← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 145: Myeloma Series, Pt. 6 - First line treatment of Multiple Myeloma (2026)
Ronak Mistry, Vivek Patel, Dan Hausrath
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Sign up now at Premium Co. 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.
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The views expressed in this episode do.
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Not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call. The Hemong podcast coming at you from Rouleau University Medical Center. I'm Ronuk.
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I'm Vivek.
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And I'm Sean.
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Guys, in today's episode, we continue on our myeloma journey, this time talking all about transplant eligible and ineligible patients. Because believe it or not, from the last time we did this recording a few years ago, even that paradigm has changed. A lot of new data, a lot of exciting opportunities to treat our patients, and we're going to go through all.
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That and more today, excited to get into this one very high yield episode. The first time we recorded this series, it was extremely popular. We're now updating this, so we're really going to equip you guys with all the relevant trials and all the interesting things that are happening in the space of multiple myeloma.
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There's a lot that's always changing, but this is a great way for new listeners and also for our listeners from before to get updated on what the sort of most advanced regimens that we use in 2025 are for first line treatment in myeloma.
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Sounds great, guys. Without further ado, let's roll that show. So last time I listened to the introduction and you guys were hating on me for not being around, but this time Dan's not here. And might I remind you all of why Dan's not here. He's currently cooking tagine.
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Yeah, Dan has some weird fancy thing that he bought. I don't even know. He's like something imported from Iran. I don't know. I don't want to get Dan in trouble. You know, Ice might be listening. Dan, gotta watch out. You gotta watch out.
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He did send us a picture of what he was cooking though, and it did look really good.
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It did. It objectively looked very, very good. But yes, he claims that he has saffron from overseas that he already used to try to make this dish. And so he was unavailable to record about myeloma this evening, but nonetheless, the show will go on. Guys, we've been having some really fantastic discussions as we update our myeloma series over the last few weeks. And today we finally get to the highly anticipated myeloma treatment episode. And as we have been alluding to, a lot of changes have been made in this space since the last time we recorded all of this. And so maybe let's start off with the case and jump right into that data. How's that sound?
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I'll kick us off with that first case here. So we have a 63 year old previously healthy male with newly diagnosed IgG Lambda Multiple Myeloma. He presented really with evaluation for hypercalcemia. Then an SPEP was done which showed an m spike of 3.2. The immunofixation showed IgG lambda serum free. Light chains were ordered, the Kappa light chain was 10 and Lambda light chains were 1,600 with a ratio less than 0.01. CBC was notable for a hemoglobin of 8 with a normal MCV. Creatinine was normal at 0.79. And baseline disease evaluation with a PET CT showed widespread involvement of osseous structures in multiple rib fractures. Bone marrow biopsy showed involvement by 60% plasma cells by IHC with an abnormal immunophenotype by flow cytometry. Fish testing was done which did not show translocation 4, 14, 14, 16, 14, 20, deletion 17p, gain 1q or deletion 1p. Notice we added a lot of things there that it's always important to look up and we're going to go through that in our episode today. Karyotype was also unremarkable, so this patient had standard risk disease. So here we are, we have the 63 year old, previously healthy male, newly diagnosed IGG Lambda Multiple Myeloma. Now I'm going to ask a loaded question. How do we approach treatment in multiple myeloma from the frontline setting in 2025?
