Biology and symptomatology of primary amyloidosis

DR LOVE: Welcome to Oncology Today: Management of AL Amyloidosis. This is medical oncologist Dr Neil Love. For this program, I met with Dr Jeffrey Zonder from the Karmanos Cancer Institute in Detroit. In addition to this interview, there is also a corresponding program featuring Dr Zonder’s slide presentation. To begin, I asked him to describe our current understanding of the biology of AL amyloidosis.

DR ZONDER: AL amyloidosis is usually a plasma cell dyscrasia. Misfolded monoclonal light chains are being produced by a small, but unfortunate plasma cell clone. Often, the plasma cell biology is not really myeloma-like, in the sense that usually the bone marrow plasmacytosis is mildly elevated, often less so than the minimum requirement to make a diagnosis of myeloma. Although, there’s nothing about a 10% cutoff that suddenly automatically makes it myeloma. If the bone marrow has more plasma cells, but the only symptoms are related to the consequences of misfolded light chains and protein deposits, then we still call it amyloidosis — it’s just an adverse risk factor to have a plasma cell burden like that in the marrow.

Occasionally, it’s actually the result of a clonal lymphoproliferative disorder, like a low-grade lymphoma. Often, in that situation, it can be light chain, but it can also be like a mixed heavy light chain amyloidosis, but it’s still related to misfolded immunoglobulin fragments or immunoglobulins — immunoglobulin chains, I guess.

And the underlying treatment principle actually isn’t very different. I mean right now the standard approach to treating immunoglobin derived amyloidosis light chain usually, is to target the clonal cell population that’s making the light chains with some kind of therapy that’s aimed at that. And so, for the usual plasma cell variety, we repurpose myeloma type regimens. And for low-grade lymphomas, we use a regimen more suited for that, like a bendamustine/rituximab type strategy. But, again, you’re still targeting the clone; it’s just what’s the optimal regimen for doing that.

DR LOVE: Can you talk a little bit more also about sort of the pathophysiology about how you see end organ damage? How these, I guess unfolded proteins, damage the heart, kidney’s et cetera?

DR ZONDER: Right. So traditionally, we always thought about it as an issue of purely extracellular protein deposition and damage related to that. We’re used to seeing the Congo red-positive deposits in the interstitium of the myocardium, in the glomeruli, in the walls of blood vessels and that does have consequences for organ function. However, it’s also clear that the soluble misfolded light chains themselves are toxic. And on the heart, we know that myocardiocyte —cardiomyocyte contractility is decreased after exposure to amyloidogenic light chains compared to a typical myeloma light chains in, like laboratory settings, in animal models.

We also know that misfolded light chains are toxic to mesangial cells in the glomeruli, and there is an inflammatory damage cascade set off when mesangial cells are exposed to those misfolded light chains.

So there’s a direct proteo-toxicity, in addition to the mechanical consequences of those protein deposits.

DR LOVE: I know you see a lot of people who kind of were bouncing around and finally get to a diagnosis after a longer period of time that would be optimal. What is a typical presentation? And what are some of the challenges that you see in trying to actually make the diagnosis?

DR ZONDER: So, it is usual — I mean there have been numerous papers or studies addressing this. There was a pretty highly publicized online patient survey where patients — that was done by the ARC, Amyloidosis Research Consortium, where they surveyed patients, and, on average, patients saw multiple physicians over a period of really a few years before a diagnosis was made in most cases. And delays in diagnosis really contribute to poor prognosis. The more advanced organ function — the more impaired organ function is when the diagnosis is finally made, the worse the outcomes. And that’s true for survival, based on cardiac involvement. It’s also true for renal outcomes, what’s the likelihood of ending up on dialysis. It sort of is based on — it’s affected by how severely the kidneys are affected the day the diagnosis is finally actually nailed down.

