Peter Voorhees, MD
Levine Cancer Institute - Atrium Health
Interview Date: May 18, 2021

Quad therapies (four combined myeloma treatments) are becoming more popular, even for newly diagnosed myeloma patients. In this show, Dr. Peter Voorhees of the Levine Cancer Institute shares details about how the addition of a monoclonal antibody like daratumumab, isatuximab or elotuzumab may be used in combination with other standard myeloma treatments for newly diagnosed patients. This is a major shift for newly diagnosed patients to use these monoclonal antibodies in earlier lines of therapy instead of reserving these new treatment drug classes for later use. 

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Karyopharm Therapeutics, for their support of this Myeloma Crowd Radio episode. 

As a reminder, also we are running several studies inside the HealthTree Cure Hub platform, and one of those studies is a genetic study to learn which treatments are showing the best results in the real world. It's a very practical question that we can help contribute to finding the answer for if we do this. So to join that study, you can go to healthtree.org and request that we help complete your profile for you. We have a team of people who can help you do that. So it's easy. We have over 500 patients participating to date, and it's particularly important to have a really large group of patients because once you break patients into these different subgroups, you want to have enough examples and real experiences so you can see patterns. 

Now on to today's show. So treatment for newly diagnosed myeloma patients is changing quite dramatically. We've always thought of the standard of care being the use of a immunomodulator like Revlimid, a proteasome inhibitor like Velcade or carfilzomib, and then dexamethasone. But about seven years ago, new monoclonal antibodies like daratumumab and isatuximab and elotuzumab were introduced. And as usual, they were approved for patients who had relapsed multiple times. But then they started bringing these treatments up to earlier use. 

In today's show, we're very fortunate to have Dr. Peter Voorhees with us from the Levine Cancer Institute in North Carolina. So welcome, Dr. Voorhees. We're so happy to have you with us. 

Dr. Voorhees: Thank you so much for having me. It's great to be here. 

Jenny: And before we get started, let me just do a short introduction for you. 

Dr. Peter Voorhees received his medical degree from the University of Michigan. He continued his postgraduate studies with internal medicine residency and chief residency at the University of Wisconsin and the Hematology and Oncology Fellowship at the University of North Carolina Chapel Hill. Dr. Voorhees is Director of Outreach for Hematologic Malignancies in the Plasma Cells Disorder Program in the Department of Hematologic Oncology and Blood Disorders at the Levine Cancer Institute in Charlotte, North Carolina. He was previously an assistant professor in the Department of Internal Medicine in the Division of Hematology and Oncology at the University of North Carolina at Chapel Hill. 

Dr. Voorhees is board certified in hematology and internal medicine. His research focuses on the development of new strategies for the treatment of myeloma. He's also interested in chemo-related toxicity and developing tools that predict for adverse events with treatment. Relevant to today's show, he was very key in running the GRIFFIN trial, one of the earliest tests for the use of daratumumab in newly diagnosed patients, and he also studies resistance to myeloma therapy. So you're a perfect person to interview the show with us today. So thank you so much. 

Dr. Voorhees: Sure. Thank you.

Jenny: Well, let's get started. As you look at this myeloma landscape that is changing, we're so fortunate to have these newer treatments getting approved and so much development. Do you want to give us an overview of overall strategies to develop longer remissions for newly diagnosed myeloma patients? 

Dr. Voorhees: Sure thing. There's really kind of three components to initial therapy or what we call frontline or first line therapy for multiple myeloma patients, and we can modify any one of the three components to try and improve the duration of remission for myeloma patients. So the first component is induction chemotherapy which is the initial treatment strategy for myeloma patients with the goal of driving the burden of myeloma down substantially and by doing so improving the symptoms that a patient is experiencing from their multiple myeloma. Then there's the consolidation phase. 

Now for those patients that are older or have numerous medical conditions or elect not to pursue transplant, consolidation may just consist of continuing the initial induction therapy to drive the burden of disease lower. For those patients that are fit and potential candidates for high-dose melphalan chemotherapy and autologous stem cell transplant, we will oftentimes use that as a way of kind of consolidating the initial response, basically driving the response even further, and by doing so prolonging the remission. And then the third component is the maintenance phase. This is easier on patients. So after the initial induction, with or without the transplant consolidation, patients will go on a lower dose of perhaps single agent Revlimid or lenalidomide, although there is emerging data on the use of two-drug strategies for maintenance therapy as well. And again, you can tweak any one of these three modules to improve remissions for patients. 

Jenny: Do you want to talk about this idea of your first remission being your best remission? Because I sort of want you to emphasize that. I didn't know that as a newly diagnosed patient. I wish I had learned that when I was taking my first treatment. 

