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The Fellow on Call: The Heme/Onc Podcast
Episode 152: Myeloma Capstone, Pt 1 - Smoldering Myeloma & Frontline Treatment in the Elderly
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 Reload University Medical Center. I'm Ronak.
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B
I'm Vivek.
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C
And I'm Sean.
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A
And in today's episode, we kick off the first of our roundtable discussions with myeloma experts.
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B
This.
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A
This is a capstone discussion with people that do this every day. We're gonna talk to them about the nuances in myeloma management. And we're so excited for this episode for you all.
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B
Part one here today, we're gonna focus on smoldering myeloma, that aquila data and frontline myeloma treatment in the elderly patient. I think both of these are very, very important topics, practical topics for patients you're gonna see in clinic.
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C
I think for all of the discussions that we have with our experts, I think it really highlights some of the things that in the myelino field that we particularly enjoy. It also highlights some of the things that people outside the myeloma field find very frustrating, which is there's a lot of variation in how we practice and a lot of it is based off of specific patient factors and a lot of it's based off of the ever evolving data. So it's, I think, going to be a great discussion to see how a couple of different experts approach similar situations. And these are situations I think we commonly encounter when we take care of myeloma patients.
- [01:23]
A
Fantastic, guys. So without further ado, let's roll that show. So, guys, we have a fantastic episode lined up today talking to two experts that treat myeloma every single day. And we're curious to pick their brains about how they approach complex decision making. And there's a lot of complexities as we've outlined in this series. So the first of our guests who is a friend of the show from this exact same conversation a few years ago is Dr. Mani Moyuddine, who's an assistant professor at the Huntsman Cancer Institute at the University of Utah. And then we also welcome a new friend to the show, Adil Khan, who is joining us for from UT Southwestern, where he's an assistant professor in the Department of Internal Medicine and in the Department of Public Health. Guys, welcome to our show. Thank you so much for being here.
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D
Thanks for having us.
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A
Thank you in classic TFOC fashion. I do want our opening question for the both of you to be. Tell us one fun fact about yourself. So Adeel, as a new friend to the show, you can go first.
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D
Well, I'm honored. One thing that I've not been shy about is that my interests in life started when I was around six years old and never changed. So I am still a huge Batman fan, Spider man fan. I love Mario. Anything nerdy. I am still all about Star Wars. If you ever see my nerd wall in my room, it's something that my wife wants me to take down every day.
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A
We love to hear it. Never stop being you. That's awesome, Mani. We'll turn it over to you.
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E
I had originally thought of something else, but I'm going to now piggyback off what Adil just said. So an interesting fact about me is that when I was 12 years old, I got together with a bunch of friends and we made our own Star wars themed movie. It was called Star kids. And I made a Darth Vader type mask. And we would bring in music from video games. Like we'd play it on TV and like, you know, that would be our background music. And we had these like effects where like again, this is Pakistan and this is a long time ago. We had like two sticks. One was a small stick so you'd hold it, then you'd like stop the camera and then take a much bigger stick and you put the camera back on. It would look like a lightsaber popped out. So that was my what I was doing when I was 12 years old.
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A
Amazing. How can we get our hands on that? Because I'd love to.
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E
It's extremely embarrassing and guilty like you did.
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A
That's amazing. That's amazing, guys. Thanks again for being a part of this conversation. Sean, do you want to kick us off with our first question for today?
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C
Yeah, absolutely. One of the big trials that has come up in recent years has really been a focus of a lot of discussion is the Aquila study. And so for our listeners, you may remember from previous episodes that this was a Phase 3 randomized control trial that was evaluating a fixed duration of daratumumab versus active surveillance in patients with high risk smoldering myeloma. The results of that trial showed an improvement in progression free survival as well as what appeared to be an improvement in overall survival. We wanted to get your takes on how you're actually using this data clinically when you're seeing patients. And Moni, why don't we start with you. I know you wrote an excellent commentary that was published in AGH last year about this study and some of the possible critiques of it. So what are your thoughts on this approach?