The problem is that the symptoms of amyloidosis are often similar to the symptoms that you can see with other, more common medical conditions. And so a patient who has a history of longstanding hypertension, not perfectly controlled diabetes, those kinds of conditions. When you see somebody who has a little bit of proteinuria, or you see somebody who has a little bit of, or symptoms of, mild congestive heart failure, edema, a little bit of neuropathy, it’s often — going forward, it’s often more logical to assume it’s the more likely or more common diagnosis, right. And it always, in hindsight, 1+1+1+1 always equals amyloidosis, in hindsight, 3 years later, but on route to that diagnosis, it’s very common in the patient age group that amyloidosis typically occurs in, is very common to have other coexisting medical problems which are more likely explanations.

It's understandable often, how a diagnosis gets delayed. It’s frustrating when it get delayed by years rather than by months. But it is definitely understandable.

The other diagnostic challenge is making sure that you have distinguished AL amyloidosis from other types of amyloidosis, which also affect patients in the same demographics. We know that plasma cell dyscrasias become more common as we get older, including monoclonal gammopathy of uncertain significance. We also know that plasma cell dyscrasias are more common in African-American people compared to Caucasian people. And also, transthyretin amyloidosis is more common in older people and African-American people. And transthyretin amyloidosis is a completely different form of amyloid. It’s not a plasma cell disease. It’s an abnormal – it’s a protein produced in your liver, not produced by a clone of plasma cells or lymphocytes. It’s not something you’d ever treat with chemo.

Monoclonal gammopathy, if you think about the frequency in people over the age of 50, it’s a few percent of people. And people over the age of 70, it’s 5- or 8% of people. And even higher in African-American people. And so, that percentage of patients with transthyretin amyloidosis will also have a monoclonal protein.

And so there is a real overlap in the patient groups. And sometimes somebody thinks of the diagnosis of amyloidosis, they find an M-protein, and they put 1+1 together and they just assume, erroneously, that it’s AL amyloidosis. And there needs to be a bit more testing done. It’s not as easy as just saying, bingo, I found amyloidosis. Then it’s what kind? And that’s the next most important step because that gets you down the right treatment lane.

DR LOVE: So not to get too far out on a tangent, but I think a lot of people’s sensitivity to the issue of African-Americans and plasma cell dyscrasia was increases when Joe McHale did his discussion of the DETERMINATION trial at ASCO. Do you yourself have any hypotheses why we see this in African-Americans? Is there any suggestion of a hereditary component? Environmental? Any thoughts?

DR ZONDER: Well, it’s certainly not going to be a simple as like a myeloma gene. But it probably is an inherited susceptibility. It seems to be true that the incidence of plasma cell dyscrasias is higher in people of African lineage, whether they’re still living on the African continent, whether in the United States, the Caribbean, Europe, the fact of the matter is, it’s higher.

So it seems unlikely to be environmental, given the differences — the geographic differences there. To me, that supports a much higher likelihood that there’s a predisposition for developing the precursor condition, MGUS. And then from there once you have a lot more MGUS in a certain population, you’ll ultimately have more myeloma.

Staging and prognosis for patients with amyloid light chain (AL) amyloidosis

DR LOVE: Could you talk a little bit about amyloid typing?

DR ZONDER: Very, very important early step. And we see, I would say honestly, a failure of this in the real world. Let me put it that way. In the real world we see a failure to do the typing. The immunohistochemistry isn’t really useful most of the time to do typing. The gold standard is tandem mass spec, and at most centers that a send-out. Mayo Clinic laboratories does the most by far. And it will distinguish — what you need to do that testing is, you need a biopsy sample that stains positive with Congo-red, with a large enough deposit that it can be microdissected off the slide. And then from there, you can identify what the amyloid is.

It not only distinguishes AL amyloid from other types, like transthyretin, or LECT2 or other known types. But even with a specific type like transthyretin, it can give you information to suggest whether that’s an inherited subtype of transthyretin amyloid, or whether it’s what we call wild-type transthyretin amyloid where there’s no mutation.