Dr. Voorhees: Sure. So I think we have the opportunity when the disease is new and has never been exposed to prior drugs to achieve remission that in many instances, particularly for standard risk patients, can last many, many years. And one of the things that I always tell patients when I'm counseling them on whether or not they want to pursue, for example, autologous stem cell transplant as consolidation therapy after initial induction treatment or when we're talking about maintenance strategies after they're done with their initial therapy, I always stress to them the fact that the landscape for myeloma therapy is dramatically changing. To your point, you talked about a program that we'll be having later on ABECMA or ide-cel, which is the new CAR T cell product directed against BCMA that was recently FDA approved for treatment of relapsed refractory multiple myeloma. And while that is a milestone achievement for multiple myeloma patients, it's clear that we have a lot to learn about CAR T cell therapy and how to make it better. We'll only get better at it as time goes on. We'll have bispecific antibodies that are FDA approved in the near future. We'll learn how to use those bispecific antibodies better as time goes on. We'll have novel combination immunotherapies for relapsed multiple myeloma. So the longer your first remission is, the better we're going to be at treating relapsed disease. 

Jenny: That's an important point because I've had some friends who have had myeloma for 25 years, and they were able to do that by jumping from one new thing to the next new thing to the next new thing. And as you look at this wave of new therapies that are coming to the clinic and now you're bringing them up earlier, like what we're going to talk about today, it's really stunning how many options there are for patients. 

Dr. Voorhees: I completely agree. The landscape has improved dramatically over the last several years. Just within the last year, it's really quite stunning, the number of new FDA approvals that we've seen in myeloma. This is not just new combinations of therapies. I mean, we certainly have seen that but completely new therapies that have been FDA approved as well. So it's really an exciting time. 

Jenny: That's amazing. Do you want to talk about the strategy to use these monoclonal antibodies in earlier lines of therapy? I've heard some of these drugs referred to as like bacon, like it's better than everything in the later lines of therapy. So obviously, you have to start there in the clinical trials and then you bring them up to earlier lines. What's the logic and the rationale for doing that? 

Dr. Voorhees: So whenever you're testing a new therapy and you're uncertain about its safety profile and how effective it's ultimately going to be, first you are going to kind of explore the use of that agent for patients who no longer have the ability to benefit from the therapies that are tried and true and readily available to them. So looking at the CD38 antibodies, so you've got Darzalex or daratumumab and then you have Sarclisa or isatuximab. Let's just focus on daratumumab for the moment. That was the one that was first FDA approved back in 2015. And it was initially FDA approved in patients with relapsed refractory, multiple myeloma, who had disease that was resistant to an IMiD like lenalidomide, for example, as well as a proteasome inhibitor like bortezomib or patients who had received at least three lines of therapy, and it was approved as a standalone treatment. And in that context, we saw response rates of 30%. And for those patients that had deep responses to just single agent daratumumab, they had actually quite durable remissions. 

Now, in cancer therapy, in general, whenever you see a hit, a good hit for efficacy, particularly if it's well tolerated as daratumumab and isatuximab are, you tend to move those into earlier therapy. And not only that, if the safety profile of a particular drug is good, that lends itself well to being able to combine with other strategies. So with both daratumumab and isatuximab, a large number of studies were launched in earlier relapsed myeloma where the CD38 antibody was combined with kind of standard of care combination strategies for relapsed myeloma patients and consistently, I mean, whether you're looking at dara or whether you're looking at isatuximab, the addition of one of these CD38 antibodies to kind of standard regimens, whether it's pomalidomide and dex, carfilzomib and dex, bortezomib and dex, lenalidomide and dex increases the likelihood of response. It increases the likelihood of a deep response, including complete remission, increases the likelihood of achieving minimal residual disease negativity. And in all of the relapse studies that translates into an improvement in progression-free survival. And not only that, but that the addition of these antibodies was shown to be very safe. So we then take the next step and is to bring these into the frontline setting. 

Jenny: I think it's amazing what's happened, especially when you think about these combinations. I've heard other myeloma experts say that these 30% responses or 35% responses are common for individual drugs, right? So carfilzomib and some of the other types of therapies are kind of in that same range for relapsed patients. But then when you combine them, it significantly increases. But you have to test it first alone, right? 

Dr. Voorhees: That's exactly right for the reasons that we mentioned before. We have to understand the safety. We have to understand how active the agent is in and of itself. But again, when we have a positive signal, then we test it in combination strategies, and we bring that earlier into the treatment paradigm. This is not just the case with multiple myeloma. It's the case with cancer therapy, in general. Now we have frontline studies with daratumumab in multiple myeloma, both in the transplant and in the non-transplant setting that again completely recapitulates what we see in the relapsed setting, which is adding dara to standard upfront myeloma therapy is safe, improves the depth of response, increases the likelihood of minimal residual disease negativity, which is the holy grail of complete remissions and can improve progression-free survival. 

Jenny: I think it's amazing, the impact that it's had. So can you address just strategies? Sometimes I hear some doctors talk about save these therapies for later. And then I hear other doctors say, no, you should just use everything the best up front. Do you want to address that sort of controversy in the myeloma world and bringing these up?  

Dr. Voorhees: So absolutely. And it's an understandable question. The thought is if you bring these new effective therapies into the frontline setting, the question is that relapse, how are you going to control the disease, and are the patients going to have more difficult to treat disease at the time of relapse? And how does that impact their long-term overall survival? So there's this metric that we look at in clinical trials to kind of get at this issue. It's called progression-free survival 2. Basically, what that is, it looks at -- so a patient with newly diagnosed myeloma goes on a multiple myeloma clinical trial. From the time they start that trial they go through their initial therapy as part of the trial. They then relapse down the road. It could be many years later. They receive second line therapy, and then we measure when the disease relapses or progresses after that second line of therapy. 

