MM Answers Now: Are Bispecific Antibodies the Future?

Yolanda Brunson-Sarrabo: Hello everyone. Happy Friday. My name is Yolanda Brunson-Sarrabo, and I want to thank you all for joining in today for a segment of Answers Now. Today, we are going to talk about the hot topic in the myeloma world, which is about bispecific antibodies and the treatment of multiple myeloma.

I’m joined today by one of the multiple myeloma experts in this area, Dr. Muhamed Baljevic, from Vanderbilt-Ingram Cancer Center. Dr. Baljevic. Thank you for joining today, and could you tell the audience a little bit about yourself?

Dr. Baljevic: Absolutely. Thank you very much for having me. It’s always a pleasure to connect with the group, and of course, try to do anything we can to answer questions from our patients. So I work as a myeloma specialist at Vanderbilt University Medical Center. I lead our multiple myeloma and amyloidosis programs, and I have specific research interests in plasma cell malignancies. And it’s my pleasure collaborating with colleagues around the country, working on different areas of improvement for treatment options, as well as supportive care options for our myeloma as well as amyloidosis patients.

Yolanda Brunson-Sarrabo: Dr. Baljevic. Okay. This program has proven very timely. Because many in the myeloma world know that, just last week, the FDA has granted accelerated approval to the first bispecific antibody treatment. That’s big news for a lot of patients. So I think that’s a good place to start in terms of explaining, a little bit, what is a bispecific antibody and how it works.

Dr. Baljevic: Yes, absolutely. I agree. It’s very exciting times. And we are very pleased that these powerful and really, important treatment options are coming to the treatment armamentarium for myeloma with increasing speed. When you think about some of the latest immune therapies over the last – just over two years, we’ve had a number of important agents approved for the treatment of relapsed/refractory myeloma, whose job is targeting this BCMA molecule or B cell maturation antigen.

So starting back in August 2020, we had Blenrep, or belantamab mafodotin, which is an antibody-drug conjugate, so slightly different than a bispecific antibody. And then in March 2021, we had our first CAR T-cell drug approved, the abecma, or ide-cel. And then in February, ’22, a year later, we had the second autologous CAR T-cell therapy approved, Carvykti, or cilta-cel. And then as you just mentioned, just last week – this month, in October of this year, we had, for the very first time, the approval of a bispecific antibody. And all four agents are targeting this BCMA molecule or BCMA protein on the surface of myeloma cells.

So what is a bispecific antibody? They’re grouped in a group of these agents that are called BiTEs. And depending on the structure and the design of the protein that’s performing the function – in this case, we have an example of a bispecific antibody. So there’s an antibody molecule that has the ability to bring together – on one side – a CD3-positive T cell. This is an active cytotoxic immune cell whose job is, normally, to attack invaders of our immune system in our body.

And on the other arm of the antibody, there’s a specific portion that is actually supposed to attach to the BCMA molecule on a myeloma cell. So by bringing them together, there’s an activation of a T cell that’s achieved through that arm that attaches to the T cell, and then the killing of that T cell is directed towards the BCMA-positive multiple myeloma cell, and of course, the tumor-killing is accomplished in that way.

So this is a first-time approval of a bispecific antibody in multiple myeloma in general. And as I mentioned earlier, it just so happens to be actually, the fourth drug, in just over two years in multiple myeloma that is approved for the treatment of patients with BCMA targeting.

Yolanda Brunson-Sarrabo: Right. So – which, again, is remarkable. I mean when I started my journey over 10 years ago, I didn’t see all of this happening. So this is very appreciated in terms of what the future is. Hopefully, they can just wipe this out completely. So, just in layman’s terms, can you tell us what is exactly a BCMA?

Dr. Baljevic: Absolutely, yes. As we mentioned earlier – so BCMA stands for B cell maturation antigen. This is a protein that’s expressed on the surface of the late-stage B cells. These are sort of mature, differentiated plasma cells. There’s a minimal expression of this protein on other blood cells, like hematopoietic cells or non-hematopoietic tissues. This basically means other tissues around the body, so in other organs. That’s important because that allows the drug to minimize the so-called off-target effect, right? So for the drug to go and attach itself or target other tissues and other organs in our body, so that’s important. We think that BCMA plays a role in the survival of plasma cells, and in growth, also, of plasma cells. And also, the survival and growth of these long-lived plasma cells, that we think are important in the maintenance of the disease and the creation of disease tumor burden. They were also previously associated with drug resistance.