DR LOVE: So maybe we can talk a little bit about the relationship between time of diagnosis or stage of diagnosis and long-term outcome? And what the staging system actually is?

DR ZONDER: So there are several sort of variations and the same thing with the staging system, but they’re all based on cardiac involvement. And we are generally using different laboratory parameters. There are models which use NT proBNP and troponin T. You can use Troponin-I. You can use BNP. There are different systems. There’s a system that incorporates the level of the light chains, the misfolded light chain, as well. But basically, it divides patients up into groups based on the degree of cardiac injury at the time of diagnosis. And the different systems sort of divide people up into usually 3 or 4 stages.

The most commonly used staging system is the — and older 3-stage Mayo staging system, with what we call the European modification where there’s Stage I, II and III, III being the worst. And then within Stage III, based on the level of the NT proBNP and the resting systolic blood pressure, you can further divide Stage III into a IIIa and IIIb.

And the importance of that is actually IIIa patients track — survival-wise, they track a little bit more like Stage II patients. But IIIb patients are legitimately poor-outcome patients. That is the highest risk group.

And what stage really predicts is the likelihood of having a life-threatening cardiac event within the first 6 to 18 months after diagnosis. And so, whether you’re Stage I, II, or III, the steepest part of your survival curve is that first year or so. And then after that, the survival curves actually flatten out a little bit. So once you’ve sort of bobbed and weaved through that high-risk period, assuming that at the end of that first year the clone is controlled and the light chains are reduced, survival going forward is actually a bit better. So prognosis changes after the first year to 18 months.

Along the same lines, there is something called renal staging. The Pavia, Italy group, together with colleagues from the German Amyloidosis Group, put together this model based on GFR and the degree of proteinuria. And basically, based on whether you hit certain thresholds for these 2 parameters, again, you would be divided up into a renal stage I, II, or III. Renal involvement doesn’t predict survival the way cardiac involvement does, but the renal stage predicts the likelihood of ending up on dialysis. And it was actually quite high for patients who were Stage III, who already had impaired GFR, who already had tons of proteinuria.

I think in both cases, the cardiac and the renal staging, the effect of those lab parameters on prognosis, really what those labs are telling you is how much damage have those organs already sustained? And is there a damage cycle that, or spiral that’s hard to pull out of? The likelihood of not being able to prevent an arrythmia in the case of advanced cardiac involvement? The likelihood of having continued proteinuria, even if you managed to get some reduction in protein loss in the urine with treatment, is there still enough left that this continued nephrotoxicity from proteinuria?

So this kind of gets back to what I was saying earlier about time is of the essence in terms of making your diagnosis. If you don’t nail down the diagnosis until there’s advanced organ involvement, there may be irreversible injury that’s already in a spiral you will not be able to pull out of.

Supportive care for patients with advanced disease

DR LOVE: What about supportive care of these patients? What are some of the issues that come up as you manage heart failure? Also, I know these patients can have diarrhea, malabsorption. What are some of the supportive care issues, particularly in those patients who don’t survive?

DR ZONDER: First, I think it’s incredibly important to assemble a team of knowledgeable and engaged physicians to manage the symptoms. And I think patients will always do better if they have good subspecialty care available.

The hardest issues, I think the GI involvement is very difficult. You mentioned malabsorption. And you can get that. you can also get problems with gastric emptying. So, that can be incredibly frustrating and difficult, uncomfortable, and really impact ability to deliver care. And probably one of the hardest symptoms to manage. And it sometimes makes the use of certain therapies, high-dose chemotherapy and stem cell transplant for instance, very, very difficult. because a little bit of GI toxicity from therapy can go a long way in somebody who’s already struggling.

The other very challenging issue is management of fluid overload and edema in a person who’s often hypotensive and functionally hypovolemic to begin with. Patients have congestive heart failure, but they also have significant third spacing from hypoalbuminemia — from hypoalbuminemia because of their urinary protein loss of albumen. So they’re often fluid overloaded with a low resting blood pressure. And trying to get fluid off with diuretics can be incredibly challenging. The ability to tolerate diuretics is hard. Having a good cardiologist and nephrologist to help with this is super important.