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E
Absolutely. So if you do a deep dive into the Aquila trial and you also do a deep dive into the FDA ODAC meeting and all the material that was generated from it, you come to the conclusion that it's fairly clear that giving daratumab compared to just observing people with smoldering myeloma leads to improved numbers. Whether or not it truly changes, like morbidity is a little bit more of a nuanced discussion. So I'm going to give you, like, some specifics here because of how we define myeloma. If, let's say, you arbitrarily reach a light chain threshold of 100 or your bone marrow biopsy plasma cell percentage hits more than 60, you're going to be called as having myeloma. Even if you feel the exact same and even if nothing else has changed. A lot of how myeloma was diagnosed in this trial was these events just asymptomatic lab changes. Now, if you look specifically at anemia, which is a crab feature, all anemia events appear to be like asymptomatic, like drops in hemoglobin. So the median hemoglobin drop was 1.7 gram per deciliter. This did not correspond to fatigue on patient reported outcomes. And there was not a single case of anemia that was severe enough to require a blood transfusion. Now, the other thing that happened was bone lesions. And again, bone lesions can be associated with a lot of morbidity, a lot of discomfort. I do not mean to minimize that, but in this trial, bone lesions that were picked up were generally asymptomatic. There were 166 progression events. Only three of them were symptomatic bone events. All of the other ones were just asymptomatic things picked up on imaging. And of these three, two of them were actually in the Daratumumab arm. So if you put this all together, Aquila. The Aquila approach using daratumumab improved numbers, but morbidity is very low with modern surveillance approaches. I wanted to put a brief plug about how surveillance was done in this trial. And in this trial, the use of a PET scan was optional. It was actually CT scan that was considered preferred. I spoke with the head of Janssen shortly after this trial is published, and I'm like, hey, how many people got a PET scan. And he said he would get me those results. And it's been over a year and a half and there's still public results on how many people got a PET scan versus not. I suspect that CT scan was what was predominantly used and even mri. So the mri, they did use mri, but they only used a spine and pelvis mri, not a whole body mri. So you could be missing small focal lesions elsewhere. So their surveillance approach was not what I do in my practice, which is every six months, whole body MRI at least for the first few years and then frequent labs in addition to that. Because that's one important point, that their surveillance is different than our surveillance. And with our surveillance I would expect results to be even better for the observation group. And then the overall survival benefit, I think this was 83% versus 97% at latest follow up. I think that that's hard to believe. That's what we're going to get with contemporary United States patients. A lot of these patients, when they progressed, they got therapy that was fairly subpar by today's standards and actually subpar even by a few years ago standards. Right. There were people who weren't getting triplets universally. There were people who got just doublets. There were people who got like monotherapy. And there were some people who didn't even get treatment when they actually like developed the diagnosis of myeloma. So I think that's, I'm hard pressed to believe that applies to a patient in clinic today who has smoldering myeloma who may not need treatment for three or four years. And three or four years later they're going to get something like BCMA directed therapy. So I'm really hard pressed to believe that they're surviving, survival will be better by treating the smoldering myeloma today versus later. There were also some patients who died before receiving any treatment. And that is fairly odd, I would say. And it makes me wonder if like things like AR amyloidosis were rigorously screened for. This was a global trial. And I think that just like hard to extrapolate the overall survival results to my clinic today. So that's my take on this study,
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D
all great points, and I'll bring up about the Aquila trial, is that it attempted to answer a very important question in the field. But its applicability in this current modern era still ends up being a little bit limited. Part because of the way that it was designed and the era in which it was designed. It came off the heels of the Phase 2 Centaurus trial, which showed success of the use of daratumumab in intermediate risk and high risk. Smoldering myeloma as defined then in what they then used for Aquila as their phase three study is actually not what we consider to be high risk nowadays. We use nowadays the 20 to 20 cytogenetics criteria, but that is not what they used in the trial. There are similarities, but it was different. So for instance, IgA immunoparesis, these are considered high risk factors in Aquila. That is not conventionally what we consider to be high risk with our modern definition. And so with just the era in which it was designed, it loses a little bit of applicability. But I'll also say that is in part the issue with smoldering myeloma overall. And if I may, I'm going to give just a little bit of an anecdote of why smoldering myeloma ends up being such a controversy. Part it's because I'd like to contend it's a little bit of an arbitrary category. I say that because the term smoldering multiple myeloma was come up with in 1980 by Robert Kyle, to whom we owe a great deal. He's also the individual who came up with the term MGUs. And his work done at the Mayo Clinic was really seminal in the field. And I had the benefit of doing a visiting fellowship a few years ago and I was able to ask him directly, why did you come up with smoldering myeloma? And he insightfully said that