So, over time, BCMA ended up surfacing as a really important and applicable target on plasma cells, for the researchers and physicians to try to think about targeting in various different ways. And some of those drugs that we mentioned earlier are actually exploiting the power of the immune system and targeting the BCMA molecule in various different ways. Belantamab mafodotin, or blenrep, is targeting it as an antibody-drug conjugate, with a toxic payload that’s attached to the antibody. So, once the antibody gets through BCMA, that payload is delivered into the myeloma cell, and then the killing happens.

The two autologous CAR T-cells that were approved, basically, are therapies where we take a patient’s immune cells, and we send them to school. And we teach them how to recognize BCMA by actually inserting the genes that are then expressed on the surface of these CAR-Ts, so that they are primed to recognize the BCMA expression on the myeloma cells, on the myeloma surface. And then as they recognize them, they literally attach to them and then kill them directly after the contact.

And then lastly, we just mentioned teclistamab or Tecvayli. So this is now an antibody molecule that usually has – it’s a Y-shaped protein structure – that on one side, is going to attach to a CD3 molecule on T cells. On the other side, it’s going to attach to BCMA molecule myeloma cells. It’s going to bring them together and then cause them to interact. And importantly, here, because the T cells actually do the T cell-directed killing of the tumor cell.

Yolanda Brunson-Sarrabo: Fascinating. It really is. The more that I hear how this is explained, the complexity of our bodies is just amazing.

Dr. Baljevic: It is.

Yolanda Brunson-Sarrabo: So with this particular bispecific antibody treatment, where would this fit in with a person’s treatment sequence?

Dr. Baljevic: Yes, that’s a very important question for us. And it’s necessary to point out that all four of these agents that we mentioned are, in fact, approved in the same exact space, and carry the same exact label, which is, after four previous lines of treatment. So that goes for teclistamab as well, that was just freshly approved last week. So patients can get it as a fifth-line treatment.

Now, this is an important point as well. What is considered a line of treatment? So, oftentimes that’s a point of contention and misunderstanding even among physicians, and sometimes even among those that actually treat myeloma patients in the community. Lines of treatment can be considered slightly differently. So, in the beginning, if you get a combination of medicines, like VRd, for example, or even these days, theraVRd, or some sort of quadruplet, and then you get a transplant and you go on maintenance. All of that is considered one line of therapy. And then, once the disease gets worse and you switch treatment, then that’s your second line. And once treatment stops working and the patient stops responding, you have to get the third treatment. That’s your third line, et cetera.

So technically, slightly different depending on the situation where you are. I mean, if patients get a second transplant – so, after they get a second transplant – after the treatment that they got to get better. In order to get a second transplant, and then be on maintenance after the second transplant, that too is also considered all one line of therapy.

So this is, of course, in the relapsed/refractory space for previously-treated myeloma. None of these drugs are approved yet for newly diagnosed myeloma. But it’s also important to mention that they’re being explored, actually, in newly diagnosed settings. So, for example, among the CAR T-cells that we have available, there are studies that are actually exploring, including CAR T-cell treatment, in the context of the entire first line of treatment for high-risk patients – the CARTITUDE-5 study, for example, with Carvykti, or KarMMa-4 with abecma. They are looking at incorporating CAR T treatment within the first line.

So that’s important. Because we’re going to increasingly start learning about if there’s any difference in terms of how successfully it can work, and how long it can last, depending on if you give it as a fifth treatment versus if you give it as a part of the first treatment that patients will get. And of course, anywhere in between, there are also studies that are looking at these agents in the second line or third line, et cetera.

Over time, we’re going to learn more and more. And, over time, I do expect that these agents – particularly, an agent like teclistamab, right, which is a bispecific antibody that is more optimized for outpatient use and for community use. That they are going to be increasingly studied and they will hopefully come for availability for myeloma patients in earlier lines, not just where they’re available right now, which is a fifth treatment.

Yolanda Brunson-Sarrabo: Okay. So, you somewhat spoke about this. But I guess, maybe to clarify. Which multiple myeloma patient would have this conversation with their doctor in terms of this bispecific?

Dr. Baljevic: That’s a very good- Yolanda Brunson-Sarrabo: Let’s think about it – but yeah.

Dr. Baljevic: No, absolutely. That’s a good question. Because not too long ago, we didn’t have any of these BCMA-targeting drugs, and now we have four.

