Thomas Martin, MD
University of California at San Francisco
Interview Date: June 5, 2020

New treatment options are availalble for myeloma patients including a newly approved monoclonal antibody called isatuximab (Sarclisa). Learn from Dr. Tom Martin about this new option and how it works differently from other CD targeted monoclonal antibodies used today. He shares how isatuximab is administered, how it is being combined in further clinical trials, when it might be considered and more. Interestingly, Dr. Martin shares that isatuximab can be considered after the use of daratumumab (or visa versa) if the use is separated by a different line of therapy that allows the CD38 expression to re-appear. Learn more about this important new tool in the myeloma toolbox. 

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, Takeda Oncology, for their support of Myeloma Crowd Radio. 

Now, in these past several months of chaos, I feel that some important news has been really been lost in the shuffle. I know progress is being made in the world of myeloma and things are still advancing. There have been key FDA approvals that are providing myeloma patients with additional options for treatment. This is particularly true for relapsed and refractory myeloma patients. So with us today is Dr. Tom Martin, a renowned myeloma specialist at the University of California at San Francisco to share one of these important approvals, a new monoclonal antibody targeting CD38 called isatuximab or Sarclisa. Welcome to the program, Dr. Martin.

Dr. Martin: Hello. Thanks for having me.

Jenny: Before we get started, let me just introduce you quickly. Dr. Thomas Martin is Professor of Medicine at UCSF, an Associate Director of UCSF Myeloma Program and Director of the Unrelated Donor Transplant Program for Adults at UCSF Medical Center. Dr. Martin is Clinical Research Director of Blood Cancer Malignancies at UCSF Helen Diller Family Comprehensive Cancer Center. His research interests include developing treatments for myeloma and leukemia as well as expanding the use of bone marrow transplants. He has a special interest in umbilical cord transplants, interestingly, and is involved in efforts to improve outcomes for patients who have transplants from unrelated donors. He earned his undergraduate at Cornell University and his medical degree at the University of Connecticut School of Medicine. After residency at UCLA, he completed a fellowship in Hematology-Oncology at UCSF. He then joined MD Anderson Cancer Center and then returned in 2001 to UCSF. 

Again, Dr. Martin, thank you so much for making time, especially as we're entering the weekend. Thank you so much.

Dr. Martin: That's quite an introduction. Thank you so much.

Jenny: Certainly! We are here today to talk about this newly approved drug. Maybe we just want to start with the basics if patients aren't familiar with it and give us just an overview of monoclonal antibodies, how they work and just let's start there.

Dr. Martin: Okay, sure. Monoclonal antibodies for multiple myeloma actually started testing back in 2010. We were one of the first centers to actually start investigations with isatuximab. We did a number of studies in the laboratory to see how it worked and what the function was. Then we went on to do studies in patients. 

Now, these antibodies, these CD38 antibodies -- and there's another one against SLAMF7, elotuzumab, that work by binding to the surface of the myeloma cell. They all bind a specific receptor. In the case of isatuximab, it binds to CD38. It actually acts like a flag. So you have this flag attached to the cell surface. You have many of them. Our immune system is prepared to look at cells that have antibodies bound to them as being foreign. What happens is when all these antibodies bind to the myeloma cell, our macrophages, our NK cells are parts of our immune system that really interrogate all the spaces around our body, say, “Wow, that's a bad guy.” They actually then go and kill cells that have these antibodies coated up. 

These antibodies, they're called naked antibodies because they work in a passive way, meaning they just bind to the cell and they promote some of these immune cells to come over and chew them up and eat them and kill them, which is great. Now, what we found out over time, actually, there's a few other mechanisms of action for these drugs. Now, isatuximab, specifically, one of the things it can do by binding CD38 is by binding to that receptor, it can induce a cell death signal inside the cell. The cell actually has an ongoing circuit that says, “Okay, this antibody is bound. I should kill myself.” And it can undergo cell death called apoptosis. So that's one of the ways that's unique to isatuximab. It can kill the cell.

But the other way is when you have multiple antibodies bound, there's another set of proteins that's called a complement. And our complement also can see antibodies bound to cells. Then they combine to a bunch of antibodies and lineup a bunch of proteins on those antibodies. Actually, they can work by pushing a hole through the cell surface. So the complement works by pushing a hole to the myeloma cell surface and thus killing the cell -- another interesting way. 

CD38 actually has enzymatic function. It controls a lot of calcium metabolism. It controls other cell surface molecules that can actually send signals to the local environment, specifically to the microenvironment, into the immune cells environment. They could tell them to either be passive to that, “Don't worry about us. We're fine,” or be active, “Hey, come help. Give us some help.” So by blocking that enzyme, we actually may be able to help the immune system engage into the myeloma cell and kill off the myeloma. So it has a bunch of different activities. 

But lastly, there are other cells that are around the microenvironment of the bone marrow where these cells live, including some T-cells and B-cells that are called regulatory cells that do give this negative signal to the immune system that, “Ah, these guys are okay. Don't worry about them.” And CD38 binds to some of these regulatory cells and eliminates them. So you get more of a signal to, “Come kill this guy. Let's take this guy out.” So multiple mechanisms has proven that, really, over the last five years of clinical research to be quite a potent therapeutic for patients with multiple myeloma in combination with a number of drugs.

Jenny: Why is CD38 such a popular target?

Dr. Martin: The thing that stands out about CD38 is its expression on the cell surface is very high in the malignant plasma cell, much higher than a normal plasma cell and much higher than some of the other cells in the body that have CD38 on them, like some of the T-cells and the B regulatory cells. Even some blood cells can have a little CD38 on them. In stem cells, those levels are really low. In fact, most of the antibodies go and bind to the myeloma cells because they have so many of these receptors on them. And that's really what's been so positive in terms of you're really targeting the myeloma cell are these cells are coated, extremely coated with all these antibodies. And that just makes it a lot easier for the immune system to see it and kill it where some of the other ones that have less expression of CD38 hopefully don't get killed.