So if the disease is terrible at the time of relapse when you've incorporated your new therapy into the frontline setting, the durability of remission in the second line should be far shorter. You may wind up seeing that the progression-free survival 2 between the two arms is the same. But, in fact, that's not the case. I mean, if you look at the MAIA trial, which was lenalidomide and dexamethasone with or without daratumumab and the non-transplant setting, progression-free survival 2 was longer for those patients that received daratumumab as part of initial therapy. And then there was another study, looking at the melphalan, prednisone, bortezomib backbone, which we don't use much in the United States with or without daratumumab. Again, in that trial, progression-free survival 2 was longer when daratumumab was part of the frontline therapy. 

So yes, I understand the theoretical concern that treatment of relapse may be a bit more challenging when you bring these effective therapies to frontline. But the fact that progression-free survival 2 continues to be longer suggests that these patients have disease that can be readily managed at the time of relapse and the benefits of the longer initial remission by bringing your best therapy to the frontline far outweighs that theoretical risk of harder to treat disease at relapse. So I think that the majority of us feel that you've got to put your best foot forward. 

Jenny: I've heard that a lot, and I just kind of wanted you to emphasize that because it's important what you do at the very beginning to get the longest remissions possible, back to your earlier point. But there are a lot of drugs in development and different types of treatments and new targets in development. So there will be a lot of options to try that relapse. But the longer that you're in, the better the development or the more development is being done too. Well, you mentioned the three, the monoclonal antibodies, daratumumab, isatuximab and elotuzumab. Is elotuzumab really used a lot in the early setting? Because I see most of the trials are using daratumumab and isatuximab. 

Dr. Voorhees: So with elotuzumab, we hit a bit of a surprise, if you will. So elotuzumab is an antibody directed against a protein called SLAMF7 that's expressed on the surface of myeloma cells, and it's approved for use in combination with lenalidomide and dexamethasone for relapsed myeloma patients. It's also approved in combination with pomalidomide and dexamethasone for relapsed myeloma patients. So there was a study that was done in the frontline setting. These were patients that were not transplant eligible, and they either received lenalidomide and dexamethasone or lenalidomide and dexamethasone with elotuzumab. Unfortunately, the progression-free survival was not different between the two arms. So even though elotuzumab help relapsed patients, at least the preliminary readout is that it did not achieve its primary objective (this appeared in a press release). 

So I don't think we're going to be seeing much use with elotuzumab in the frontline setting. Daratumumab has clearly shown benefit in the frontline setting whether it's combined with therapy in the non-transplant setting or combined with therapy for patients that are eligible for transplant, and there are ongoing studies incorporating isatuximab into standard of care regimens for newly diagnosed myeloma patients. And those studies have yet to read out. 

Jenny: Maybe it's just a different target, right? So SLAMF7 is the target for elotuzumab but for daratumumab and isatuximab it is CD38, right? 

Dr. Voorhees: That's correct. When elotuzumab was first being tested in the relapsed space, it didn't have any significant single agent activity, but it seemed to enhance the efficacy of drugs like lenalidomide and pomalidomide. So whereas both isatuximab and daratumumab had a single-agent response in the 30% range or so. I do think a standalone therapy, the CD38 antibodies are more potent than elotuzumab and that may be in part why we're seeing better efficacy of dara and isa in the frontline setting. 

Jenny: Now, daratumumab and isatuximab both started out as IV administration where you have this really long infusion the first time, and it kind of gets shorter over time. And then I know Janssen developed Dara FASPRO. I think Sanofi is in the process of developing a subQ administration for isatuximab as well. Are there any advantages or disadvantages in terms of how well they work or side effects or just ease of administration for the IV versus the subQ shot? 

Dr. Voorhees: So there was a randomized study that looked at subcutaneous daratumumab with IV daratumumab. Again, this was done in relapsed refractory myeloma patients as a standalone therapy. And to make a long story short, the response rate was identical between the two arms. Interestingly, there was a lower rate of infusion-related reactions with the subcutaneous administration.

So from a side effect perspective with that first dose, the infusion-related reactions seems to be less with the subcutaneous administration. And then, obviously, the infusion chair time is significantly shorter with the subcutaneous approach. Potential disadvantages with the subcutaneous approach, some patients will have some level of discomfort at the site of injections.

It's a bit unusual for someone to have to switch back to IV in that circumstance, although it sometimes occurs. And then the other thing is potential cost. Subcutaneous daratumumab is more expensive than intravenous daratumumab and how that translates into increased costs for the patient is going to be dependent on a particular patient's insurance plan.

Jenny: I did not know that. Well, I think if somebody is on daratumumab, they should probably ask their doctor if FASPRO is an option for them, and then they can have that conversation, at least to know that it's an option. They might get you to spend less time in the clinic. 

Dr. Voorhees: Absolutely. 