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You often hear that people say that the first branch point is whether someone is transplant eligible or transplant ineligible. And if you refer back to our series from a couple years ago, this is one of the big focuses. This is still important, but actually the decision is a little bit more complicated in some ways in 2025. So we also want to think about whether or not someone is eligible for induction with quadruplet therapy or if they are maybe ineligible for quadruple induction therapy. And a lot of that is based off of functional status and fitness. But before we get into that, let's talk a little bit more about just a general conceptual understanding of how we treat Patients with newly diagnosed multiple myeloma. In general, there are three phases of induction, consolidation and maintenance. With induction therapies, we start off with treatments that help to debulk the disease, typically with about four to six months of therapy. And ideally, we want to get to a point where the M spike is nearly gone, that is either it's not quantifiable or minimally quantifiable, but still detectable on immunofixation. We talked last week about the different levels of response criteria with the imwg, and ideally, we want to try to get to a VGPR if we can. The deeper response that we can get with the induction, the better this is for our patients in the long term. We also think about collecting stem cells at the end of induction. The idea is that we want to try to get as much of a stem cell collection as possible before that yield goes down when patients have been on therapy for a prolonged period of time. Next, we move to consolidation, and this is where we tend to deepen our response with more therapy. And so we know that myeloma cells are very responsive to melphalan, which is an alkylating drug. High dose melphalan is very effective at treating myeloma, particularly when we give it at doses of 200 milligrams per meter squared. And this is the dose that we use with stem cell transplant. This is really the key way that stem cell transplant benefits patients with myeloma. The problem, however, with that dose of Meoflan is that it causes so much toxicity to the bone marrow that it can't recover on its own. And so with this type of transplant, we're using what we call a myeloablative regimen because of the severe marrow suppression that happens after patients get this high dose of mephalan. We have to give them back their stem cells in order to allow them to recover. And so really, you can think of stem cell transplant for the purpose of myeloma is that it's actually really better described as high dose chemotherapy with a stem cell rescue. And so this is why we use a patient's own stem cells, that is an autologous stem cell transplant, for the purposes of myeloma other than transplant, we can also consider other types of therapy for consolidation. So, for example, it may be additional cycles of the same regimen that was used, or other types of therapies that are still a little bit more intense compared to maintenance, which is the next thing that we'll talk about. The final phase of treatment for newly diagnosed myeloma is Maintenance. And the main idea here is that we are giving a low dose of therapy for as long as possible to help patients prolong their remission. And so we may be using one, two, sometimes even three medications, but at lower doses than what we would use in induction. And again, the idea is that we want to keep patients in remission, but we are also trying to minimize the side effects that can come with prolonged treatment and help patients to maximize their quality of life. Most commonly, you'll see oral lenalidomide as the sort of main backbone for maintenance therapies, but this can oftentimes be paired with other medications. So for example, daratumumab or in some cases medications such as bortezomib.
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So, Sean, I think that was really, really good. And it's important to understand those phases of treatment, debulk, consolidate our gains and then maintain our remission, maintain for as long as possible. We're hoping that soon we'll be able to do fixed duration maintenance therapies. But often now in multiple myeloma, we keep maintenance therapies going indefinitely until progression, which can become challenging. And so, Ronak, how do we know if a patient is quadruplet induction eligible and transplant eligible?
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Great question. So for the transplant question, we're actually going to get to this in a later episode, and we actually had previously recorded this episode with some master clinicians in this space, and so definitely look out for that. But essentially my recollection of that conversation is that in general we're talking about patients that are less than 75 years old. Although there's no technical chronologic cutoff, it's really just based on physiologic reserve and the absence of major comorbid conditions. So patients that are less than 75 can often be considered for transplant for patients above that age of, specifically the age of 65 to 70. So patients that are may still be transplant eligible but are certainly a little bit older. That's where we may start to see using reduced doses of melphalan. So Sean mentioned using melphalan at a dose of 200 milligrams per meter squared. You may hear in some of these older patients getting Melphalan, we use MEL140 or 140 milligrams per meter squared. And this dose is also used for patients who have renal dysfunction that are going to transplant. Bottom line, if you want to think about it in this way, patients that would be eligible for a major surgery, those are probably going to be the same sorts of patients that may be eligible for a transplant. Now, this question of quadruplet eligibility is a little bit more nuanced and there's a lot more gray area there because there really aren't any good established guidelines for this population in general. Fitter patients who are independent and walk regularly on their own in their 80s may even be candidates for therapy. There are going to be randomized trials to determine whether the quadruplet actually improves overall survival for this older patient population, as treatment related severe infections could significantly impact quality of life. But those are on the horizon and not yet ready in 2025.