Jenny: And it seems like this is one that can work independently of other myeloma drugs although they're used in combination. It looks like CD38 might be a better target. I know the SLAMF7 monoclonal antibody is not really super effective by itself but maybe with other myeloma drugs.

Dr. Martin: There are two CD38 monoclonal antibodies - daratumumab and this one, isatuximab. We tested isatuximab back in the early teens, 2012, ‘13, ‘14 as a single agent in patients that were relapsed after receiving the standard immunomodulatory drugs like Revlimid or lenalidomide, or bortezomib or otherwise known as Velcade. In the refractory population, the response rate was somewhere between 20 and 30%. Now, that's amazing for just an antibody to get a 20 to 30%. But that and in combination with other drugs, we've shown that now, we can even double that, sometimes even almost triple that with some of the combinations, that potential we'll talk about.

Jenny: Yes. Awesome. You mentioned daratumumab. I think everybody's pretty familiar with that. Do you want to explain what the difference is between isatuximab and daratumumab? I know Dr. Richardson, on our last show, mentioned that they're similar in ways but they have different mechanisms of action. 

Dr. Martin: They are, actually, in fact different. In terms of drug development, usually, what happens is when you look to get an antibody against a particular cancer, you target it for one mechanism first. Then you see if the other mechanisms actually also work. 

So when isatuximab was developed, it was actually developed in mind for it to induce that apoptotic signal, that just the antibody binding to the cell would kill the cell. So they selected isatuximab amongst many other different candidates based on its ability to kill the cell by itself with just the binding of the antibody to the cell surface. It had no immune cells associated with it. This was just simply the binding. 

Now, daratumumab was actually developed based on its ability to induce that complement-dependent cytotoxicity. So they they had a bunch of candidate antibodies. When they found daratumumab, they said, “Wow. This is the one that really produces the highest amount of CDC.” If you compare those two in the test tube, daratumumab does more CDC and isatuximab does more apoptosis. So that’s actually how they were developed. 

Now, in addition, if you look at CD38, it's a 3D protein that comes off the cell surface. If you look at the 3D structure of the protein and where that antibody binds, there's actually very little overlap between where daratumumab binds and isatuximab binds. And isatuximab, too, might have a little bit more potent inhibition of the enzymatic activity of CD38. So those are the biochemical and structural differences in terms of the binding of those drugs. 

Now, I will say that when we go to do the clinical results, if we go to all the studies that we've done, single agent studies, combinations with lenalidomide or Revlimid, or Pomalyst or pomalidomide, or bortezomib, Velcade, they're very similar, actually, when you combine them with drugs. In terms of if you do it in the relapsed setting or if you do it frontline with either one of those drugs, they both have very similar clinical response rates, which is interesting. 

Jenny: I think it's fascinating. I want to ask some questions about just FDA approval in general because I know the first approval for isatuximab is with pomalidomide and dexamethasone in the relapsed setting. And that's most of the time where drugs get approved. It’s in their highly relapsed setting. Then they bring things up to newly diagnosed setting. Same with daratumumab, It seems like a lot of the things we're going to talk about today are in the newly diagnosed setting. So do you want to just give patients just a quick overview of this approval process? 

I think from a patient standpoint, it's very exciting that all of these drugs are approved. As we're watching COVID, things try to get hyper-rapid approved. I don't know. It seems like we have to wait a long time to get things approved (in cancer), but I guess that's just the process.

Dr. Martin: I know. It is, unfortunately. It is a long road from when the drug is first actually used in the test tube, then in mice or animal models, then in humans and then until we actually -- it's on the shelf and we can just pull it off the shelf and use it for a patient outside of a clinical trial. It's too long. 

COVID, I think I do agree with you that COVID has changed that a bit because the research for COVID is going so fast right now. And we're seeing that, “You know what? Maybe we do have too many regulations in place. We have to do these things much faster because patients need these drugs, et cetera.” I agree. 

For isatuximab, when we showed that it worked as a single agent and also, we showed that it worked in the relapsed/refractory setting. The initial study that we did and we published was together with lenalidomide or Revlimid and dexamethasone in the relapsed setting. And even in patients who were refractory to Revlimid, if we combined isatuximab with Revlimid and dexamethasone in a clinical trial, when we did that, we showed that in the refractory setting -- we wouldn't expect them to respond to Revlimid -- we saw an overall response rate of 50%. We were really excited about that result. 

Jenny: Oh, wow.

Dr. Martin: We published that a few years ago in Blood. That led to us saying, “Okay. These antibodies work really good with these immunomodulatory drugs with lenalidomide.” But probably, we thought the best way to do the drug development with isatuximab, the fastest way to try to get it and approved was to go to even a later line of therapy in patients who this drug could be combined with pomalidomide, a different immunomodulatory drug. 

At that point in time, pomalidomide and dexamethasone was considered one of the standard treatments for people who had refractory disease and were refractory to lenalidomide or Revlimid. So if you're refractory to that drug, the next drug you give is pomalidomide and usually combine it with dex. What Sanofi did is ask the FDA, “Is it okay if we do a randomized trial where half the patients get pomalidomide and dexamethasone, which was standard and then half the patients would get isatuximab plus pomalidomide and dexamethasone?” For approval, they said yes. That's the large phase three trial was done. It was an international large phase three trial. Over 300 patients were involved. 

Basically, the three drug combination of isatuximab, pomalidomide and dexamethasone is much higher response rate, over 60% compared to pom and dex where the response rate was just over 30%. And people stayed in remission longer. That's called progression-free survival. The progression-free survival was actually 11 and a half months in the triple drug, isa-pom-dex arm, versus just over six months for the pom-dex arm. So doubling in the remission duration and a doubling of the response rate, so really worked quite well. 