Yolanda Brunson-Sarrabo: Mm-hmm (affirmative).

Dr. Baljevic: And initially, it was “Well, okay. We have one, and we’re going to use it.” And then we got a second, and then the question, “Well, which one would you use first?” And then we got a third. Now we have four. So the question becomes even more complex. Which among these four are you going to use first for your patients, right?

So it’s important to – and you’re asking specifically about teclistamab. So, again, these three are slightly different. Maybe we can group them, on one side, the CAR-Ts. Which are drugs that are requiring synthesis. Requiring generations. So we have to take the immune cells from patients. Generate them. That takes a couple of weeks. And then, when we have them, then they can go on and get infused into patients. Versus a drug like Blenrep, or, at this point importantly, teclistamab. These are off-the-shelf available drugs for use as we need them, so there’s no delay, there’s no generation time. These are already prepared, generated, and synthesized treatments.

And in the example of Tecvayli or teclistamab, this is an antibody. So this is actually a subcutaneous drug, that initially was tested as an infusion. But Janssen, which is the sponsor and the manufacturer of this drug, rapidly developed a subcutaneous version, as they do for most of their drugs, and it’s given under the skin.

Yolanda Brunson-Sarrabo: Mm-hmm (affirmative).

Dr. Baljevic: When it comes to, when would you have a discussion with your doctor about when you should get it? That’s an important question because, in terms of CAR T therapies, you really have to start thinking about them ahead of time, a little bit, and who is a proper candidate because of that lag in the time necessary in order to take the patient’s cells, send them to school, teach them, engineer them and then get them back. Multiply them, right? And get them back and infuse them into patients.

But teclistamab is already available. You don’t need to spend any time creating it. So this is a so-called off-the-shelf drug. Technically, physicians and patients can be thinking about and asking their doctors, when are we going to use this drug? And the reality is, this drug can only be used according to its label at this point in time, which is in the fifth line. So when patients have received enough treatments – and it’s important also to note that those treatments must have included at least one proteasome inhibitor, like bortezomib (Velcade), or carfilzomib (Kyprolis), or ixazomib (Ninlaro). And then one immunomodulatory drug, like lenalidomide (Revlimid) or pomalidomide (Pomalyst). And then one CD38-targeting antibody, like daratumumab (Darzalex), or isatuximab (Sarclisa) these days as well.

So those are requirements, really, that are in the label. So technically, physicians and patients alike can start thinking about what would be that time when we can actually start incorporating teclistamab as the next line. And at this point, that would be just a fifth treatment. So after four previous treatments, if you wish, you could technically speak and use teclistamab as the next treatment.

Yolanda Brunson-Sarrabo: Okay.

So we have an audience question. If you have a bispecific treatment, what exactly does that look like?

Dr. Baljevic: So, a lot of the centers around the country are going to start getting organized and certified in order to be able to deliver this therapy. At this point in time, what that would mean is the centers will be planning to deliver the initial so-called step-up dosings of teclistamab, which again is an under-the-skin drug. So this is a shot under the skin. The dose would be given on day one, and day four, and day seven. Day one and four dosings are considered step-up dosing. Day seven dose is the first treatment dose. And then after that, the drug will be given once a week at the preset dose of 1.5 milligrams per kilogram.

It’s important to note that so far, the studies that were done with teclistamab were admitting patients into the hospital, for these initial doses and ramp-up dosing, to get them to that full dose they would be receiving. So, by day seven, they’re going to be getting the full dose that they would be getting once a week, so 1.5 milligrams per kilogram. It’s also important to point out that per label, there is actually a recommendation to try to hospitalize.

The label is clear: where they say patients should be hospitalized for about 48 hours after administration of all doses within the teclistamab step-up dosing schedule. The step-up dosing schedule, as we mentioned, is a dose one on day one, and dose two on day four. And then, day seven dosing, which is the first time you’re using the full dose that the patients will be getting once a week.

So, a lot of places will be getting organized and ready to plan rolling out. But there’s really an expectation that this drug would be delivered in the in-patient setting initially. And then hopefully, if patients don’t develop a CRS complication with this drug, and those that do after it’s sorted and managed, then the expectation is that they would hopefully be able to continue in the outpatient setting, receiving the remainder of the doses of the teclistamab drug.