there were these patients who seem to have a lot of monoclonal protein. They had more plasma cells in the marrow than would be comfortable. And so he didn't feel right calling it MGUs. But he did not see the clinical misbehavior. What we would say is crab criteria back then to say that they had active disease and to warrant some of the much harsher things that they would be given back then. And so this intermediary state was then seen. And that was very insightful. I think the problem was is how to define that intermediate state. And so he chose round numbers because you have to start somewhere. And so he chose 10% plasma cells in the marrow. You chose more than 3 grams per deciliter of M protein the blood and more than 500 milligrams of proteinuria per 24 hour period in the urine. These nice round numbers are then what we define multiple myeloma and smaller myeloma at least. But that doesn't necessarily match the biological reality that we now know of there's a lot more heterogeneity there, and it's much more of a spectrum. And acknowledging that who within that spectrum needs to treat versus needs treatment and doesn't need treatment is what we continually try to answer. And Aquila doesn't quite do that, even though it does, I think a very worthwhile attempt. As Manny said, the biochemical improvement in numbers is very much what is seen. I would contend that you do need biochemical improvement in the numbers before you see clinical benefit, but this is a good study in those who are savvy with trials of potentially statistical significance, but not necessarily clinical significance. That being said, acknowledging the improvement in anemia, the improvement in bone disease, while one could contend that it's modest, you know, it has been motivation to offer this to patients. And so that is something that I have a conversation with people who have higher risk smoldering by the modern definition, not necessarily the Aquila definition of this is a consideration. It is certainly not what they need to do, and I would never advocate that based on this data, but it is a consideration. And so that ends up being then something that's in the patient's hands because oftentimes they do have strong preferences. I will say, interestingly, in those patients with whom I have discussed it, high risk smolderers, the uptake is actually very low. It's interesting how as much awareness as there has become about Daratumumab in the patient advocacy space for smoldering disease, people who actually want to commit to the treatment has been low, few and far between. I've had more success in actually promoting certain clinical trials that we have. And I can in fact count them on one hand, since we've had this data first presented at ash in 2024, with the NEJM publication in early 2025.
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A
I think that's so interesting and that's such an interesting perspective just because again, to people that don't do this every day, it seems like we're really pushing the use of DARA and highly considering it based on this information from the trial. But clearly patients are aware of the data, but they're also aware of their disease thanks to counseling from their doctors. And so it is insightful to hear that most people are not actually reaching for. I think it continues to be a point of discussion. Are we over treating patients? What are the implications about, you know, infection risk, financial toxicities, et cetera, time, toxicity, coming to the office? All these things need to be accounted for.
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B
One question that I had for you guys as well is let's say, does patient age make a decision, a factor in your decision here? If you have an older patient who might be 80 with smoldering myeloma, that may be higher risk. Are you saying, ah, maybe daratumab can kick the can down the road or potentially prevent them from getting a more intensive regimen. Are you thinking about that way? Are you saying, hey, they're 80 anyway, I don't want to expose them to the toxicity. Does that age ever change your decision on whether to recommend, you know, not just offer but recommend daratumumab for smoldering myeloma?
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E
So this was not what the trial studied, but in my practice, the one time where I have recommended it was precisely this, like an older, frailer adult where the numbers are beginning to worsen. It's clearly not myeloma. I've done advanced imaging and proved that. But we're all afraid of the eventuality of needing an intensive three drug or four drug therapy. And we sort of moved forward with daratumumab in that situation. So I do think that this is one use where it could be helpful. I'd say that for younger, fitter patients if they have otherwise smoldering myeloma, but the numbers are clearly worsening. I will probably lean towards like myeloma type treatment rather than just teratumumab for such a patient. Acknowledging again, this is like my personal opinion and not perhaps based in data.
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D
One thing I would note that Akhil was not able to answer and most of our models actually do don't approach this is the rate of change of labs and situation over time. Most of these risk estimators are really using single points in time and that includes, you know, what we do with 2220, what we do with Pangea 2.0. We haven't had a good model that really tracks someone's rate of change, which you would think about with respect to age would have a lot more implications and we just don't have that. But someone who's rapidly rising in M protein I'm way more concerned about than someone who might have gotten to the 2 grams over 10 years. That's just not the same patient, even though in the model it would look the same. At the end of the day, patient discussion and individual decision making is still what is ultimately recommended. And as I've said in other circumstances, when there's not a clear right answer, there's not a clear wrong answer either. So enjoy the gray.