With those data, the FDA said, “Sure. It's now approved for use.” And it's approved for use in patients who have relapsed refractory myeloma, who've had two prior lines of therapy. There's the label. And that's the first approval. Hopefully, everybody will be able to use it soon.

Jenny: Right. Now that it's been approved, I know there are a lot of clinical trials. So let's talk about some of those. ASCO just happened. There was a trial with isatuximab with KRd or Kyprolis, Revlimid, dex for high risk myeloma. And I think that was for newly diagnosed as well, right?

Dr. Martin: Yes. That was done by Katja Weisel from Germany, one of my favorite myeloma people. She's awesome. She does wonderful research. She did a nice study in Germany where they had high risk patients. If they are young and fit and were eligible for transplant, they received isatuximab with Kyprolis, Revlimid and dexamethasone, so i-KRd. They got several cycles, collection of stem cells, autologous transplant and then additional cycles afterwards, followed by maintenance based therapy. And she showed an impressive overall response rate of 100%.

Jenny: That’s amazing.

Dr. Martin: Yes, 100% response rate. They also showed that these responses were quite deep. And in the first group of patients that have proceeded past the stem cell transplant phase and they looked at minimal residual disease testing, over 60% of them were MRD negative. So that's going to be a really impressive combination for frontline treatment. 

Now, obviously, we can't use that right now because it's not FDA approved and still in clinical research trials. And most of the frontline studies, they're going to take a long time these days because the regimens are so potent. Those people that now get i-KRd, we expect for them to be in remission upwards of six to maybe as many as eight years. So they're going to be in remission from frontline therapy for quite a long time and that's together with transplant. 

Now, she also did in some patients that were older, older than I think – it was 70 years of age that did not undergo transplant and again, saw an over 90% response rate, extremely high response rate in that population. Amazing.

Jenny: Well, let's talk about MRD testing. Yeah, that is amazing. Let's talk about MRD testing for a minute because I know people are looking to use minimal residual disease testing or this MRD testing potentially as an earlier clinical trial endpoint instead of waiting those six to eight years that you just mentioned.

I noticed that some of these clinical trials, when they were doing the MRD testing, look like they were using mass spectrometry in some of the MRD testing. Do you just want to weigh in on that? How could we shorten up some of these results so that we don't have to wait another six to eight years to just get something approved for newly diagnosed myeloma?

Dr. Martin: That is a really great question. The primary endpoint for Dr. Weisel’s study was MRD negativity. Now, in the phase three trial, so far in phase three trials, the FDA has not allowed MRD to be the primary endpoint, okay? But let's think about what I just said and the question you asked and that is if it's really going to take us ten years of follow-up to do a trial in frontline of myeloma, how are we going to encourage more people, more pharmaceutical companies to do these trials if it's going to take ten years to get the result? They're never going to be able to license their drug in that area. It's going to take a decade. That's too long. 

If what we're trying to find, and especially in a study like Dr. Wiesel’s study, that at two years or three years later that with this study, that we get 60, 70, 80% of the people that are MRD negative and then we follow those people over time, and we show that those patients that are MRD negative in fact do have a PFS of eight to nine years, then we can potentially use MRD at the two or three year time point to tell us that those patients are going to be in remission for eight to nine years. So for comparing two study, two different arms of a study and we say, “Okay. Let's compare at two years what the MRD rate is. If in one, it's 90% and the other is 20 at two years, then of course, the one that's 90 is going to be doing better than the one at 20 five years down the road and ten years down the road.” 

So that's what we're trying to say to the FDA. It’s we want to use it as an early assessment of how well study arms are doing so we don't have to wait the ten years. I think we're almost there. The FDA wants from us, the myeloma community, more data to show them that the early time point of MRD negativity does correlate to improve remission durations, progression free survival and maybe at some point would show over time improved overall survival. But right now, we're just looking for progression-free survival. So that's where we think MRD testing is going to come in handy with frontline studies.

Jenny: Well, I would applaud that because we can't wait ten years to get one new indication (drug approval). That's ridiculous. Especially with all the different combinations, there's just no way that you can run that many clinical trials in all the different combinations that need to be run. It doesn’t make sense. 

Dr. Martin: Also, the conclusion for patients, I think, out of this is that we are doing so much better in that this is a good problem for us to have to say that, “Oh my gosh, the first treatment you're going to get, you're going to stay in remission for six, seven, eight, maybe ten years.” That is awesome, right? Because when you go to get your second regimen six years from now or eight years from now or ten years from now, it's even going to be better than the one you're getting now because all the drugs we're testing down the road are going to be even better than these ones. So it's all good. It's all really good for the patient.

Jenny: It's great. And the use of quad therapies, let's talk about that for a minute because a lot of these in these ASCO results and in many clinical trials now are adding drugs like isatuximab to a triplet that's normal for induction therapy or whatever. And quads seem to be the way people are going. What do you think?

Dr. Martin: Well, yes. I think there was another presentation from Spain looking at isatuximab together with either Velcade, Cytoxan and dexamethasone, what we used to call CyBorD or isatuximab plus RVd, Revlimid, bortezomib or Velcade, and dexamethasone. Both of those had really high response rates, more than 90%. I do think that the combination of the antibody plus an immunomodulatory drug like Revlimid, plus a proteasome inhibitor -- and that's either bortezomib Velcade or carfilzomib Kyprolis with dexamethasone -- that those four drugs together are incredibly potent at the current time for frontline based therapy. We've had data now from multiple meetings with four drug combinations in the frontline setting including a CD38 antibody and it's just really impressive how deep of remissions we’re getting. Some people think that, in some of the combinations, the four drug combinations, again, that we're going to see remission durations pushing eight, nine and ten years.

Jenny: Fantastic. In the Spanish study with VCD versus VRd for newly diagnosed myeloma, did they include a transplant too? Because the German study did, right? 