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I think that's really great. It's really important that we don't assume that patients who are 65, 68 years old are not transplant eligible, particularly for those patients who have high risk cytogenetics, which we'll go through here again in a second. It's really important to get those patients to transplant. You know, we know that we need to prolong that first. Pfs, maintaining their remission is really, really important. They respond. It's maintaining that response and deepening it with something like a transplant is really important. So really, really good discussion points there. Sean, can you talk to us a little bit about the idea of a triplet regimen and a quadruplet regimen? You'll hear these terms used a lot. And in our prior episode we even talked about doublets, but really that's kind of not really what we're doing anymore. So can you talk to us a little bit about triplet and quadruplet induction regimens?
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With myeloma treatments, we tend to combine multiple different types of medications across different medication classes. And so historically, you know, when you look back, we may have used things like doublet regimens, for example, but over time we've realized that if we can combine medications from these different classes, we can get a lot better response to treatment. And it also helps us to avoid some of the toxicities that could occur if we were relying just exclusively on high doses of one class of medication. And so when we think about induction, there were a couple of different important classes of medications to be aware of and to understand how they make up either a triplet or quadruplet regimen. And our original episode on the pharmacology of myeloma treatment is actually a really great review of this. Just as a reminder, so in 2025, the majority of patients, when we see them for newly diagnosed myeloma, are most likely going to get either a triplet or quadruplet regimen. Two of those medications tend to be relatively similar in terms of the classes, regardless of which one you're choosing. So in the modern day, really, all patients who have it available should be getting treated with an anti CD38 monoclonal antibody. And so the main examples of this are daratumumab and isatuximab. And so using one of those medications tends to be incorporated in the first line of treatment nowadays because of how effective these agents are, as we'll discuss in some of the later trials that we'll review. In addition to this, patients should also be getting dexamethasone. And this is given once a week and is part of their treatment regimen. It also can help to mitigate some of the possible side effects that come with daratumumab, particularly the first time that you give it. As far as infusion reactions, we have those two classes of medications, and then we typically will add either one drug which would make it a triplet, or two drugs which would make it a quadruplet. The main examples of medication classes that we select from would be the imids. So think of medications that end in omide, like lenalidomide or pomalidomide. These are sort of one of the core classes of medications that we use for myeloma treatment and is very common, particularly in triplet regimens, to be the medication that we pair with the first two that we talked about. We also can potentially use proteasome inhibitors. And these are the medications that end in zomib, for example, bortezomib and carfilzomib. There are different ways that we combine these medications as we discuss. But just remember that we're choosing an anti CD 38 medication, steroids, and then one of the other medication classes or both of the other medication classes that are most commonly used in induction.
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Yeah, Sean, I think that's great. And so remember that an IMID is an immunomodulatory drug. And we have lenolidomide and pomalidomide. This is also called revlimid for lenolidomide that you'll hear all the time. And many of our regimens, we abbreviate that with an R. Sounds very, very complicated. When it comes to myeloma, we're going to have a chart that explains the Alphabet soup of multiple myeloma in our shownotes. So remember, lenalidomide equals revlimid. The other thing that you'll see very commonly is that proteasome inhibitor class and you mention they end in zomib. Well, that's also called Velcade. And that's why you'll see V used in a lot of regimens. So bortezomib equals velcade. Lastly, you have that thing called carfilzomib and that's another proteasome inhibitor ending in zomib. And carfilzomib equals kyprolis with a K. So basically there's a chart. Lenolidomide equals revlimid. Bortezomib equals velcade for V, Carfilzomib, kyprolis for K. And it's really important when you see these regimens that you'll see these letters being used because you're probably wondering, what does all this mean? So this is something that eventually you'll commit to memory and we're going to break it down easily for you in our show notes. The last thing I want to mention is sometimes you'll see alkylating agents used like cytoxan for cy or cyclophosphamide. That's something you might be used in patients, particularly with renal dysfunction. Acutely in the inpatient setting, you might see the incorporation of cytoxan into these triplet or quadruplet regimens. In this case, we've got our 63 year old male. Last week we talked about what it means to be high risk. Just to recap that, Rhona, can you go through a little bit about what high risk means in multiple myeloma?