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A
I want to move the conversation a little bit now to a patient with diagnosed myeloma. So let's say we have an 80 year old male who's quite fit with newly diagnosed IGG Kappa myeloma. I'm curious how you approach therapy for these older patients. Are you reaching for quadruplet therapy? Are you using triplets like Adara RD based on for instance the Maya trial? And if you are utilizing dexamethasone in these older patients, do you ever consider stopping this therapy? And at what point? Time point. So a lot of questions for you Adil, why don't you start that question
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D
in a little bit of an older era. What we really gave some of these older folks was RVD light. So just sort of modifying our conventional triplet that we had had for a few years to just make it tolerable and just proceed with that. But the Maya trial with the use of an anti CD30Mr. Antibody with lenn index really had great numbers. I mean if you look at some of the PFS values there, it seems like it almost makes some of those patients immortal. Now in practice that's of course not what we see, but we do see that it was much better tolerated. So that had become our standard for a number of years until 2024 when we had the presentation of the IMRAS data which then used isatuximab with rvd. And we now have a similar trial that used daratumumab to then reintroduce quadruplets for these patients. And needling the thread across all of it, what I tend to do is that unless someone is particularly and by and large that's a lot of the eyeball test, I will try to do a quadruplet. The data is there. Usually people can handle it for at least a little while and if so that drops their disease down. So they get DARA or ESA rvd. And I try to make that as tolerable as they can then handle. But if someone is truly genuinely frail, one I question if I'm really going to benefit them with treatment. You have to sometimes really consider their comorbidities if you're really going to be changing their situation or not. But if I do think that they're frail but will benefit from treatment, that's where Dara Lendex I think work works very well and that's what I try to pursue. I do try to make things also still more tolerable for folks. So I've been a big fan of the down with Dex movement to just minimize use of dexamethasone as much as reasonably possible. So I really never do the 40 milligrams. I do 20 milligrams at most. Very often I'll go down to 12 milligrams and I'll start to peel it off as soon as three cycles and almost universally at six cycles, saying that it's probably going to do what it's going to do. And we have retrospective data to support that. The final piece to mention is that frailty is also in the eyes of the beholder to some degree. And I want to acknowledge that there is a little bit of an arbitrariness in what we determine to be frail versus not. And if someone is really looking like their performance status is struggling because of the myeloma, that is actually someone who might benefit from a little bit of intensity to drop that burden down and to give them back a little bit more quality of life.
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A
Very well said, Mani. Same question for you.
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E
Yes. So I think that as super specialists, we do sometimes tend to get really bogged down with all of these minute details and lose the forest for the trees. Multiple studies have shown that older adults there, the most important thing to them is functional independence and quality of life, not preserving or prolonging PFS at all costs. So what I do is that I extrapolate from the benefit study, which is ISA VRD versus ISA rd. So it's the study that actually isolates the effect of the proteasome inhibitor. I'm going to tell you how I present it to patients. So the numbers are almost accurate, but they are rounded a little up and down. So what I tell people is that if I were to add bortezomib, you're going to have to come once a week for much longer. Like, you know, we're talking like eight months or a year as opposed to only two months if we're doing data Revtex. By adding Velcade, I am going to double the chance that you're going to have neuropathy. So it'll go to about 20, 50% from about 25%. I am also going to increase efficacy. The chance that we get to a point where your bone marrow has no plasma cells, this is like 10 raised to power. Minus 5 is about twice as high with ISA VRD compared to just triplet. And that's about again 50% versus 25%. And then I'd say that the long term outcomes such as overall survival are unknown. It is exceedingly unlikely that overall survival will be better because we have a lot of good options down the road that we can use and in younger adults and in many other studies, PFS is not always correlated to OS because of good post protocol therapy. So I have this discussion and a lot of the times patients will just choose to just choose a triplet and that aligns with their values. And some people will choose quad and that aligns with their values. They want something more intensive and that is okay as well. So I just have that nuanced discussion and I still think that for many older adults, triplet is very acceptable. And as Adil pointed out, a C38 based triplet is preferred not because we know that it improves overall survival relative to VRD for this patient population, but because it's more tolerable.