Dr. Martin: Yes. That was not transplant based therapy. As far as I remember, I don't think there was transplant in there. I don't know. I can't remember on that one. Do you know that one?

Jenny: I don't think so. 

Dr. Martin: I don't think there was transplant in that. No. 

Jenny: Okay. That's great. Well, it sounds like with the German study, doing this kind of quad and then following up with transplant and then doing it as consolidation or something may be the way to go especially for these high risk patients. I guess is there any indication that isatuximab has special impact for high risk patients or specific genetic features?

Dr. Martin: It's a very good question. In all the relapsed refractory studies that we've done with isatuximab, the high risk patients have done better than we would have expected. So it does look like it contributes to the combination. However, there's no drug at the current time or no combination in my mind that completely eliminates some of the effects of high risk disease. We're still looking for more drugs to help make high risk disease respond just as well as non-high risk disease. So that, we're still looking for.

Jenny: Well, that's such an interesting study that she did with the high risk genetics, especially in newly diagnosed because you just never know how evolved the myeloma is by that point, right?

Dr. Martin: Correct. In her study, really, the important component, she had a great response rate, et cetera. The important component will be how long that remission will last. And that's going to be the key of that. It’s how long will that remission last.

Jenny: Do you know how long the follow-up was on that study? I'm just curious.

Dr. Martin: It's still short. It's still very short. For high risk, we got to follow them at least 24 to 36 months because some people with high risk end up starting to relapse within 18 to 24 months. And that's where we start to see some treatment failures. That's the time point. I think it wasn't quite more than a year for that follow-up.

Jenny: Then I saw that there were other studies that were open or going to open or something with isatuximab with like bendamustine, which is another chemotherapy, right, and prednisone?

Dr. Martin: Yes. 

Jenny: You can skip over any of these or talk about them in more detail, whatever you prefer.

Dr. Martin: Sure. Yes. I think in terms of the next generation of studies for isatuximab, what I think is the two most important ones, one is a phase three trial that has been accepted as a late-breaking abstract, the EHA. And EHA is next week. This study is also in relapse phase three in relapsed/refractory myeloma. And it's isatuximab plus carfilzomib and dex versus carfilzomib and dex. So the three drug versus a two drug combination. Although I can't reveal all the results right now, I will tell you that it was accepted as a late-breaking abstract because it's going to be a really big splash in terms of -- in my mind, most of these studies have shown that three drug is better than the two drug. And I think we can anticipate that hopefully, isatuximab plus carfilzomib and dex is a good combination. 

Now, we started that combination of isatuximab and carfilzomib. We treated the first patient with that combination at UCSF back in 2015. We started the study that actually led to this phase three study. We did it because carfilzomib induces apoptosis. And isatuximab, like I’ve said, one of the mechanisms of action is to induce apoptosis. We thought there would be some synergy between those two. We've always found them to be a great combination. We have presented at ASCO a couple years ago preliminary results of our isatuximab plus carfilzomib data. We showed that even in people with carfilzomib refractory, if we added isatuximab, we saw responses. The response rate was even as high as 60%. So the two together actually worked quite well together. 

That's the one. The isatuximab, it's going to be I think it'd be a great combination with carfilzomib and dex. That's one study that I'm very excited about. And data should be available literally in the next -- I think the 14th is the presentation, so eight days, nine days.

Jenny: Oh, that’s great. We're going to have a roundtable for that. So this is the European Hematology Association for people that don't know what EHA is, right?

Dr. Martin: Correct. Yes. And it usually follows a week or two or three after ASCO. 

Jenny: And you're always usually there, except not this year.

Dr. Martin: Yes. Not this year unfortunately. I’ll be there by video. Then the other trial that I think is going to be an important trial is called the IMROZ trial. This is the licensing trial for a four drug combination. It's isatuximab, Revlimid, Velcade and dexamethasone versus Revlimid, Velcade and dexamethasone as treatment of newly diagnosed frontline multiple myeloma. That trial is ongoing. It’s being evaluated for responses and remission durations. They basically do, every once in a while, look at the results of the study. The statisticians look to see if they have to unblind it or stop the study because one arm is better than the other. Right now, they're just watching arms to see if one arm proves to be better than the other. That one potentially could be the approval, lead to the approval of a four drug combination as frontline therapy for multiple myeloma with isatuximab.

Jenny: I have a question. I know you said some of these approvals may take six to eight years. But if there's already something approved in the drug class in general, does that speed up that process in terms of bringing isatuximab up closer to the newly diagnosed setting? Or is it just the same? You just have to go through the same process and it's just all the same?

Dr. Martin: That's a really great question. So sometimes, if the drug is approved in the relapsed/ refractory space and there's a large phase two study that it shows a promising response rate and no additional toxicity from combining the drugs, sometimes, the FDA will say, “We will give you approval for that combination in that space.” 

However, if you're going to a different space like to the newly diagnosed space, I'll say there's no free lunch in that regard. The FDA makes you test your drug in that line, in that specific space. So for all of these CD38 antibodies and even the SLAMF7 antibody, elotuzumab, to get into that space, you have to do a phase three randomized trial.

Jenny: Well, that makes sense especially because they approach things differently. Anyway, they're not exactly the same, so that makes sense that they would need to test it all. Can we talk about isatuximab for smoldering myeloma? Because I saw some trials there as well.

Dr. Martin: Yes. There is going to be a trial. There is an ongoing trial. It's been going on for a while with isatuximab in the smoldering myeloma space with the premise that you're simply using an immune-based therapy in the smoldering myeloma. You're not hopefully going to induce any long-term side effects from it, but you're merely trying to enlighten the patient's own immune system to where those bad cells are and to go and get them. 