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Yeah. So we previously used things like LDH, albumin, the beta 2 microglobulin for risk stratification. In the RIS grading system, an elevated LDH and a beta 2 microglobulin were poor prognostic factors, especially if their value was greater than 5.5. So in 2025, at the time of this recording, the IMWG update has been released and they define high risk as defined by cytogenetics. So specifically, a deletion 17P or a TP53 mutation is high risk. And always remember, 17P is where P53 locus exists. And so deletion here is high risk, as is in other hematologic malignancies, presence of either translocation 4 14, translocation 1416 or translocation 1420 along with the deletion 1p or gain 1q. Or you could have a biallelic deletion 1p or deletion 1p with gain 1q. Or you can have a beta 2 microglobulin greater than 5.5 with a normal creatinine. We will put these in our show notes. You don't have to commit these to memory right now. But you do want to take a look at these and at least get familiar with them so that when you're looking at your pathology reports, you're able to quickly start stratifying patients into higher risk or not. But just go back and listen to this again and review those in our show notes for sure. Let's take a moment to learn more.
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About the sponsor for today's episode.
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Being a fellow means tough questions, fast changing data and the pressure to know it all. But you don't have to figure it out all on your own. With Primum, you can ask leading oncologists directly and get clear, thoughtful answers in hours. Show up looking like a star, backed by real expertise. It's mentorship from over 100 experts. One on one, completely free. Start today at premium co. Based on all of this discussion, guys, I think this sets the stage for us to start talking a little bit more about treatment itself.
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Right.
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So now we've said that in addition to just determining whether somebody is transplant eligible or ineligible, we're also trying to determine if they are quad eligible or not. Maybe in a later discussion we can talk about some of these high risk features and how that plays into our decision making about mainly maintenance options. But how about we now dive in a little bit into how we got to the current paradigm of treatment for myeloma. Maybe briefly we can cover some of the highlights of the historical context, noting that our old episode really goes into this in detail. It's fascinating and I highly recommend our listeners check that out. But why don't we give the highlights now and get us up to speed of where we are in 2025, almost 2026.
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All right, Rodick, I'm going to do this as quickly as possible. So remember, check out our prior episode if you really want to get very, very granular details on the historical perspective. Essentially this is what happened. There was a drug called melphalan, that alkylating agent at a very low dose. This was used from the 60s onwards. Then we jacked up the dose and did what Sean described with this idea of doing a stem cell transplant. He jacked up the dose so high you'll fry out all the myeloma cells. We need to rescue the patient with their own stem cells. That happens somewhere in the 80s. Until then, low dose melphalan with prednisone was really standard of care for most patients. After that there was the development of these immunomodulatory agents. You had thalidomide initially used in many clinical trials, as well as the proteasome inhibitor bortezomib. And this bortezomib medication, in addition to thalidomide, was used in multiple different combinations in many different clinical trials, which ended up leading us to find out that the use of an immunomodulatory agent in the frontline setting is actually better than chemotherapy. So I mentioned low dose melphalan and prednisone. The other thing that was happening was use of anthracycline agents. We were giving cytotoxic chemotherapy agent to patients with multiple myeloma. And then eventually we said, actually simple old imid plus dexamethasone beats chemotherapy. And the same thing happened with different combinations of the alkylator cytoxan with the proteasome inhibitor bortezomib or velcade. So we got the regimen Cybor D, cytoxan, bortezomib, dexamethasone, also known as vcd, velcade, cytoxan, dexamethasone. Again, it's just that Alphabet soup. And so then we had these regimens and there was a pivotal study called the SWOG0777 trial that randomized patients to VRD induction, which was Velcade reflimid, dexamethasone versus Replimid and dexamethasone, a doublet cause really there was the chemotherapies. But the IMID plus dexamethasone beat the chemotherapies. That was the revlimid dexamethasone. That was standard of care for quite some time. And it was found that that triplet improved overall survival for both transplant eligible and ineligible patients. So we had the triplet VRD as the standard of care, reigning king since that pivotal SWOG 077 trial. What happened after that was the introduction of the second generation of Velcadelbertezomib called carfilzomib or Kyprolis. And it said, let's do that thing called krd. Let' replace the bortezomib, the Velcade medication, use the second generation. That must be better. And there's a randomized study comparing the two and there's no difference at all. So that's why VRD remained king for a while. But the thought was maybe the second generation Kyprolis drug can cause deeper responses. There was a phase two study called the Forte trial that showed maybe it's good and high risk. Again, check out our older episodes for that so you can hear some more discussion about that. But Keep that in mind that some people think Carfilzomib, this Kyprolis medicine, might deepen responses. But ultimately VRD remained king, that triplet. And this led the stage to some of the pivotal studies that we have in 2025 that really changed the landscape of multiple myeloma treatments. And Sean, can you tell us a little bit about the study that looked at the quadruplet induction regimen, Dara VRD versus vrd, because remember that triplet remained king from this historical perspective that we just discussed.