Jenny: And in these new trials, I mean, we can go through several of them because there are so many of them. I looked them up last night and, wow, there's a whole bunch that are for fit patients, unfit patients before transplant, after transplant. But what you're saying is that you can use these potentially quad therapies like RVd or something like that or KRd, in addition to isatuximab or daratumumab, whether you're going to transplant or not, right? So it applies for you regardless of that transplant plan. 

Dr. Voorhees: I guess what I would say is in the US and I think in many areas of the world, I think most of us agree that the triplet backbone of an IMiD like lenalidomide, a proteasome inhibitor like bortezomib or carfilzomib, and dexamethasone is kind of the backbone.

In the transplant setting, we've shown that the addition of daratumumab to that triplet backbone improves depth of response. The CASSIOPEIA trial, which looked at bortezomib, thalidomide, and dexamethasone with or without daratumumab showed an improvement in depth of response, including MRD negativity with the addition of dara and that also translated into improvement in progression-free survival. 

In the GRIFFIN trial, we showed that the addition of daratumumab to the lenalidomide, bortezomib, dexamethasone or RVd backbone, more than doubled the likelihood of achieving minimal residual disease negativity, and our follow-up is a bit shorter. So we've yet to show that progression-free survival advantage. But we're hopeful that with longer follow up, we will see that emerge. I think the idea of using a quadruplet and a non-transplant patient is a work in process. There are two studies that are ongoing, addressing that very issue, looking at RVd with or without daratumumab. In transplant ineligible patients, that's called the CEPHEUS trial, which is ongoing. 

Sanofi has a very similar trial called the AMAROS trial which is looking at RVd with or without isatuximab for patients not going through transplant as part of initial therapy. I know that there are some providers that are using CD38 antibodies with a RVd in the non-transplant setting. But that remains a work in process. I think there's very strong data now in the use of quads in the transplant setting, though, for sure. I think for the non-transplant patients, though, daratumumab with lenalidomide and dexamethasone has performed remarkably well and I think you're seeing a lot more utilization of daratumumab with lenalidomide and dexamethasone over bortezomib and lenalidomide and dexamethasone just given that the data from the MAIA trial. In that particular trial, I mean, progression-free survival, four years out is still at 60%. It's going to be the longest progression-free survival of a non-transplant study that's ever been reported. 

Jenny: Oh, wow. I did not know that. Well, that's amazing. And even without the proteasome inhibitor, that's so interesting. I wonder what the role of that is. Like skipping that would reduce neuropathy, for sure. 

Dr. Voorhees: Yes, absolutely. And that's an important question. I think we'd love to see a comparison of daratumumab-len-dex to bortezomib-len-dex to see how they would perform against one another. But to your point, certainly from a safety perspective, you'd certainly see more neuropathy in the bortezomib arm.

So do all newly diagnosed transplant ineligible patients need a quadruplet? They may not. They they may actually benefit very much from a triple therapy. And I think that the CEPHEUS and AMAROS trial will help us better understand the role of quadruplets in that setting. But for the higher risk patients, that may be very appropriate. I think that that's where you are seeing quadruplets used increasingly, and the non-transplant setting is for those patients that have high-risk disease. 

Jenny: What's important about what you're saying is there are so many different ways that you need to test this in clinical trials, like you could compare dara-Rev-dex with the whole quadruplet, dara-Rev-bortezomib-dex there. You could compare it with Kyprolis. And as I was looking at those different clinical trials, this is actually why we started this radio program, to help patients understand the clinical trials that are open and available, because these are important research questions that will benefit us as patients. We don't know until you're able to run the trial and get the data out to say, oh, gosh, you could do dara-rev-dex if you're a newly diagnosed patient and that might be just perfect, and you might not need the quad. 

So I always encourage patients to consider clinical trials at every stage of treatment whether they're newly diagnosed or relapsed. But this clinical trial process that you're doing is so important because you mentioned the GRIFFIN trial and in looking at the open trials for newly diagnosed patients, there's so many. There are trials for transplant ineligible in older patients. There's Kyprolis use with daratumumab like KRd plus dara in older but fit patients. There's daratumumab and interestingly like dexamethasone, thalidomide, Revlimid, and bortezomib in patients with kidney issues. I mean, you're doing so many trials to learn so many things for us. 

Dr. Voorhees: I completely agree with you. I think participation in clinical trials is incredibly valuable. I think it's important for folks to know that, typically, when we have a clinical trial open, if it's a randomized trial, you're never been randomized to placebo intervention or no therapy. I mean, you're getting the best available standard of care, and we're really looking to see whether changing that or modifying it, whether it's adding a new drug, whether it's replacing one of those drugs with one that we think may be more effective, you're getting excellent therapy. I think it is important to pay it forward. We wouldn't have drugs like bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, isatuximab, elotuzumab, et cetera, et cetera. We wouldn't have these things if people did not participate in clinical trials. These things wouldn't move up into earlier lines of therapy, making that initial treatment more effective unless people participate in clinical trials. So it's incredibly important to consider a clinical trial as part of your therapy not only to improve the therapy that you may be receiving, but to answer the questions that we need to answer for patients that will be diagnosed in the future. 