Now, I have to say that I'm a little biased about smoldering multiple myeloma. My bias is smoldering myeloma is essentially a time where you're catching a patient that has likely early multiple myeloma and that if you follow them more over time, they are going to have some symptoms from those malignant plasma cells. They're going to grow to a certain amount and they're going to be symptomatic. The hard part is you don't really know in that time between they're not symptomatic to when they're symptomatic when's the right time to do therapy. When is the right time to start therapy? The other question is not just when is the right time to start but then what really is the best medicine. For newly diagnosed active myeloma, none of us are saying, “Let's just use a CB38 antibody in the newly diagnosed myeloma.” We're giving them three and four drug combinations, right? So my bias is just use an antibody in smoldering myeloma. It’s probably not the right setting. 

In smoldering myeloma, there's probably a couple of different groups of patients there, those that are soon to be active myeloma and you really should treat them like active myeloma or there's another group of patients who have really low, kind of smoldering low, proliferative, very – sometimes, I call it sleeping myeloma where it's really not that active. You might be able to wait five or ten years before doing something. So why perturb that person at that point in time? Unless you can make it go away completely and cure that person at that point time. I think sometimes, it's best to be left alone and let the immune system do what it's doing, hopefully keeping it sleeping. So I have some biases in the smoldering myeloma camp in terms of whether we should use CD38 antibodies in that space.

Jenny: Well, it's so interesting. I watched one of Dr. Lonial's presentations from ASCO where he was talking about smoldering myeloma. He was just saying, “Smoldering myeloma isn't really different. It's just the absence of this end organ damage.” Then they were talking about some of these early -- like the CESAR trial where they were just throwing everything at smoldering myeloma. Still, it wasn't like it was curing everybody. I don't know. It just made me think just of what you said. Every patient is different. 

Dr. Martin: Exactly. So we don't have the solution. 

Jenny: I don’t know. It’s so hard.  

Dr. Martin: No, we don't. We don't have the solution. For me, it's not just the CD38 antibody. It's not just Revlimid. We need something better. The CD38 antibodies, I said, are naked antibodies. They require some help from the immune system. In the next two to five to ten years, we're going to be in more of a space of these active immunotherapies, these bi-specific T-cell engagers and these other drugs that might actually have a better role in that early smoldering myeloma space. That's my suspicion. But that's for next time, new days.

Jenny: Can I ask you a question about what you just said too? It just made me think of a question about the current status of your immune system. So maybe the smolderers are able to continue smoldering because their immune system is at a certain status or powerful enough to tamp it down. Do you see any work being done on identifying the difference in immune system status and why some patients are progressing from smoldering myeloma or relapsing faster or those types of things? Because it seems to me that it would make a lot of sense to just say, “Okay. Your immune system is this status and you're more likely to do this. So we're going to do more for you just because you have a weaker immune system.”

Dr. Martin: Yes. That's actually the Black Swan project from the IMF. That is the goal of the Black Swan. It’s to figure out what is basically the transition zones from MGUS to smoldering myeloma, smoldering myeloma to active myeloma. What are those transitions? So that is being heavily investigated by many researchers including those in Iceland. 

Iceland has a very homogeneous population. They're looking at their MGUS patients. They're looking at the genetics and isolating bone marrow cells and immune microenvironment cells and trying to see, “Okay. Which one of these immune cells are really the ones that are keeping everything in check or which ones are going to sleep and not doing their job and letting the myeloma progress? Also, what are the genetics of the progression? Is there something happening inside that myeloma cell, et cetera?” That's part of the Black Swan initiative. 

There is another initiative from the MMRF that's looking at this transition. Irene Ghobrial from Dana Farber is also doing tremendous work on looking at these early precancerous stages and why do these patients progress. She has a huge database. She asked patients, those with smoldering MGUS, to go to her website and put their information in so they can have this huge, big database about it. So there's a lot of research actually going on in this. This is going to be key for us to cure myeloma before it happens.

Jenny: Right, so much so. Let's talk about administration of isatuximab for a minute. How is it administered and how is it different from other options?

Dr. Martin: That's a really great question. Isatuximab is administered by an IV infusion. It's given, for the first cycle, weekly. It's four doses for the first cycle. Then starting from the second cycle onward, it's given every other week. So it continues to be given every other week, ongoing. 

For the IV administration, the dose is ten milligrams per kilogram. For the first dose of ten milligrams per kilogram, typically, it's in the order of three and a half to four and a half hours for that first dose. Then subsequent doses afterwards, it's more in the two and a half to three hour range for the subsequent doses. 

Now, Saad Usmani presented at the European Hematology meetings last year that after the third dose, that you can give it actually over a faster time point. You can actually give it over 75 minutes without toxicity. So they have started that study and they’ve given it -- or that study proved that you could give it over 75 minutes. So that was just an hour and 15 minutes, which is that's pretty doable, I think, for most patients. 

When we were developing isatuximab, we actually tested a higher dose. We tested 20 milligrams per kilogram. In fact, it took a lot longer. The first dose was about six hours and subsequent doses were four to five hours. When we looked actually at how much medicine was left in the system after you did that and how many responders versus the ten milligrams, what we found is we probably were, for most of the patients, giving more dose than we needed. So in combination with other agents, isatuximab -- I think, the optimal biologic dose and then how it will be the approved dose with isatuximab, pomalidomide and dex and then eventually, if it gets approved, with carfilzomib or Kyprolis would be again ten milligrams per kilogram. Isatuximab plus Kyprolis and dex  is the optimal dose especially when used in combination. That's in general how it's given. 

It is given intravenously. And as you know, daratumumab just got FDA approved for subcutaneous injection. There are studies that are going to test isatuximab in the subcutaneous administration mechanism. But right now, all we have is IV. It'll be IV formulation.

Jenny: Nice. Then how does it compare with infusion related reactions? I know people -- that was a new side effect that people weren't that familiar with and now, they’re more familiar with it. It's manageable, but is it any different? 