Sometimes supportive measures like midodrine or things like that may make it more possible to use diuretics. But that’s a very, very challenging sort of aspect of amyloid management.

DR LOVE: I was just sort of fantasizing what it’d be like to listen in on one of your — I don’t know, do you have interdisciplinary conferences where you have the whole team sit down and go through cases.

DR ZONDER: Yeah, we do.

DR LOVE: I’m curious who goes to it. It seems like half the hospital would be there.

DR ZONDER: So there are certain team members there like Radiology, Pathology, Hematology, that we need there every week. But our multidisciplinary team has Nephrology, Cardiology, occasionally Neurology, all present as part of our multidisciplinary team. Bone marrow transplant is part of our team, too, obviously.

There are some centers where Rheumatology, Gastroenterology are regular attendees at a multidisciplinary meeting. And I think it depends on your patient mix. I mean for us, at the Karmonas Cancer Institute, light chain amyloidosis is by far the most common thing we see. But transthyretin amyloidosis is a close second honestly.

I think the wider the breadth of amyloid subtypes that you see, I think the wider the breadth of subspecialty care you probably need.

DR LOVE: We were talking about the real world, and I was just wondering how many patients are completely treated in the community, neve have any comment with a tertiary center? You would think that some kind of system to at least allow patients to be presented virtually might be helpful. Is there anything like that available right now?

DR ZONDER: Well, I do think that — I would say there weren’t very many good things about the COVID epidemic, but one of them was the acceptance of telemedicine as a, sort of, more standard thing to use, to utilize. And it has helped us see more patients at specialty centers who otherwise would not necessarily have made the trip.

There is still a problem doing those consultation across state lines, so it’s not — unfortunately, it’s not like everybody can go be seen at one of the 2 or 3 biggest amyloidosis centers virtually. But virtual medicine has definitely made it easier to see patients.

I don’t know the exact number of patients that are managed in the community. I think it probably varies geographically. I know in the State of Michigan, most amyloidosis patients are seen at a center with real amyloid volume. There are a few programs in the State of Michigan that see a sizeable percentage of patients. My take is that the majority of patients at least confer with physicians at those centers.

Current amyloidosis treatment paradigm

DR LOVE: You’re going to get into a lot more detail in your talk, but maybe just to briefly summarize where we are right now in terms of the treatment of AL amyloidosis.

DR ZONDER: So right now we are definitely making gains in our anti-plasma cell therapy. In my talk today, I’m going to go over some recent data that led to the first FDA approval of a regimen as initial therapy. And there are some newer drugs coming up right behind that, I think for relapse disease and maybe earlier, soon.

The result of these improvements is first, I think more people are deferring transplant. So there’s a bit less high-dose chemotherapy and autologous stem cell transplant happening. But the fact of the matter is, most patients aren’t candidates for that therapy anyhow, transplant. And so, really, also, the other main thing it’s doing is providing better outcomes, better clonal control in patients who traditionally didn’t get the same kind of clonal control that transplant patients would. And so it’s bringing the non-transplant patient’s light chain control up.

Where we’re still struggling is sort of pulling out of that spiral of organ dysfunction that is often already there at the time of diagnosis. And so, we’re still trying to make gains in reversing organ injury and arresting that. And trying to get the impact on that early cardiac risk, and also, that later renal risk that we were talking about earlier.

DR LOVE: What is the sort of clinical spectrum of responses that you see to dara/CyBorD? And in what situations, if any, do you do some type of maintenance treatment?

DR ZONDER: So, right. The regimen that you just referenced, daratumumab plus CyBorD, that’s the new FDA-approved regimen, and that was after the results of the ANDROMEDA trial, which showed that response rates were higher, but particularly complete hematologic response rates were higher adding daratumumab to the CyBorD regimen.