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So similar to what we were just discussing with that landmark SWOG trial that looked at VRD versus rd, there is additional data now looking at quadruplet regimens compared to triplet regimens. And so we have a phase two trial called the Griffin trial and that was looking at Dara VRD versus vrd and the phase three version of that trial is the Perseus trial. So you may often hear these regimens referred to as Griffin or Perseus. There's also a Cepheus trial which looked at this question for non transplant eligible patients. But the sort of bottom line summary here is that in particular when we look at things like Perseus, there is a significant benefit in progression free survival with the addition of an anti CD38 medication in the case of Perseus Daratumumab, when we add that to this sort of tried and true VRD backbone. So if we look at Perseus in a little bit more in depth, there were over 700 patients that were included in that trial. And what we found was that the four year progression free survival was improved at 84% with DARA VRD compared to 68% in the VRD group alone. And so this is great numbers for PFS, particularly when you go back just 15, 20 years and looking at the progression free survival at that point. One of the key things that they looked at in the Perseus study was also MRD negativity. We've talked about that a little bit before and we'll discuss in some of our other episodes as well. But again, we know that MRD negativity is an important outcome to look at. It tends to correlate well with things like progression free survival may also potentially suggest better outcomes in terms of overall survival as well based off some of the meta analyses. And we know that MRD negativity at the end of induction and consolidation with JARA VRD was also better at 58% compared to 33% in the triplet arm. These trials take such a long time to read out, particularly when it comes to overall survival. What I tell patients is that we've just gotten so much better at treating myeloma that it's hard to find evidence that medications are adding to overall survival because our patients are living over 10 years from the time of their diagnosis on average. And so we don't have the overall survival data just yet. But from everything that we've seen so far, Dara, VRD appears to be clearly a better regimen in terms of efficacy compared to VRD alone.
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So I think that's great. And I wanna piggyback off of that and talk a little bit about what you said about mrd. So it's gonna take a really long time. Now we have regimens, this quadruplet induction regimen that, you know, we just had melphalan pred and we had some imids and but did a bunch of different combinations and ultimately now the anti CD38 with an IMID, with a Proteasome inhibitor and with dexamethasone is king. We now have a new king here. And it's going to be challenging in the future to get drugs approved if the four year PFS is over 80%. It's going to be hard to know if one of these regimens is better than other. When we think about myeloma, we're trying to get to the patient to 20, 30 years of survival, right? That's really the key. A functional cure is the hope. And this is where this MRD endpoint became a thing. And there was a meta analysis called the evidence meta analysis that really showed us that achieving MRD negativity improved progression free survival as a surrogate endpoint. And what does that mean? That means that if we look at all the trials, each trial individually and say what is the delta in MRD negativity? Meaning how much are we improving the MRD negativity rate from treatment A versus treatment B? And then let's look at the delta and the progression free survival and let's see if those correlate right. Because it's one thing to say, well, if you achieve MRD negativity, you do well, that's called prognostic. But trial level surrogacy is when you say the delta in each trial. If we improve MRD negativity rate by 15% in trial one, by 20% in trial two, maybe by 8% in trial three, by 30% in trial four. For each of those deltas that corresponds to a similar delta, it's correlated to a delta in progression free survival Meaning that, well, if we have a significant improvement in MRD negativity rate, we can safely say that we're likely to get a significant improvement in something like a progression free survival to get an accelerated drug approval. And that was the case in the evidence meta analysis. In a later fellow on call Journal Club. We'll really explain that in more detail. But just know that these things are correlated very tightly at a trial level summary. And that's very different than a prognostic endpoint, which is why this is now an acceptable FDA approval target for multiple myeloma. So just really important that evidence meta analysis is very critical. We'll talk about it a lot more detail in a later episode. So now we have Dara vrd, but we also hear about that drug Carfilzomib. You know, we said that it can cause deeper responses. So what's the idea behind the use of carfilzomib for some of these patients? Currently, when we think about quadruplet induction.