Dr. Martin: That's a really good question. I think there are some slight differences. We haven't seen as much, I think, of the respiratory symptoms like coughing, shortness of breath with isatuximab. So the standard premedication regimen is to use corticosteroid, either intravenous dexamethasone or methylprednisolone at least for the first one or two doses together with diphenhydramine or Benadryl or also an H2 blocker. Typically, we give famotidine. 

Essentially, with those combined, the responses or the infusion reaction rate is about 40%. Now, typically, what I do is when patients are getting their therapy, they sometimes can first notice, “I have a little trouble clearing my throat,” or, “I get a little sinus congestion.” Right away, any one of those symptoms, I typically will give them more of the steroids. I'll give them another 50 or 100 milligrams of IV hydrocortisone. And I'll give them a little bit more of Benadryl, another, say, 25 milligrams of Benadryl and typically take away those symptoms without even having to stop the infusion. 

But if people have significant symptoms and they're usually grade two where they do have cough or they feel short of breath or blood pressure can go up or down briefly, you have to stop giving more premedications and then restart it. I think more than half the time, with an infusion reaction, I don't even have to stop the infusion. I will just give more premedications. 

People have to watch it. The infusion-related reactions almost uniformly happen on the first reaction. Then by the second reaction, they still have the drug in their system. It's still there. Typically, when you see the protein again on the second administration, there's usually not an infusion associated reaction. There's no steroids medication on the second or third day orally after getting isatuximab so we don't give steroids on the second or third day.

Jenny: That's great to know. I know a question that everybody will ask is -- and this question goes both ways -- if you start with isatuximab and you relapse after it or if you start daratumumab, can you use alternately the other drug? If you start with isa, can you go to dara? Start with dara, can you go to isa? I know that's just going to be a common question for everyone.

Dr. Martin: It's really a great question. There are two answers to that. The first answer is no and the second answer is maybe. The reason the first answer is no is we typically won't go from, say, an early relapse regimen using a CD38 antibody. Say daratumumab, say somebody is on daratumumab plus lenalidomide and dexamethasone or DRd, what we do, DRd. Then they relapse. We wouldn't give them isatuximab, pomalidomide and dexamethasone as their next regimen. The reason is because those myeloma cells at that point in time, they probably have downregulated a number of CD38 receptors on the cell surface. So using a different antibody at that point in time is not effective because the cell surface receptor is not there. It's not there in adequate quantity to make it work. Typically, the answer is no. You can't go from one CD38 right to the other CD38. 

Now, the answer maybe is because you can if you wait. So if you do daratumumab, Revlimid and dexamethasone, DRd, for first relapse and then they relapse and on second relapse, maybe you give them pomalidomide, Cytoxan and dexamethasone, after that one, then you can go to isatuximab. Or if you give carfilzomib as the second one, you can go to isatuximab, pomalidomide and dexamethasone. You need to give a regimen in between the regimens. Then over time, actually without the pressure of the CD38 antibody on the third CD38 receptors will come back on to the cell surface. We've seen that from clinical specimens for patients treated with CD38 antibodies. If you wait over time, the receptor density goes back up to a good level.

Jenny: That's crazy. Is there anything that can upregulate the CD38 receptors without just waiting for it naturally?

Dr. Martin: Well, that is a really, really great question. We are testing that at a research trial at UCSF right now actually where our first patient hopefully will be enrolled in the next four to six weeks. So we're using what's called the hypomethylating agent, an HMA. The agent we're using is a medicine called azacitidine. What we found in the laboratory is that if we pre-treat some of these CD38 negative or low-expressing cells with this HMA molecule, we can actually increase the expression of CD38 on the cell surface. So we're taking CD38 refractory cases. Then we're giving them first azacitidine and then we're going to give them the CD38 antibody. We're giving the azacitidine first. We're going to harvest some of their bone marrow cells afterwards, see that we've actually done a refractory, upregulate CD38, and then we're going to give CD38 as a clinical treatment and see if they respond. We are testing that. So that is a great question.

Jenny: That's going to be so fascinating. Wow. Okay. Are there any considerations the patients need to think about when using isatuximab during the COVID situation?

Dr. Martin: Well, that's a good question. I will say that all of the antibodies that we currently have, all the CD38 antibodies and the SLAMF7 antibody, they do produce some form of immune suppression, meaning they do decrease the number of lymphocytes that people have in their blood. They also over time decrease the number of antibodies, protective antibodies in their blood. People need to be on prophylaxis for reactivation of zoster virus or shingles, the chickenpox virus. So people take prophylaxis for that. And if they're getting steroids, I also have them on a medication to prevent a special pneumonia called pneumocystis. So they take a medicine to prevent that too. The preventatives tend to work, so you have to take them. 

Now, what I've told all my patients in the setting of COVID is these are immunosuppressive medicines. These have the potential of making you at higher risk of having a more difficult time clearing that virus from your body. So right now, the best defense is to not get it. Here in the Bay Area, we've done extremely well with – thankfully, knock on wood -- with shelter in place. As long as you do -- you wear a mask. You wear gloves if you're out, especially a cancer patient, you wear gloves. You try not to touch your face, your mouth, your eyes, nothing, no entry portal with your gloves, your hands while you're out doing that and just good hand hygiene, et cetera. 

Most treatment centers like UCSF and other treatment centers around the country now are prescreening all patients that go to the center, meaning the patient's getting a call before they go there. They're asking, “Do they have symptoms?” If they do have symptoms, they're not allowed in the treatment center. They can get treatment outside the treatment center. Typically, all centers have set up other infusion areas outside of the treatment or the protected treatment center where we don't want COVID. So patients should feel comfortable going to the clinics right now because we're doing really a lot of work to make it safe for all the patients.

Jenny: Yeah. I'm hearing a lot of that. Kudos to you for doing that. I mean there are a lot of things that can suppress the immune system. Like Revlimid, if you're taking too high of a dose, it can do that too and like you said, the steroids. So it's not necessarily just something like the mabs. 