It also showed that organ responses, specifically heart and renal responses, were seen at a higher clip.

There was composite endpoint called multiorgan dysfunction PFS or MODPFS, which included the usual progression-free survival endpoints like hematologic progression or death from any cause, but also included some organ-specific things like the need for left ventricular assist device or a heart transplant or initiating dialysis or renal transplant. Like severe heart and kidney endpoints. Those were also included. And MODPFS endpoint was also positive, favoring the daratumumab. And between those two things, the complete hematologic response rate and that composite endpoint, that’s what led to the approval of the regimen.

So we do see the majority of patients have a hematologic response. The majority of those are complete hematologic responses. It’s definitely higher than what we saw with just CyBorD in the ANDROMEDA study and historically. And it’s our hope that down the road this will lead to long-term benefits in terms of organ function and survival. Early survival though, even with the addition of daratumumab, was not affected in this study. So that’s where we still have work to do.

DR LOVE: What about patients with Stage IIIb and IV?

DR ZONDER: Yeah, so that’s a particularly challenging subgroup. These are patients who often — they have poor prognosis based on their cardiac risk. Part of that is the cardiac damage that they’ve already sustained, but part of it is, it’s difficult for them to tolerate therapy. And so, it’s often hard to keep them on therapy in an uninterrupted way.

It has been shown that when you deliver — when you effectively deliver therapy, that it does impact prognosis. They’re still a high-risk group. But Stage IIIb patients for instance, who do have a light chain response, do better than IIIb patients who don’t. So there’s still a reason to try and get to that hematologic — that early hematologic endpoint in this group.

ANDROMEDA did not include these patients though. So we don’t have a lot of information yet about the utility or feasibility of this regime in these super-advanced cardiac patients. We’re starting now in some ongoing studies that are utilizing CyBorD with daratumumab plus other agents, we are starting to generate the data about the use of this regimen in this patient group. But ANDROMEDA did not include them.

DR LOVE: So maybe some naïve questions but role of IMiDs?

DR ZONDER: No, it’s not a naïve question. I mean IMiDs are among the most active class of agents in myeloma. And as we talked about before, we repurpose myeloma regimens. There has been work done looking at use of IMiDs as part of an upfront induction regimen. The biggest experience is a series of patients treated with RVd by the Greek Amyloidosis Group, and it was extremely hard to deliver therapy. I mean we’ve known for a while that you can’t — like lenalidomide dosing has to be significantly reduced in patients with amyloidosis compared to myeloma. The maximally tolerated dose is usually 10- to 15 mg, not the 25 that we’re used to using.

Pomalyst, or pomalidomide may be a little bit easier to tolerate. But IMiDs as a group, the difficulty is cardiac tolerance. There’s a couple of issues. We see troponin bumps or troponin leaks with this class of drugs in amyloid patients. Even in patients who are having a light chain response, we sometimes see that bump in the cardiac biomarkers.

Also, this class of drugs causes bradycardia fairly commonly. And amyloidosis patients often don’t tolerate bradycardia or tachycardia very well because of their impaired cardiac index.

DR LOVE: Do you see this outside of amyloid? Because I’m not sure I’ve heard about cardiac a fact of IMiDs.

DR ZONDER: Well, to my knowledge, not the troponin bump, but we definitely see bradycardia. A very common side effect actually. And we have an awful lot of myeloma patients on lenalidomide maintenance with resting heart rates in the high 50s, low 60s, which is not their normal heart rate. And they do fine because that’s a tolerable heart rate for somebody who doesn’t have amyloid in their heart.

DR LOVE: What about t(11;14) and venetoclax?