Jenny: And you might get early access to some of these things. Like when you look at this strategy to use daratumumab or isatuximab, earlier lines of therapy, well, you couldn't really do that unless you join the trial because it's not approved for that yet. So sometimes it gives you a really early access and really good care because you're watched really carefully. So I don't know. I'm a super fan of clinical trials. Let me ask some questions as well. So I know some myeloma patients can relapse after these monoclonal antibodies. Are there any known causes of relapse or certain patients who tend to relapse after using them more than others that you've seen? 

Dr. Voorhees: The data on resistance to the CD38 antibodies is, I think, in its infancy. So there's probably some truth to the fact that the more CD38 you have on your myeloma cell, the more likely it is that you're going to respond to therapy. What winds up happening, anyone who goes on daratumumab or isatuximab, the levels of CD38 do drop when you start treatment. But there's no clear data yet that that CD38 level drop predicts for eventual relapse. So it's going to be much more complicated than levels of CD38 sitting on the cell surface. There's probably going to be changes kind of in the immune background that predict whether someone's going to relapse or not. I mean, these are questions that we need to answer, and these ongoing clinical trials are doing exactly that. So we need to look at the characteristics of the bylaw, that initial diagnosis, and then at the time of relapse and look to see what has changed in the disease, what has changed in the immune microenvironment or the bone marrow microenvironment to allow that to happen. 

Jenny: Or did the genetics change or like what you're saying. 

Dr. Voorhees: Exactly. 

Jenny: And then in some of the trials, I saw, interestingly, that -- and I've heard some doctors talk about this, that some combinations are steroid sparing in which they dropped the dexamethasone.  How did these monoclonal antibodies work with the steroids or -- because most of these combinations use the steroid, right? So what's the play between the two, I guess? 

Dr. Voorhees: So that's a great question. You're absolutely correct. Steroids, unfortunately, are a part of the CD38 antibody treatments. Even when daratumumab, for example, was approved as a standalone therapy back in 2015, it came with a steroid premedication. So although it was technically "monotherapy," people were getting steroid as a premedication to reduce reduce their risk of infusion-related reactions with every single dose. So they were getting weekly steroid for the first two cycles and then every two weeks for the next four cycles and then every four weeks steroids thereafter. And then with these combination strategies, since we're pairing up drugs like daratumumab and isatuximab with standard of care backbone myeloma regimens, all of those myeloma backbone regimens have dexamethasone as part of them. 

So unfortunately, the steroids show up there as well. There's actually an interesting study that was done by Sanofi, which looked at isatuximab kind of a standalone therapy with or without weekly dexamethasone, and the response rate was actually quite a bit higher with the inclusion of the weekly dexamethasone. It was statistically significant. And this was in a group of patients where you would have predicted that the majority of them had disease that had progressed at some point in the past on dexamethasone therapy. So I thought that that was kind of interesting. 

So I would say that, unfortunately, if dara or isa are combined with the dexamethasone containing regimen, that that's probably how they should be used. What I will tell you though, that in clinical practice, for those patients that really have horrible side effects of steroid, and there are many that do, you can safely remove the steroid from the regimen and not incur, infusion-related reactions. The infusion related reactions of these agents typically are seen with the first one to two doses, and then subsequently goes away for the vast majority of patients. So you can get rid of the steroid. 

Jenny: And that's why you're including the steroid in the first administrations anyway, right, to just prevent these infusion-related reactions? 

Dr. Voorhees: That's exactly right. 

Jenny: Okay, interesting. Well, do you mind if we go back to your MRD negativity comment? So you said that MRD negativity is a holy grail of treatment options. Do you want to just describe why MRD is being used more and more in myeloma clinical trials and why it's so important? 

Dr. Voorhees: Sure. So MRD stands for minimal residual disease, and there's a couple of different ways that it can be evaluated. And at the end of the day, it's just a more sensitive way of picking up trace levels of myeloma left behind. So when I tell a patient, they've achieved a complete response to therapy, there still can be a very sizeable burden of disease left behind when you dig more carefully. But we now have techniques where you can look at say over a million bone marrow cells and look to see whether any of those are actually myeloma cells or not. We can do this by a technique called flow cytometry. We can also do it by Next Generation Sequencing and Adaptive Biotechnologies has an FDA-approved MRD test that utilizes that ladder platform. 

So if you hear results presented about a clinical trial where they report MRD negativity to the 10 to the minus five level sensitivity, what that basically means is, if you count 100,000, marrow cells, you can't see the myeloma. If we say MRD negativity at 10 to the minus six level sensitivity, that's another way of saying, when we count a million bone marrow cells, we can't see the myeloma. We know that when you achieve MRD negativity, that translates into improved progression free as well as overall survival. The deeper the MRD, the better. So we know that MRD at 10 to the minus six is better than MRD negativity at 10 to the minus five, et cetera. 

So it's a valuable technique in clinical trials. It allows us to assess the effectiveness of a regimen with a much earlier readout because at the end of the day, myeloma therapy has gotten so much better in the last several year that you have to wait years to make an assessment about progression-free survival and overall survival because patients are doing so much better, and that's a good problem to have. The nice thing about MRD negativity is it allows you to assess the effectiveness of changing your therapy earlier. Hopefully, we'll be able to start using this technique to get approvals, regulatory approvals for new therapies sooner than we otherwise would, but that does remain a work in progress. 