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Regimens, that drug carfilzomib, one of the important trials to know in this case was the master study. And speaking of mrd, this was also an important component there. So this was an MRD adapted trial incorporating carfilzomib in a multicenter single arm phase two study. And again that's the master study in this case, all patients got DARA krd. And the primary endpoint here was MRD negativity. The goal was to use a risk adapted approach with surveillance for MRD negative patients instead of using revlimid maintenance. So basically we are sort of surveilling patients to ensure MRD negativity instead of just putting everybody on Revlimid maintenance. 70% of patients achieved MRD negativity on two consecutive measurements with only 4% resurgence of disease without maintenance therapy in these lower risk patients. Higher risk patients had worse outcomes with 27% resurgence of disease without maintenance therapy. I look at this and I'm reassured that it seems like carfilzomib seems to be a good option for management. But I actually think that this adds a lot of credibility to how we're hopefully going to be utilizing MRD in our approach to management of patients in the future. But also highlights, it's not so simple, right? Clearly this study is identifying that we still need to think about who is high risk, who is low risk. And maybe we have to sort of plan our approaches to these patients differently based on some of these other risk factors.
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Super cool data and to follow up on that. So remember, master trial is basically like look, we gave these patients Dara KRD for a bunch of cycles, and if they had two consecutive MRD negative measurements at specific time points, we can drop their maintenance therapy down the line. And that was huge. That proof of concept, that's an important proof of concept for people to understand for the future myeloma trials. Right. And in this case, the use of carfilzomib was thought to be maybe better because maybe it improves deeper responses. But like I said, in a phase three randomized study called Endurance VRD versus krd, there was no difference. It's also challenging to say, oh, clearly all patients need DARA KRD because of this one phase two study. Remember our phase three studies? We have that in addition to this at ASH 2023, the plenary session was the phase three Ischia trial. And this randomized over 300 patients to isatuximab KRD versus KRD. So very similar to the Perseus trial of DARA VRD versus VRD. The primary endpoint was MRD negativity after consolidation. And this was improved, obviously, with the quadruplet arm. Right. You're adding a drug, there's no question. I'm not surprised that you're gonna get deeper responses. And the MRD negative rate was 77% versus 67% after transplant consolidation. So we have very, very high MRD negativities with that Issa KRD group. But remember, again, these are numerically higher than what we saw in Perseus. But it's critical that we don't make cross trial comparisons in order to really say that we should use K over V. That would require a phase three randomized study, which we really don't have. There was another study called the Midus study that was an MRD adaptive trial that we're going to talk about in a future episode. So stay tuned for that. As we really are going to talk about MRD and myeloma in one of our future episodes, let's move on and talk a little bit about what we do for maybe quadruple ineligible patients. So, Sean, can you summarize a little bit about the data that we have for things like Dara, revlimid, dexamethasone, and where that came from. And if there are other things coming down the pipeline, and also how do we really approach who is going to get these quadruplet regimens for the transplant ineligible population?