Dr. Martin: The Revlimid thing is a really interesting phenomenon. Ten years ago, one of our researchers from the laboratory said, “You know this Revlimid? It stimulates the immune system. Why don't we give it to patients in the nursing home during flu season and maybe it will protect them against flu season?” 

Now, in fact, because Revlimid has so many other side effects, we didn't allow him to do that study. He did want to give it to patients in nursing homes to try to prevent flu. So I don't know what will happen with Revlimid. It's really an unknown, in fact. That's interesting. But most of the time, patients are not just taking Revlimid. And they should consider -- all patients who've been through stem cell transplant or on maintenance, everybody should consider themselves immunocompromised. And the best thing to do is avoid any possible contact with COVID.

Jenny: Yes, right. Not a good time to be taking part or something.

Dr. Martin: Exactly.

Jenny: My last question before I open it up for caller questions  -- you mentioned a little bit about this before about pairing it with immunomodulators, but in what combinations do you see isatuximab being the most effective? Then once we start doing other things like some of the bi-specifics get approved or CAR-T gets approved, that opens things up to a whole new set of treatment combinations that are way beyond like RVd or KRd or something. Do you see that having any synergies or any issues or anything like that?

Dr. Martin: When we take the first question and say that in terms of isatuximab, I am really excited as a combination with pomalidomide. I think it'll work really well with pomalidomide. I'm also really excited and I think -- knock on wood -- I think the data that you're going to see in the next ten or 14 days, how it's going to show that it works really well with proteasome inhibitors too like carfilzomib. We've seen in our phase one with an expansion trial that the combination is very active with isatuximab plus carfilzomib. So I really like that combination too. And I think it's really easy to give. 

We're going to do a large study now with isatuximab and weekly carfilzomib. The one you're going to hear in EHA is twice weekly, but we're going to do a study with some centers across the country doing weekly carfilzomib with isatuximab. I'm really excited about that. Now, I do think that the CD38 antibodies, they are at the current time going to be used in that relapsed space with isatuximab and pomalidomide like approved or isa and carfilzomib. But also, they're going to be moved up to frontline like daratumumab has been. It's going to move up to frontline. I think most patients are going to get a CD38 antibody as part of frontline therapy. 

Again, frontline therapy today, right now, I think it's going to be five years or more down the line when you're going to need your next therapy. And I think that next therapy, in fact, is going to be some of these newer drugs. It's going to be some of these bi-specific T-cell engagers or it might even be right to a chimeric antigen receptor T-cell or CAR T-cell. That might be the first therapy you get when you progress from frontline based therapy. Hopefully, with frontline therapy and the first relapse therapy, hopefully, we're talking ten to 15 years down the road now, that people are going to do well for the first ten or 15 years of their myeloma time, which is that's going to be an incredible advance.

Jenny: Yes. That's extraordinary and I hope for that. I think that would be terrific for everybody and hopefully, for the high risk patients too. Okay. We'll open it up for a few caller questions. We have a question - go ahead with your question.

Caller: Hi, Dr. Martin. Thank you for the call. My question is for a patient that turns MRD positive from an MRD negative status two years after the transplant. And the maintenance regimen actually was dara-pom-dex. How quick are you to use the MRD positive as a reason to change the treatment or become more aggressive? The biochemical relapse has not happened but the MRD positivity has happened. How quick are you to take action when a patient turns MRD positive?

Dr. Martin: Well, that's an extremely advanced question and I like it. There are a number of studies that are now underway that are going to look at when we should initiate therapy post MRD switch. So what I'll tell you right now is belief because there's no data to go by what your question is, so my belief. When we looked in our MRD data set at UCSF, we found that you have to have at least the two log fold increase in the amount of MRD for us to worry that it's a true progression or you need to have multiple tests. Typically, a test is every three or six months because it's a bone marrow biopsy. You have to have multiple tests that show over time a two log  fold increase.

When we looked at the people that started to have the increased MRD testing, what we found is from then to when we would call them progression -- in other words, they met the definition of progression by IMWG -- was 13 months. For the majority of people, that's a median. For the majority of people, you have over six months. You have six months to a year, maybe even longer for some, to make a decision on what the next one is and what you have to do. And you have time to see the rate of the rise and also what's on the horizon and will – potentially, you'd be eligible for some type of trial or any other therapeutic that you don't want to miss out on by starting early therapy. That's typically what we do. We wait and look at the rate of the rise and essentially start therapy only when somebody meets the definition of progression.

Caller: Sorry. The definition of biochemical progression, meaning the increase in-spike, et cetera. 

Dr. Martin: Correct. Yeah.

Caller: But the hundredfold rise in number of abnormal plasma cells in the bone marrow aspirate, that's a trigger -- you don't use that as a trigger to change the maintenance or to try another agent? So basically -- 

Dr. Martin: Correct. 

Caller: You know that you have roughly 13 months until the biochemical relapse happens.

Dr. Martin: Yes. Exactly. 

Caller: But if the rise is even faster, let's say a three log rise in the space of six months or a year, would that trigger a change in regimen even if the biochemical relapse has not occurred?

Dr. Martin: I would have to say that it depends on the clinical scenario. So somebody, we knew that person maybe had a 14;16 translocation or a 17p deletion and now, we see this skyrocketing MRD, that might change my discussion with the patient that, “You know what? We could try to see if we can stave this off and head it back in the right direction by starting early therapy.” So that, I think, is a one-to-one discussion between the doc and the patient. 

Caller: Right. Thank you.

Jenny: Okay, great. Thanks for your question. We also have an email then a question from Rosalyn and she said, “Is isatuximab a sulfa drug?” And I don't know what a sulfa drug is but maybe you can answer that question. 

Dr. Martin: There's no sulfa – in terms of allergy, no. If somebody has a sulfa allergy, there’s no cross --

Jenny: Oh, yeah. I remember.

Dr. Martin: Yeah. There's no cross-reactivity or an allergy to isatuximab.