Jenny: Right, because if you think about it, I mean, with patients living longer, your trial might take 10 to 12 years to get results from. And then if you're using MRD, it might just take three years to get results from. So with the number of trials that you're trying to run, it's better if you can learn things faster and then incorporate them into the clinic faster than waiting another 12 years to learn what you're trying to learn. 

Dr. Voorhees: Yes, that's exactly right. 

Jenny: Do you use MRD in your clinic as well outside of clinical trials? When would you recommend that your patients get them ready test? 

Dr. Voorhees: So that's a challenging question. What I would say is that it is best positioned as a clinical trial tool, for sure. But it is an FDA-approved test. So where we have used it the most is to assess response to initial induction therapy plus, minus consolidation transplant. So the most typical scenario is where patients gone through induction therapy, they've got their transplant consolidation, and after they've recovered from transplant consolidation, we basically restate their disease entirely. We will incorporate MRD testing at that time point on a regular basis. We've also been incorporating MRD testing one year and two years into maintenance therapy, and then whether we incorporate it beyond that period of time, we kind of take on a case-by-case basis. 

The one thing that I would caution is using the FDA-approved MRD testing as a prognostic tool. They did not approve it as a tool to allow clinicians to make changes to therapy. But you do see that being done in real-world setting quite frequently. I would urge a little bit of caution there. Have I stopped someone's Revlimid maintenance therapy because they were having significant side effects and they've achieved a sustained MRD negative state? Absolutely. But there, the decision was driven not just by their MRD status, but also by the fact that the patient was having side effects, for example. 

Is there any data to escalate therapy if someone is still MRD positive after transplant? That remains an open question. We don't know the answer to that. I do think that for those patients with high-risk myeloma who've gone through initial induction transplant and are still MRD positive, I do think that there are many of us who would consider consolidation therapy to drive the response deeper before moving to maintenance therapy, but that is expert opinion. That's not based on randomized trials. And there are randomized trials that are ongoing now that are looking at this very question. There are two ways to look at it. Can you take someone who's MRD negative and deescalate their therapy and do so successfully without incurring any problems? Similarly, if someone's already positive at a particular point in therapy, can you escalate their therapy and improve their outcomes? So both of these things are being assessed in a randomized setting, and we'll get the answers hopefully in the not too distant future. 

Jenny: You talked about this in the very beginning of the show with the four steps: induction, transplant, consolidation, maintenance. And just so people always get a little bit confused about consolidation. So induction, like you might use this triplet or this quad therapy first to get you ready and then you go to transplant and then you do maybe a month or two of the same triplet or quad therapy after transplant, that's what you're saying, to deepen the response and then you go to maintenance, right? 

Dr. Voorhees: Yes. Now, the utility of post-transplant consolidation therapy is a bit of a mixed bag. There was a study that was done in the United States where patients who'd been through initial induction therapy and their first transplant were assigned to one of three treatment options. One was to go directly to Revlimid maintenance therapy. The other group received four additional cycles of Revlimid, Velcade, dexamethasone followed by Revlimid maintenance. And then the third group of patients got a second transplant followed by Revlimid maintenance therapy. Then make a long story short, all three arms did similarly well. There was no difference in progression-free survival amongst the three arms. That's probably due to the fact that there was a lot of variability in the number of cycles that patients received prior to their initial stem cell transplant.

I think the point is you just need to optimize response as best you can with initial therapy before moving on to transplant, and that's probably the most important thing. When I am using a quadruplet, say, in a transplant setting like we did in the GRIFFIN trial, I actually do it in the very same manner that we did it in the trial. What I always tell patients is when in Rome, do what the Romans do. If you want to recapitulate the excellent results that you've seen in a clinical trial, you need to kind of adhere to what was done in that clinical trial to the best of your ability. And one of the things that we do worry a little bit about when we combine daratumumab with Revlimid in induction therapy is the potential impact on stem cell collection. So in that setting, what we've been doing is we do four three-week cycles of induction therapy, we collect cells, we transplant, and then we give two cycles of post-transplant consolidation with the quad after recovering from transplant and then move on to maintenance therapy. 

Jenny: Interesting. I didn't know that. Well, I might not get to all my questions. The time goes faster than you think. Let's talk about maintenance therapy a little bit. So for newly diagnosed patients, if they do these quads and then they go to transplant, you talked about usually people will do Revlimid maintenance or something like that. Can you address using daratumumab or isatuximab as part of your maintenance therapy?

Especially for newly diagnosed patients, I guess, since we're talking about that.

Dr. Voorhees: So there's no question that the CD38 antibodies are positioned well as part of maintenance therapy. The CASSIOPEIA trial, which I alluded to earlier, again, that was a study that looked at Velcade, thalidomide, dexamethasone, with or without daratumumab for transplant-eligible patients. But there was a second randomization after recovery from transplant where patients were assigned to either no maintenance therapy or daratumumab maintenance therapy, and the results have not been presented or published yet.