Yolanda Brunson-Sarrabo: Okay. So, just as you mentioned, if you’re saying that this is an in-patient experience, we figure that there’s a lot of toxicity happening in terms of all of these drugs, and to see, for each person’s individual experience how they’re going to react to it.

Dr. Baljevic: Mm-hmm (affirmative).

Yolanda Brunson-Sarrabo: With all of these treatments that we have, as many of us know, there are a lot of side effects. So what are the most common side effects of bispecific therapy?

Dr. Baljevic: Yes. It’s important to go over those. Some of the major side effects of these immunotherapy treatments actually belong to the category of so-called CRS complications, or cytokine-release syndromes, as well as neurotoxicity or ICAN complications. Immune effector side effects from the actual immune cells.

So when it comes to CRS, that’s basically a situation where we are hyperactivating the immune system as a result of the presence of these effective engagers of the immune cells. And CRS is something that can start, even with a fever, with a shortness of breath, with a change in the blood pressure. And it’s something that is serious, that needs to be recognized quickly, and it needs to also be treated quickly. So when it comes to the MajesTEC-1 study, that ended up being the study which launched the teclistamab drug; the median time to onset or start of the CRS problem was two days, and the median duration of that CRS was also about two days, with some range of variation within those numbers.

And the treatment of CRS complications is absolutely necessary. Timely treatments. So patients get these medicines that include antibodies that suppress the chemicals that are secreted as a part of the CRS syndrome, and medicines include tocilizumab (Actemra). Supportive care measures are given, like oxygen, steroids can sometimes be given, and even blood pressure medicines that support adequate blood pressure in patients.

There are also some neurologic symptoms that can develop. The good news is that the vast majority of those, as well as almost all of the cytokine release syndromes, were all lower grades of grades I and II for neurotoxicity problems. There was only one patient who was noted to have a grade III, with resolution. And neurotoxicity, like cytokine release syndrome, is also treated. It needs to be recognized quickly and treated adequately. The median time of the start of these neurotoxicity symptoms was a little bit longer, three days, and the median duration was also slightly longer, about seven days when it comes to teclistamab. So that’s one group of side effects.

And also, another group that’s really important to mention is infection episodes, which happen in about three-quarters of patients. And also, the so-called hypogammaglobulinemia – which is a mouthful – basically means reduced IgG levels in your bloodstream. And IgG is the most abundant immunoglobulin that helps defend us from infections, so reduced IgG levels predispose patients to catch infections.

So the study that initially looked at the development of teclistamab, then led to the approval of the teclistamab, noted some infectious episodes, including viral episodes, including some COVID-19 infections, in fact, and some pneumonia and those are the major side effects to keep in mind. And, as we said, some of these are really early, and you want to catch them and treat them when they happen. And the good news is, they don’t tend to recur. Once you treat them and manage them, then you have to worry more about the infectious episodes and infectious complications that patients would be at risk for.

Yolanda Brunson-Sarrabo: Okay. Based on what you said, okay, there’s a lot in terms of the bispecific therapy, along with what other lines of medication that you’re doing. So, from a patient’s point of view, what is their bounce back to go back to their life, in terms of “I’m in treatment?” For me, if I had my Velcade and [inaudible 00:23:44], I do that one day. And then, in a couple of hours, I’m feeling okay and then I can go about my business. So what is the “bounce back” in terms of this therapy?

Dr. Baljevic: That’s a very good and important question. As we mentioned earlier, there are some ramp-up dosings, right, with teclistamab. Now, first of all, it’s a subcutaneous drug, so that’s great. It’s more convenient, especially when you come later to administration times. It’s not infusional. it’s not IV. And the patients usually like that because it takes a shorter time. And actually, also, if you look at the experiences, for example, even with daratumumab, which is a common antibody that patients get. The previous studies looked at this and demonstrated that there’s about a 50% safer way to give daratumumab from infusion reactions, when you give it under the skin, versus if it’s given as an infusion.

Teclistamab is already approved as a subcutaneous drug, so we are already there. However, as we mentioned, per the label, there’s a recommendation now to admit patients for 48 hours after each – those in the ramp-up schedule, so we’ll see. It’s going to be really interesting how different centers are going to be dealing with this. I can tell you, in studies, patients were admitted for these initial doses, and they were monitored, and then a lot of them did develop CRS, which was treated. And then, when it was done and handled, later on, the rest of the administrations did transition into an outpatient setting.