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C
So as we brought up earlier, there's a question of is someone eligible for a transplant or not? There's also a question, is someone eligible for a quadruplet regimen or not. And so typically for patients that are transplant eligible, they should also most likely be quadruplet eligible too. But you may have some patients that are transplant ineligible and can still get quadruplets and some patients that are transplant ineligible and maybe are better served with a triplet regimen. So when I'm seeing a new patient and I'm evaluating whether or not they are appropriate for a specific type of therapy, I'm really thinking about their overall functional status and their comorbidities. Again, we mentioned quadruplet versus triplet regimens. One of the most common triplet regimens that we use for our patients who maybe are a little bit more frail or have more comorbidities is daratumumab, revlimid and dexamethasone. And this was studied in the phase three MYA trial and you may also hear this referred to as the Maya regimen. This trial included over 700 patients and randomized them to Dara RD versus RD alone. The 5 year PFS for this was over 60% in the Dara RD arm versus just about 30% in the Revlimid and dexamethasone arm. This trial provides some of the best evidence for a effective regimen for patients who are on the more frail side and maybe are better served with using a triplet regimen rather than four different medications. There are a couple of other studies however, looking at patients who are maybe fit enough to receive a quadruplet regimen, but maybe not the best candidates in terms of high dose chemotherapy that you would get with stem cell transplant. And so the two studies to keep in mind here are Cepheus and Mroz. So Cepheus looked at Dara VRD followed by maintenance with Daratumumab and revlimid in patients who were transplant ineligible or transplant deferred and they compared this to vrd. The primary endpoint in this study was MRD negativity and with the quadruplet regimen, as you might expect, there were higher rates of MRD negativity. The 5 year PFS in this regimen was also Quite impressive at 68% in the quadruplet arm versus about 50% in the triplet arm. IMRAS is the counterpart to this using isatuximab. So it looked at isatuximab VRD versus VRD alone and again the 5 year PFS was 63% in ISSA VRD versus 45% in the VRD triplet. As expected, there are some increased side effects with the addition of anti CD38 medications. And so in MRAs they did note that there were a higher rate of grade three infections or greater at 45% versus 38% and they were double the rate of infections that led to death at 6% versus 3%. And so this is all in line with what we expect with anti CD 38 medications there is an increase to the risk of infection but in general there's also a pretty significant increase into the how well we can treat myeloma with the addition of these medications.
- [32:39]
B
And I think this is great. So we had that Maya trial. The biggest problem with that is the comparator arm was a doublet revlimid dexamethasone. The SWOG0777 trial, the pivotal study that everybody needs to know about VRD was standard of care for transplant ineligible patients. So there was no reason to not do triplet versus tr. So that's one knock against that. But like you said, I think one of the most important details that came out of some of these quadruplet regimens versus VRD for the transplant ineligible patients there is a higher risk of infection. So you have to choose your patient wisely. Who that patient is we don't know because should we do things like there's things called VRD lite dose reductions of some of these things, these are being trialed. We just don't know in 2025 who should get a quadruplet and who shouldn't. But like Sean said, we know for sure if you get a quadruplet we're going to maximize your pfs, we're going to maximize that progression free survival. What we don't want to do is have treatment related mortality and have a detriment in your quality of life if you're getting bad infections. So the patient selection is key. Mona, can you round this out? Because really what we want to know though, the PFSs here that Sean had mentioned, those five year PFSs, over 60%, that's the same as Maya. Maya had a five year PFS of 60% and that was just three drugs. Anti CD38, Revlimid, Dexamethasone, Dara, Rab, Dex, these other studies with Cepheus and imraz, they're anti CD38s versus VRD. So Ronak, is there any study that's actually comparing to anti CD38 Revlimid dexamethasone nowadays?
- [34:10]
A
There is indeed and it's definitely one to look out for and it's called the benefit study. So as Vivek is alluding to here we are finally comparing what are the major classes of drugs that we're utilizing for our patients in 2025 into 2026. So this is a study, the benefit study is a randomized study, and they randomize patients to ISA, VRD versus ISA RD. So here, quad versus triplet, both of which contain the anti CD38 that we've been talking about. Some things to note, in this study, they excluded patients above the age of 79, which generally limits the generalizability of some of these studies or this study in particular for our older myeloma patients. But still, it has a lot of good data in there. What they're looking for is improved MRD negativity and response rates. So far, there's no difference in progression, fee survival or overall survival. Although the data are immature. The one interesting thing that I do want to point out is that they didn't really publish a lot of the adverse outcome data, especially the infection data, which we just spent so much time talking about is a major risk to our patients. So maybe a little bit of a. Of a flaw there in the data we have so far, but hopefully they share that when the data is more mature.