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C
We've talked a little bit about the different side effects related to some of these medications, so things like Velcade and Revlimid. But I think it's also important for us to think about, just as Adeel was saying earlier, the steroid component is not without its own side effects and particularly in these more old and frail patients. For our viewers, we'll link to a couple of different studies in our show notes, but there's I think two that really have changed how I've thought about how to use steroids in these older frail patients. So one was a secondary analysis of two large SWOG trials. And what this showed was that in these trials, which again is as close to as strict to by the book as you could possibly be, about two thirds of those patients ended up having to have their steroids reduced during the treatment. And when they looked back at that, there really didn't seem to be any difference in the outcomes in the patients who were able to stick to the full dose the entire time versus those who had to have it reduced, the other trial is the IFM2017 03 trial. And this was actually kind of designed in a way somewhat similar to the design of the Maya trial in some ways. But what they did differently was that they actually looked at stopping steroids after the first two months. So patients got dexamethasone 20 milligrams for the first two months just like you normally would, but then after that they actually stopped the steroids entirely. If patients still needed premedication for their dara, they were allowed to get things like prednisone beforehand. And but what they saw there too is that actually the outcomes looked pretty good. And if you compare it to a similar subset of frail patients from Maya, it does look again, relatively similar. And so I think all that goes to show that although we know that Steroids are important in myeloma care. We may have been potentially over treating in some of our patients, especially when you start to have to balance the higher risk for side effects that come with steroids in these older and more frail patients.
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B
Speaking of toxicity, the other question I have about these older patients, so we have two different opinions here, which is always good. One side of the coin that says, hey, look, we can get deep, deep responses in this myeloma is terrible. If it relapses, you're going to have horrible quality of life with that. Let's knock the myeloma down. The other thought is, well, what about the toxicity of that neuropathy? That 50% risk of neuropathy is real. Maybe we shouldn't go as hard for these patients because they're still going to have really excellent outcomes. And the benefit study, what's the benefit of Velcade? It's to be seen. We'll see what the long term follow up shows in that data. But for both of you, or for Mani or whoever wants to answer this question, how do you think about the starting dose of revlimidation when you're using either a triplet or quad in these older patients? And what's your often most common dose reduction? What do you think patients actually tolerate?
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E
Yeah, so I think for really frail older adults, revlimid causes a lot of issues, a lot of like symptomatic, like side effects. And the single most important drug to give these people, in my opinion, from a tolerability and efficacy standpoint, is the CD38 monoclonal antibody. So for the really frail adults, what I often do is I'll just start off with CD38 monoclonal antibody, have a small amount of steroids to, you know, decrease allergic reactions, ease them into treatment, and then add an IMID later and then add an IMID at a very slow dose, perhaps like 5mg or 10mg depending on kidney clearance. Give them a month or two, see how they do and then consider going up. I think that if you were to start these people on 25 milligrams, it's going to be like too much for them and then you're going to have to like backtrack all your steps. You can wait a cycle or two to start, in my opinion. And if you are to start really low and then go up, and I honestly think in practice for these people, it's hard to push beyond like 15 milligrams. So that's how I approach IMID dosing.
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D
In this population, I agree with that. I think the number one factor is really renal function. You really do have to make sure that you're giving them a dose that's appropriate to their kidneys. So that is really number one. Two, if the goal is to reduce the myeloma, I don't want to give them extra side effects, as Manny is saying quite well here. And so 15 milligrams has kind of been my sweet spot. Now there's some folks who I think I might be able to get the full 25. And sometimes I will say what we decide to do initially is not necessarily what we're destined to do later. We can start at 25 and rapidly drop it down and they can sort of prove to me that they're quote, unquote, not tolerating it. But for the older, Frailer folks, the 25 can be a bit much and the 15 tends to be a little bit better. There are ways to drop it down obviously even further. And so I sort of think of it as a stare, kind of do your best where you can to start with and just recognize that they don't have to remain there. And if even they get a few months of the treatment in where again, it does drop the disease burden down. I do think the anti CD38 monoclonal antibody does a lot of heavy lifting, as Manny also said. And so you're getting a lot of value out of that alone. And that tends to be just about as side effect free as we can get in our field.
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B
I think that is very helpful to hear how to practically approach these patients. This is not an uncommon patient that we see in clinic, in a community or an academic center. I think this echoes similar. I always bring things back to lymphoma, how you start somebody on our mini chop, for example. I'll start them on our mini chop and dose escalate, depending on how they tolerate it. That's my approach, similar to what Monty was describing, that you can go up from that dosing if you're worried about the patient. If you think, hey, the patient can tolerate, they're pretty fit, start high and then go down. Either way is fine. It depends on the individual patient in front of you.
- [25:14]
A
We have so much more that we want to discuss with you, but maybe we'll stop here and give our listeners a chance to digest just the wealth of information you've already shared. So next week we'll be back and we'll continue this conversation with our guests Adeel and Mani. Thank you guys again for being here today. I think for today, that wraps up another fantastic episode of the Fellow on Call. So until next time, we'll see you all later.
- [25:36]
C
See you later.
- [25:37]
E
Thank you so much.
- [25:38]
D
Thank you.