But there was a press release by Genmab, which originally developed daratumumab a while back now stating that the second randomization achieved its primary endpoint. In other words, daratumumab maintenance therapy was superior with regards to progression-free survival relative to no maintenance therapy, which is a bit of a no-brainer.

I mean, you would expect that. But the issue of combining say Revlimid, for example, with daratumumab in the maintenance setting is being addressed in a randomized fashion as part of an important SWOG trial. So the SWOG study is taking patients who've been through initial induction and transplant, and it's basically randomizing patients to either Revlimid maintenance therapy, which is the current gold standard versus Darzalex and Revlimid. And they're looking to see whether the addition of Darzalex to Revlimid maintenance therapy improves the likelihood of achieving MRD negativity and, in fact, improves overall survival. So that'll be an incredibly important study to look at going forward. 

The other neat thing about that study, and this goes back to what I was talking about before, is that it has a second randomization later on which I think is perhaps an even more important question to answer and that is for those patients that are MRD negative, after two years of maintenance therapy, there is a randomization to either continuing your treatment or stopping. It will be very interesting to see if those patients who stopped you just as well as those that continue.

We may learn that patients can have a long treatment free interval after their initial therapy, which would be a wonderful thing for patients. But we don't have randomized data yet on Revlimid with either dara or isa as maintenance therapy. Now, again, in the GRIFFIN trial that we ran, those patients that were assigned to the daratumumab arm did get to drug maintenance therapy for the first two years of maintenance. And then when they were done with that, they continued their Revlimid alone. 

So again, when I'm kind of counseling patients, and we're using that platform, that GRIFFIN platform for therapy, when we get to the point of discussing the maintenance, I do encourage them to consider the possibility of continuing the daratumumab under the circumstances, just given the positive data that we've seen from that trial with regards to MRD negativity. And I will say that after one year of maintenance therapy in that trial, we saw the MRD negativity rates increase substantially in that daratumumab arm. So by my strong suspicion is that the daratumumab addition to Revlimid will make a difference with regards to progression-free survival.

Jenny: That's so interesting. Okay, very practical question. So if you are newly diagnosed patient and let's say you get the quad therapy like RVd or KVd or something with daratumumab or isatuximab up front and then you go through treatment and you get your stem cell transplant and you go on maintenance therapy and you relapse, would you consider using daratumumab or isatuximab again at relapse? Or like, let's say use dara at the beginning, would you use isatuximab at relapse or, I don't know, how do you think about that as a myeloma expert? 

Dr. Voorhees: So I think it depends on the circumstances. So let's just say, for example, you decide to treat a patient per the kind of GRIFFIN protocol, if you will. So they have dara added to their RVd pre and post-transplant. They go on dara-Rev maintenance therapy for two years, and then they continue their Revlimid alone thereafter, and let's say they relapsed six years later. That patient has not seen daratumumab for years. So the overwhelming likelihood is that the disease that has come back is that there's a good chance that that disease may still have sensitivity to a C38 antibody. 

So I would argue in that exaggerated example that I give that a dara or isa-based strategy would make a lot of sense. And in that setting, someone progressing on Revlimid maintenance therapy, either daratumumab or isatuximab with say Kyprolis and dexamethasone would be a wonderful strategy to treat that patient if the patient is actually progressing on the CD38 antibody. So if I have a patient with high-risk disease, for example, who's getting treated for the GRIFFIN algorithm and let's say their disease breaks through the combination of Revlimid and Darzalex maintenance therapy say a year and a half after their transplant, I don't think that an isatuximab containing strategy in that situation is going to be successful. I think you're going to see clear cross-resistance in that setting. 

There was actually a recent publication. Dr. Joe Mikhael is the first author on which looked at isatuximab therapy post-daratumumab resistance, and the response rates are incredibly low in that situation, which does suggest that there's cross-resistance to the two antibodies. Now, the question though becomes if you wait a period of time, can sensitivity to the CD38 be restored? And there may be some truth to that. We do see CD38 levels, for example, increase over three to six months post-blast dose of daratumumab or isatuximab. There are ongoing studies that are looking at this specific issue, but a lot of studies where a CD30 antibody is being used in a combination. If the patient has had prior resistance to a CD38 antibody, they're requesting at least a six month washout before they get treated with the CD38 antibody again. Again, it's to reestablish those CD38 levels on the myeloma cells. But I think it's a work in progress as far as how effective they'll be in that setting.

Jenny: Great. Okay, I think my final question will be combining these, or do you replace them or combine them with other immunotherapies? Like, as you said earlier in the show, like the bispecifics are coming and CAR T's coming, and these drugs are really quite effective. So do you use them now in combination with these new things, or do -- because these are monoclonal antibodies, right? And then some of these others are bispecific are going after two targets instead of one. So how do you look at that as a specialist? 

Dr. Voorhees: So it depends on the nature of the monoclonal antibody and the immunotherapy that you're planning to combine it with. One of the interesting things about the CD38 antibodies is that not only do they have direct action on the myeloma cells, but they actually do have effects on immune function in myeloma patients. And you can see enhanced T cell responses to myeloma after treatment with daratumumab and isatuximab.