So, in terms of when can people go back to their lives, there’s probably a reasonable expectation that some of these early days are going to have to be, probably, in the vast majority of places, part of the in-hospital experience, I can tell you, at Vanderbilt, we have developed experience and expertise in delivering CAR T therapy as an outpatient, where we follow patients very closely with various devices that monitor the vitals. And we have demonstrated the safety and visibility of this type of approach, even in CAR T-cell therapy.

It’s going to be interesting to see how many places get REM-certified, right? Because getting teclistamab is going to have to be a part of the REM-certified institutions, which are basically, institutions that have experience and expertise and have these medicines and formulary, and pharmacy, and other supportive care measures that are needed for patients if they develop these side effects like CRS and neurotoxicity. It’s going to be interesting to see if everybody is going to be admitting patients, essentially, for almost nine days, right?

Yolanda Brunson-Sarrabo: Mm-hmm (affirmative).

Dr. Baljevic: So, as we said, the dosing is on days one, four, and seven. And if you do the math, right – 48 hours of admission after each dosing – brings you to about nine days or so. Or if people will be developing ways to keep the patients safe and maybe even monitored in the outpatient setting, it remains to be determined.

Yolanda Brunson-Sarrabo: Okay.

Dr. Baljevic: But subsequent dosings are expected to be in the clinic, certainly, so that’s in an outpatient setting. That’s a big difference, right, as well, when you consider treatments like CAR T-cells because you asked when can people go back to life. Well, getting CAR T-cells is a little bit like getting an autologous transplant, which many patients get. You have to get some chemo beforehand, and you get your cells. and then there’s a protected period of counter-recovery and monitoring, et cetera. Whereas – and then you’re “one and done,” right? You just got your infusion and then you’re observed.

And it’s important to point out there that people have usually not been on any maintenance, right, so they’ve been therapy-free. And depending on how they did, they could have had many months, sometimes 12-plus months, of response and a treatment-free period, which some people like. When it comes to these bispecifics, they are developed to be dosed continuously.

Yolanda Brunson-Sarrabo: Mm-hmm (affirmative).

Dr. Baljevic: So that’s a big difference. People will be needing to come to infusions and get their drugs. And all of our drugs that are approved in the relapsed/refractory space are given in a way where you’re continue giving the drug as long as you’re getting a response. And even when you get a deep response, you still continue giving it, trying to prevent disease relapse. So we know that patients – if you look at the teclistamab study, patients that were treated in that study actually had a median of prior five lines of therapy. Some had as high as 10-plus, even 14.

So these people were patients that were very difficult to treat that have progressed on other multiple treatment options. And the intention there is to continue treating for as long as you’re responding, as long as you don’t have any toxicities and any prohibiting factors from making doctors stop the treatment. Because the idea is – and this is a general principle in myeloma treatment – that you are continuing to suppress these clones that would otherwise resurface and bring the disease back again.

Yolanda Brunson-Sarrabo: Right. Interesting.

So we have a slew of audience questions. One question which is very interesting is, after five or more lines of treatment, will a myeloma patient still have enough healthy T cells for the BiTEs to be affected?

Dr. Baljevic: That is a fabulous question, right? Why? Because how does teclistamab work? As we said, it’s an antibody that brings the immune cell on one side, and the myeloma cell on the other side. It brings them together so that the immune T cell can kill them. So, therefore, teclistamab is hoping and counting on a healthy T-cell repertoire in our bodies, so that they can do a good job, or as good a job as possible. There are going to be an increasing number of correlative studies trying to answer some of those questions. But the expectation is that, after you get a bunch of different treatments, your immunity, and maybe, your T-cell health is probably not as good as it might be if you did not get as many therapies. But frankly, that still remains to be definitively proven.

We certainly see that in these situations, or even as I mentioned, the median number of previous treatments for the teclistamab trial was five, so that’s a lot of treatments. People had a lot of standard drugs. They went through them. And still, teclistamab performed excellently. And we can touch on some of that if anybody had a question about how well these things are working. That would be an interesting thing to go over briefly as well. But the reality is, T-cell health is an important aspect, and that’s an important question.

One more thing I will mention is, it’s going to be an interesting area of study for us to find if there’s anything that we can do to maybe contribute to T-cell health. And to help improve the T-cell health, maybe even concurrently, with the administration of teclistamab, such that we’re continuously helping to maintain the healthy T cells and improve their availability. For example, certain drugs – this is a very preliminary study – but certain drugs have been associated with an improvement in the availability and survival of these healthy T cells in patients with myeloma. So the idea is then well, can you combine some of those drugs with drugs like teclistamab together, so that you can work actively on continuously improving the T-cell health for the teclistamab to work even better?

