next topic. But. But say you're seeing a patient who's already had one transplant and got revlimid maintenance following that transplant and seemed to be doing pretty well, eventually relapses and reinducing with Darapom. Dex, would you consider a second transplant on a patient like this or is that something that we really just aren't doing anymore?
- [45:41]
B
So that's a great question. I think it's not something in terms of second transplants. It's very well studied. There are very small studies looking into this. My inclination is to actually avoid a second transplant. The utility of a second transplant is not something that's been borne out in sequential studies unless a patient has achieved a great amount out of their first transplant. And what I mean by that is several years past the average. Right. So we expect at least four to five years of control disease or progression free survival with upfront transplant. And if they have not achieved that, their likelihood of achieving anything close to that is very slim with the second transplant. If they've achieved eight or nine years with their first transplant and they have cells left over, I might consider a second transplant. They achieved quite a bit of benefit from their first one. That might be an area where I would look into a second one. But again that's the, the exception, not the rule. So very, very rare cases in which you would consider a second transplant just given the toxicity of Malplan in the future?
- [46:48]
D
Yeah, it makes complete sense. And I'm going to ask one last question. Let Ronick wrap it up. Amer, you're an aloe guy. Do you think we're ever going to allo in myeloma anymore? And secondly, what's the. And we'll talk about bites and car T's in another episode. But just out of curiosity, was there any benefit to doing aloe in this patient population?
- [47:08]
C
Unfortunately, I think that what we've seen bear out over the years is that there's very little evidence that there's a strong graft versus myeloma effect with donor transplants. And so at this point it's, you know, there are people who derive benefit. The patient I'd given the example of earlier who had the donor derived leukemia has been in remission from their myeloma for about five and a half years now. And even now coming in with the AML now, I mean, there's probably an element of marrow crowding, but at least for a large stretch of that time, it seems like that patient did actually have graft versus myeloma effect and cure. But so I think that there's always going to be examples of patients who have success with this. But the number of patients that relapse suggests that the cost, and when I say cost, I mean human cost here of patients going through an allotransplant for myeloma just does not provide enough potential for benefit for most people. There is always talk of it and certainly like I just came from the tandem meeting in Orlando this year, and with some of the evidence seen with patients going through car t therapies with IDE cel, one of the questions that came up was whether there was potential for using a cell therapy like IDE cel or Cilta cel as a way of bridging to an allotransplant. If the combination of the two might provide enough effect against the myeloma that we can start talking about cures. But that is very much an open question, probably several years out from even getting a really definitive study.
- [48:32]
B
I will say in regards to allo transplant, I obviously am not a person that does a lot of allotransplants. However, and this is purely anecdotal, the only cases in which I've seen a quote unquote functional cure in myeloma is actually a syngeneic transplant. So if your patient happens to have an identical twin that does not have any other underlying diseases, that's something I would possibly consider. There's very little data on it, but the outcomes are relatively good. I can say when I was a fellow I had one patient that was a syngeneic transplant who I was seeing in follow up and this was 17 years out from their transplant and at that point they actually were off maintenance, so truly had achieved a functional cure. Again, this is anecdotal evidence, so take it with a grain of salt, but that would really be probably the only case in which I would consider an upfront aloe.
- [49:25]
C
The nuance of that is actually particularly interesting because in most other settings for aloe transplant, we've seen, especially in leukemia in particular, that syngene transplants are borderline inferior to getting a matched sibling transplant that's not identical or a matched unrelated transplant, matched sibling transplants being the gold standard, but finding that you don't get enough graft versus leukemia effect in the setting of syngene transplants. Whereas here again, in small numbers, you do seem to see a graph versus myeloma effect in these patients and maybe just a combination of the different immune milieu that's there. For some reason, it seems to work better. But it's a very kind of interesting nuance when you talk about allotransplant and myeloma.
- [50:04]
A
Wow, that's fascinating. I never even thought about that patient scenario before, but it's definitely cool to conceptualize. That's awesome. And 17 years is also insane in light of all the discussions that we've had.
- [50:17]
D
For sure. Yeah.
- [50:19]
A
All right, guys. Well, any final thought thoughts that you guys have on your minds?
- [50:23]
B
No, I mean, I think you said it well earlier, right. That transplant is really an individualized discussion. Now, in myeloma, it's not the rule across the board that just because of an improves PFS that this is something we should be doing. I think you definitely have to look at several factors related to the patient's myeloma, related to the patient themselves, their condition, their socioeconomic factors, and their wishes and what their goals are. So it has to take a number of things into account when looking into transplant and myeloma, but it also is. It's not gone yet.
- [50:58]
C
Exactly. Just jumping off that. I think transplant is very much, maybe going from the standard consolidation to very much a personal choice, both on the side of the clinician, but more specifically on the specific patient and their needs.
- [51:12]
A
This is so important and, you know, something that we've been highlighting, and so this will be my final statement as well, that we've been highlighting in the treatment of myeloma is trying to get patients the best quality of life possible. And I guess that's the case with most diseases, but trying to minimize unnecessary medications, toxicities, et cetera, to get them the best quality of life. And so I think that this conversation that we had today is fantastic because it helps us kind of frame that discussion, helps us think about what we're offering our patients, and it gives us kind of a perspective of the other side of the table. Right. Like, we don't always think about all the things that patients are tasked with because we're not a part of those conversations all the time. So having you guys join us has been really eye opening, extremely insightful. And so thank you so much for being here today.
- [52:03]
B
Absolutely. It's our pleasure.
- [52:05]
C
Yeah, it's been wonderful. Thanks so much for having us.
- [52:07]
D
And last thing I want to say, I finally know what pleurxifor is. Anyone who listens to fellow on call. Cannot miss that. The ITE is going to throw the question out now. Now a hundred percent. Everyone's got a hundred. This STEM cell mobilization. CXCR4. That's it. I got it.
- [52:18]
B
There you go. And unfortunately, what's still on the board is triplets are still better than doublets.
- [52:25]
A
Also good to know we have it is coming up very soon.
- [52:28]
D
So swab trials still.
- [52:31]
B
Still VTD is your answer.
- [52:33]
D
Yeah, yeah, yeah.
- [52:34]
A
All right, guys. Well, until next time. We'll see you all later.
- [52:38]
D
See you later, Sam.