DR ZONDER: So venetoclax, a BCL2 inhibitor, has been shown in myeloma, in combination with dexamethasone or bortezomib, and frankly now increasingly other agents as well, including some of the newer novel drugs, has been shown to have anti-myeloma effect that is pretty much limited to patients with the t(11;14) translocation. So in myeloma, that’s a 15% subset of myeloma patients. But in amyloidosis, it’s 30- to 50% of patients. It’s a much more common translocation in amyloidosis. And so you have the potential to impact far more patients with amyloidosis because of that. And there is a growing amount of clinical experience, data, showing that venetoclax in this 11;14-posiitve amyloid subset, it definitely can have — can induce hematologic responses.

DR LOVE: And is that being looked at as single agent or combined with a PI, for example.

DR ZONDER: Both. And other combinations as well. But, yes.

I think there’s a lot of interest in looking at in combination with proteosome inhibitors, and also CD39 antibodies. Because those are really the backbone of current anti-plasma cell therapy in amyloidosis.

Monoclonal antibody therapy for patients with AL amyloidosis

DR LOVE: So let’s talk a little bit about attempts to reverse some of the underlying pathobiology here, starting out with CAEL-101. And first I want to ask why it doesn’t have a name that ends in “ab” like most monoclonal antibodies?

DR ZONDER: I think it does have one that is not in use yet, actually.

DR LOVE: I couldn’t find it.

DR ZONDER: I think it’s anselamimab, I think is the name of it.

DR LOVE: Oh yeah, you’re right. That’s right. Yeah. Yeah.

DR ZONDER: You can double-check, but I think that’s the name of it.

DR LOVE: No, you’re right. I saw that. You’re right.

DR ZONDER: Internally though, I think it’s still being referred to as CAEL-101. And it’s a monoclonal anti-fibril IgG antibody. And the mechanism of action with this is that by binding soluble oligomers and the interstitial protein deposits, it helps promote immune clearance of these deposits.

There is some data to support that it does do that. I’ll be citing some of that data in my talk. But there’s definitely, there are hints that it improves organ function. The difficulty with developing this sort of general class of therapies, whether it’s CAEL-101, whether it’s birtamimab, which is formally called NEOD001, the light chain, the free light chain assay that we use doesn’t measure what these antibodies target. These are downstream from there. And so, right now, we measure free light chains assuming that those downstream bad actors are being reduced. And there’s lots of proof — lots of supporting evidence for that.

These antibodies, like CAEL-101, targets those downstream entities. So it doesn’t have an effect on the measured free light chain levels, but it does affect — it, theoretically, will affect what is not being measured.

DR LOVE: So I know it would be a challenge just to focus on organ function since the patients are often getting other therapies, there are other things going on. Do you see, can you look at anything pathologically or any assays to actually show that these fibrils are getting eaten up or whatever happens to them?

DR ZONDER: Well, there are some like preclinical model systems that you can show that you can promote macrophage ingestion of amyloid in a dish, for instance. You can, with some fibril targeting agents, you’ve been able to show that you can improve clearance of amyloid fibrils, in mouse models, of amyloid. But the main kind of evidence we’re looking at, unfortunately, is the markers that we use to assess organ response in amyloidosis, which are very difficult to apply, quite honestly. I mean it’s a very hard business assessing like how well is the heart responding? How well is the kidney responding? Because markers like NT proBNP, markers like albuminuria, those are dynamic markers that can go up and down. And so, you can hang your hat on 1 reading. You can look at trends. I mean that functionally, we all struggle. And pharmaceutical companies trying to do trials, also struggle to apply the organ response criteria that we have in place. It’s hard. It’s a very challenging — it is a super challenging niche to develop a drug, a therapy, in.

DR LOVE: Can you kind of summarize what we know right now about CAEL-101 and these other monoclonal antibodies? And also, talk a little bit about the ongoing, I know there are a couple of Phase III trials. One of them is supposed to have 350 patients. I don’t know where you get 350 patients. It reminds me of T-cell lymphomas. But can you comment a little bit about of what we know and we’re hoping to find out with these trials?

DR ZONDER: So what we know — I’ll just focus on CAEL-101 specifically, since you asked.