Jenny: Okay. Great. I think she had a lot of allergies to sulfa. Another caller, go ahead with your question.

Caller: Hi, Jenny. Hi, Dr. Martin. Thanks so much for taking the call. Dr. Martin, do you need to have specific blood typing labs prior to the first infusion with isatuximab for future blood transfusions? 

Dr. Martin: Yes. So another really great -- you guys are awesome -- another really great question. What we're finding is that there probably is some CD38 on red blood cells and that any CD38 antibody will bind to the red blood cell and it will bind to the assay that's done in the blood bank to try to pick up an antibody of some who needs a blood transfusion. If you need a blood transfusion, we need to see in your serum, do you have an antibody that's going to bind to the red blood cells coming into your body? So daratumumab almost always 100% of the time, you'd have a positive prescreen that says, “You got something in your blood that's binding to these red cells and we got to figure it out.” And it's almost always that's daratumumab. 

With isatuximab, it's about half as high as daratumumab. It’s probably 50%, maybe 60%. But still, it's high enough that yes, you have to have a sample sent to the blood bank before you get your therapy just so the blood bank knows. And you need to tell anybody if you need a blood transfusion, “I'm on isatuximab,” just like you do for daratumumab. That's probably going to be for all CD38 therapeutics. They probably all going to do the same thing. Yes.

Caller: Okay. And what about is there specific testing to tease out the artifact created by this drug just like there is for Darzalex?

Dr. Martin: There is. Yes. 

Caller: There is?

Dr. Martin: Yes. The blood bank can treat it with a chemical to actually remove the CD38 receptor. Then they find that the antibody doesn't bind and they say, “Okay. Well, it's the CD38. Let's not worry about it. We know they're on that drug.”

Caller: Okay. Good. So that would affect actual myeloma lab so too, correct, this artifact?

Dr. Martin: Not necessarily. So the antibody, because it's a little bit of a lower dose, I've clinically found -- because I've treated about a hundred patients. I've had less patients that have had an artifact with their SPEP and their Serum IFE than I have had with Darzalex.

Caller: Really? That's really interesting.

Dr. Martin: I've had less, but there's this test that you can run. They've developed the binding assay that you can just bind up the daratumumab and do run the assay that works fine. 

Caller: Great. Could you just take a minute to explain the limitations of bone marrow biopsy based MRD testing, specifically sample bias? How do we actually overcome that?

Dr. Martin: Well, actually, I was asked that question earlier and I didn't finish my answer, so thank you for bringing that up. Obviously, the biggest limitation for MRD testing is that it is a bone marrow biopsy, right? And the truth of the matter is that we don't have a smart needle to go in and say, “This is the perfect place to get that bone marrow biopsy from. This is a nice juicy spot.” We numb up the backside. We go in the bone and we hope that we get to a space where there's good bone marrow. There's never 100% chance that you're going to get good bone marrow. So there is that variability on the site that the needle goes into. 

Also, myeloma is patchy. In one site, you might have a lot. In another site, you might have very little. So that is a big problem with MRD testing. The two things that we're trying to do with that one is to try to say, “Well, can we make it a blood test?” Because the truth of the matter is some of those myeloma cells that are in the bone marrow, they do end up circulating in the blood. It's a smaller number, but they do end up circulating in the blood. So we're trying to develop better assays so that we can detect some of the circulating myeloma cells. Maybe if we could get a really better assay that can detect circulating myeloma cells, we'll be able to at least say when the circulating myeloma cells are completely gone at that level of this much MRD. We don't have to do bone marrow biopsies until we completely get to that level in the blood that's really low. Then if we want to see if we can go even deeper, then we potentially can try the bone marrow.

Caller: Are we close to those blood-based questions? 

Dr. Martin: We are. Yes. I do think so. Yes. I think within the next two to five years. But better yet, we have a better thing that's almost ready in the next year. That is mass spectroscopy for evaluation of M-protein. So everybody's myeloma cell makes a specific light chain and makes a specific heavy chain. Sometimes it doesn't make every channel. It only makes a light chain. Sometimes it doesn’t make a heavy chain, it just makes a light chain. The majority of people have some heavy chain and have some light chain. Right now, the assay that we have to detect that is actually not that good. But if we do it by a mass spec, which separates proteins by sizes and shapes, you actually can detect a very, very low level of that protein in the blood. In fact, it may prove to be better than MRD testing in the bone marrow and there will be a blood test.

Caller: And that’d be nice.

Dr. Martin: Yes. 

Jenny: Yes, fantastic.

Dr. Martin: Yes. The Binding Site is working on that, this company called the Binding Site. They're working together with the Mayo Clinic. They're opening seven centers across the country soon on doing and starting to do this mass spec testing and in quantitation of the M-protein.

Caller: Fabulous. Is that going to be done in a clinical trial? Or is it just going to be those seven centers will have that available?

Dr. Martin: No, seven locations, like seven places where they build test facilities around the country. So anybody can use them. They're going to be located in seven geographically well designed places around the country so that people can use it. 

Caller: Got you. Okay, excellent. Well, Dr. Martin, thanks so much for your time tonight. I appreciate it very much. I live in New York City, so I've been quarantine for weeks and weeks and weeks. Scary times, but you gave a lot of hope tonight in your discussion. I appreciate it.

Dr. Martin: Wonderful. Good luck there. And yup, stay sheltered.

Caller: Yes. Thank you so much. Good night now. Thanks.

Jenny: Great questions, Dana. Thanks. Okay. Dr. Martin, thank you so much for joining us especially on a Friday evening. We just really appreciate you weighing in and sharing this important therapy. I just felt like it was really important to not just overdo COVID all the time because progress is happening in myeloma. And we need to know about it as patients. So thank you so much.

Dr. Martin: Thank you for having me.

Jenny: We'd like to thank all our listeners of Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest in myeloma research and what it means for you.