So there's actually a strong rationale to combine a CD38 antibody with an immunotherapy such as a bispecific antibody or CAR T as a way of enhancing the effectiveness of the immune response to the underlying myeloma. And a nice example of this is the TRIM 2 trial which is ongoing now. That's a study that's opened a number of different centers. We have it open here at Levine Cancer Institute.

And this is looking at the bispecific antibodies teclistamab which is directed against BCMA and talquetamab which is directed against GPCR5D. It's basically looking at those two bispecific antibodies and combining them with subcutaneous daratumumab with or without pomalidomide. So again, it's a way of looking at kind of enhancing the immune response with the bispecific antibody by incorporating the daratumumab or, in this case, also the immunomodulatory drug pomalidomide. So there's definitely a rationale for doing that and it's definitely being tested in ongoing studies. 

Jenny: Well, that will be so fascinating to see like the combinations with the bispecifics and combining it with the CAR T's. I know that for these CAR T's and these bispecifics, sometimes people are saying that the effectiveness of those newer immunotherapies really are relevant to the status of the patient's immune system or how strong their immune system is or how strong their T cells are or whatnot. Does using these early monoclonal antibodies have any impact, positive or negative, to future use of other immunotherapies? 

Dr. Voorhees: That's a great question. I don't know that we know the answer to that at this point. What I would say in general is that, to your point, the immune system is typically healthiest earlier in the course of the disease and when the disease is under better control. So many of us feel that the immunotherapies are going to be best suited for earlier in the course of therapy. But I don't think that the use of a bispecific or a CAR T earlier is going to have a negative impact on the use of a subsequent immunotherapy. The one thing that I would say is that if the target of the immunotherapy that you use subsequently is the same, it could potentially have an impact. So for example, we know that one of the mechanisms of resistance to BCMA directed CAR T cell therapy is that the myeloma cell loses expression of BCMA on its cell surface. So if the myeloma is not making the target, the BCMA is invisible, becomes invisible to the CAR T cell therapy. 

So at relapse, if you go in with a BCMA-directed bispecific antibody, the bispecific antibodies got nothing to attach to on the surface of the myeloma cell because BCMA is gone. So there, you're going to see cross-resistance in that particular setting. But I don't think that the story of resistance to BCMA-targeted therapy is cut and dried is just loss of BCMA expression. That's going to be one path to resistance, but there's going to be many different paths. And the path to resistance is going to dictate whether or not coming in later with another BCMA-targeted therapy is going to be effective or not. 

Jenny: Okay, it's so interesting, we have so much to learn. So thank you so much for running these trials. So I want to open it up for caller questions. If you have a question for Dr. Voorhees, you can call 347-637-2631 and press 1 on your keypad. And I also want to just mention, we talked a lot about clinical trials.

We have a clinical trial finder tool that we partner with Spark Cures on HealthTree. And so if you go to healthtree.org and you have an account there, you can see all the specific clinical trials that you are personally eligible to join. So instead of going to clinicaltrials.gov and finding 450 open trials, you can actually find maybe 10 or 20 or 30 that you're actually eligible to join. So it makes finding the clinical trials a lot easier. 

Okay, we have caller, go ahead with your question. 

Caller: Hi, I appreciate you taking my call.  I'm just curious as to why is there so much development happening right now in myeloma? 

Dr. Voorhees: Yes, so that's a fantastic question. I think although it's not the most common cancer out there, to put it mildly, I do think that it is an area where there are a lot of active investigators in the laboratory trying to better understand how myeloma comes to pass, how it works, and what potential targets that are out there. I think success begets success. This has been the case in the setting of melanoma, for example. Once you start seeing success stories in a particular disease, that engenders additional enthusiasm to study that disease more rigorously. Patients with multiple myeloma are living far longer than they used to which affords more opportunities to develop new therapies. 

Again, I think, once you know the success, successes begin to occur that just opens it up for additional opportunities going forward. One of the other things that I think that has really been helpful, and this is the case in other blood cancers as well, particularly non-Hodgkin's lymphoma, you can find targets on these cells that you can therapeutically target either with car T cell therapy, for example, or with bispecific antibodies without incurring severe collateral damage, if you will. The targets are relatively selective for the disease of interest. In the solid tumor setting, say, for example, in breast cancer, it's harder to find those tumor-specific targets that aren't expressed on normal tissues. And I think that we've benefited from that as well. 

Jenny: Great question. And thank you for your response. Thank you mostly for just doing the research in myeloma. So grateful that you and so many other talented investigators are doing this for us and helping us figure out what's best for relapse patients, what's best for newly diagnosed patients, and extending those remissions.

So Dr. Voorhees, we're out of time. But thank you so much for joining us today and helping us understand more for newly diagnosed patients with using these monoclonal antibodies. 

So we'll close with that today. Dr. Voorhees, thank you so much for participating today. We just appreciate you so much and all the work you're doing for us on our behalf.

Dr. Voorhees: Not a problem and thanks for inviting me. 

Jenny: Thank you so much for listening to this episode of Myeloma Crowd Radio. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.