What we know is that CAEL-101, when it’s given by itself, has a very tolerable safety profile. In the original Phase I studies, the Ia and Ib study, where patients received anywhere from 1 to 4 doses, there was never a dose-limiting toxicity no matter what you escalated the dose. They never hit MTD.

What we saw, even in those early studies, where relatively few patients being treated with very few doses, we actually saw evidence of improved global longitudinal strain on echo cardiograms in patients who had known heart involvement. Which, I mean, there’s not another obvious explanation for that in that study, and in fact, that change in strain was limited to patients who had cardiac involvement. If you looked at serial strain measurements in patients who weren’t suspected of having cardiac involvement, they’re global longitudinal strain was actually stable. So it seemed to be a very specific effect seen in patients with deposits that you’re hoping to target with this antibody.

And then subsequent to that work, there has been an ongoing, I guess safety run-in study, where CyBorD and CAEL-101, with or without daratumumab, were given to patients in combination, basically to prove that it was feasible to deliver all of these therapies together. And the safety profile was pretty much exactly what you would think the safety profile for CyBorD plus dara should be. There wasn’t a significant safety signal seen from adding CAEL-101 in. Now, not all the patients in that safety run-in were these Stage IIIb and IV type cardiac patients either. And, in fact, not all the patients were even newly diagnosed in those safety run-in studies.

So we’re really going to learn what we need to about this regimen from the randomized studies that you mentioned. And right now there is a pair of industry-sponsored randomized studies, one for Mayo Stage IIIa cardiac AL amyloid patients, and one for Stage IIIb patients. Two separate studies. Again, because as I mentioned, prognosis for IIIa and IIIb really is different. And so both studies have survival as a hard endpoint, a primary endpoint on the study, and you don’t need the same number of patients to prove that benefit because the risk of those groups are so different.

So they separated them into 2 distinct studies. Each study has a 2:1 randomization, which means that everybody is getting CyBorD and dara or CyBorD. There is flexibility on what the anti-plasma cell therapy is. But the CAEL-101 is, again it’s a 2:1 randomization, meaning out of every 3 patients, 2 of them are getting the CAEL and 1 is getting placebo.

DR LOVE: And I think you have a poster at the upcoming ASH meeting looking at I guess ANDROMEDA/CAEL-101?

DR ZONDER: Yeah. Well, this is the study that I was referring to. It’s the study of CyBorD with CAEL-101, or CyBorD plus dara plus CAEL-101. And basically what it shows is that there was minimum of adverse events that were attributed to the CAEL-101. It turns out that it was feasible to deliver all of these drugs together. But in the study that we’re presenting, where patients weren’t being randomized, as you can probably imagine it’s not really possible to determine what contribution CAEL-101 is making. All the study that we’re presenting shows is that it’s feasible to use without a significant increase in toxicity compared to CyBorD plus daratumumab.

DR LOVE: Do you think people are going to be able to guess which arm people are — patients are on in the randomized study?

DR ZONDER: My guess is no, honestly. As I mentioned, organ responses are more common with CyBorD plus dara than they are with older regimens like just CyBorD by itself. So you’re going to see organ responses in both arms of the study. And also, the honest truth is, the side effect profile of CAEL-101 is quite benign. And that’s actually true of the other antibody that’s in development also, birtamimab. I mean the toxicity profile, it’s amazingly benign.

And so, I don’t think they are going to be a lot of infusion reactions or anything like that, that are going to help patients figure out what they’re actually on.

DR LOVE: Are the patients in the control arm going to get CAEL-101 on progression? And is survival an endpoint in the trials?

DR ZONDER: Survival is the endpoint, the main endpoint of the trial. It’s not the only endpoint though. And because there are other endpoints besides survival, there is not going to be a crossover.

DR LOVE: This concludes our program. Special thanks to Dr Zonder, and thank you for listening. This is Dr Neil Love for Oncology Today.