- [35:25]
B
Yeah, and I think one interesting thing. The benefit study showed improved MRD negativity rates, but no difference in PFS or os. Now the data is immature, so we really need to see what happens in this study. And like Ronick mentioned, the biggest knock I have when I read this study was when you look at the adverse event table, they reported grade two or higher infections, not grade three or higher infections. And that makes a huge difference. Grade 2 infection means I'm not hospitalized. Grade 3 infection means I'm very sick and hospitalized. And when it comes to doing a quadruplet regimen, I want to know if that's different than the triplet regimen. That's the infection. I care about some colds that keep me at home, and maybe I take oral antibiotics at home with a pneumonia, yeah, that's something. But that is not the same as a severe infection. So my question is, you're nesting your subgroup here, saying grade two or higher infections are the same between the groups and actually numerically a little bit higher in the quad arm. But what I want to know is what are the grade 3 or higher infection rates between the two arms, which we've seen in prior studies with VRD versus the quads are higher in the quads. But I don't know if the anti CD38 is just that immunosuppressive. It might be we don't know know that that data's not presented. And so that's the question we want. So it's. It was disappointing to see. We'll link that study in our show notes, but just an important thing to keep an eye out on when you read these studies.
- [36:41]
A
Guys, I think we went through a lot of really notable data about how truly the landscape of myeloma has changed in the last few years. And so just to sort of highlight some of the key themes here, we talked a little bit about how we now think about not only transplant eligible but ineligible. We're also thinking about quad eligible versus triplet eligible patients in the modern. And most importantly, we talked about how we put all these drugs together in combinations to make effective regimens for our patients, including an anti CD38 agent, dexamethasone and an immunomodulatory agent, an IMID. And then in patients that are more robust or have higher functional status, adding that proteasome inhibitor in and lots of different options available in this day and age. A lot of data coming out about this, but just remember, this is the combination that we're often picking for our patients.
- [37:35]
B
Guys, any final thoughts that you all have?
- [37:38]
C
One thing that I think is always helpful to know, and especially because this is a more recent change, is that if you are, let's say a fellow or a non myeloma specialist, maybe you're practicing in the community, you don't necessarily need to be the person making the decision on whether or not a patient should get a transplant nowadays, especially because we know that quadruplet regimens can be utilized for patients and provide benefit regardless of whether they are going for a transplant or not. The main decision you have to make when you start induction is is this person best with a quadruplet or a triplet? The decision on whether or not someone should undergo a transplant is definitely a very nuanced one. It takes a lot of experience and sometimes it's not always super straightforward. There's a lot of factors that go into it. So I always encourage people to make early referrals to a transplant center, have someone who their job is to evaluate whether or not a patient would benefit from transplant and also someone who is able to have that conversation with the patient about what does transplant look like, what are the potential risks and benefits. Because I think that's where you can get to the sort of best decision making both in terms of long term outcomes, but also making sure that you're helping patients to choose what's most in line with their own goals of care. When you're picking that regimen, pick the regimen that is going to be most effective and refer that patient to someone who can make that evaluation on whether or not to do a transplant.
- [38:58]
B
Sean, I think that was great. My last point with this is essentially to very, very simplify this. A quad induction regimen will give you the longest pfs, but a quad induction regimen in a frail patient will cause them to have treatment related morbidity and potentially mortality from infection. So that decision point is not easy. And you're not wrong by doing a triplet with an anti CD38 agent. That is a very good regimen with very good pfs. And we have really good options in the later line settings which we're going to talk about in future episodes. And I'll also say this, we talked a lot about Dara, VRD and daratumumab based regimens. We are not paid by Janssen, but in general it came first. It's subcutaneous, it's convenient. It is something that we use predominantly in the United States. Isatuximab is infusional. There are these on body injectors that are being studied. But again, it's just not the same when we have this subcutaneous daratumumab option that we are all very comfortable nowadays. And so that's really important. Check out our pharmacology episodes coming up as it's important to think about prophylaxis for both thromboembolic events and for things like shingles. So that's another important component to this that we will talk about in our future episodes. But really, really excited to really get into more details as we move through this series.
- [40:14]
A
All right guys, well I think that wraps up another fantastic episode of the fellow on call. So until next time, we'll see you all later.
- [40:19]
B
See you later.
- [40:20]
C
Better see you later.