Yolanda Brunson-Sarrabo: Okay.

I want to go back, briefly, for a second now. Now that CAR T has been approved for two years now, there have been some concerns about accessing that treatment. So, do bi-specific antibody treatments replace a CAR T-cell treatment? What are the advantages, briefly, between the two?

Dr. Baljevic: Exactly. So that goes into a question of how are we going to sequence these things. And just because we have BiTEs now, these bispecific antibodies, what should we do? Shall they completely replace our consideration in our patients, and be given preferentially over CAR T- cells? What should we do with the drug like belantamab, right, Blenrep? Should we be thinking about using it at all, and what’s the best way forward? That’s a complex question, an important question. And the short answer is, we don’t have an ideal answer right now. But the truth is, probably, that not every single patient is going to be an ideal candidate for all of these drugs at the same time, right? So remember, earlier, we lumped them into two buckets. One is the CAR T-cells – autologous CAR T-cells – let’s point that out. That means the patients themselves need to go for training, for amplification, and then they need to come back for infusion.

So that’s associated with some time delay, right? Versus these off-the-shelf available drugs like teclistamab, like Blenrep. So, a big difference. If you want to use CAR T-cells, you can’t do it immediately. You have to wait until you generate it. Versus if you want to use Blenrep or teclistamab, you can do it immediately because it’s available. So if you are dealing with a situation where myeloma is advancing rapidly, where patients are rapidly losing fitness and having compromised organ functions, the reality is that patient’s probably not going to be the best candidate for CAR T-cell. And that patient, I would preferentially give teclistamab, which is a very powerful bispecific antibody that can give us a somewhat comparable efficacy. If we are dealing with situations where the disease burden is worse, but not rapidly escalating, and there’s access – you brought up another important point in that question – the key question is access.

So for CAR T-cells, you need to have the ability for the company to generate the CAR T-cells. There have been some difficulties in recent times with the vector. This is the viral component that is used in the education, basically, of T cells for the generation of CAR-Ts. So some of those shortages and availabilities have put a limit on how many CAR T-cells you can generate, really. And the centers that are even onboarded and have the capacity to give CAR T-cell standard of care, they don’t have the capability of giving dozens of these every month. They have a limited number of treatment slots that they can give, and they have to select what are the best patients for them.

So it’s a more complicated question and complex question, trying to understand, how are they all working? Are they comparable? Is there one better than the other? But the reality is, many different things are going to have to be considered when figuring out which one of these medicines should be preferentially considered for our patients. Even distance from a referring center to the, let’s say, CAR T center can sometimes be a consideration. Comorbidities, right? Patients that have central nervous system disease, they’re really at risk to be receiving these types of medications. And in fact, the studies have usually tended to not include them, for example, for CAR T-cells, just because of the danger of side effect development. So a lot is still left to be learned in terms of figuring out what’s the best decision at every single point for any given patient.

Yolanda Brunson-Sarrabo: Okay. We have another audience question, which is a good one. If you have one of these four treatments that are all targeting the BCMA, would there be any benefit to having one of the others at relapse? Or does relapse mean that the other drugs with this target won’t have any effect?

Dr. Baljevic: Excellent. I was waiting for that question. And that’s everybody’s question among the physicians too, right? As I mentioned earlier, there was one at one point, so that’s the only one available, so you’re going to try to use it if you can. But then, two years, this coming March, it’s going to be basically, two years since we had the first CAR T approved. And already, this past August, was two years since we had the first BCMA drug approved, Blenrep. So what I can say is, at this point in time, we actually have some important insights and findings, especially among these bispecific drugs.

__So we’re talking about teclistamab because that’s the first bispecific that just got approved. But it’s not the only bispecific, and it’s not the only bispecific that’s targeting BCMA. There are other bispecific drugs that are also in development. For example, [inaudible 00:__37:05] from a different company. It’s also targeting BCMA and [inaudible 00:37:11] as well as teclistamab have data where they have looked at how well can these bispecific antibodies work in patients who have previously had some sort of bispecific, or rather, who have previously had some form of BCMA therapy. In previous times, that tended to be either patients who got a CAR T, that’s targeting BCMA, or an ADC, a drug like belantamab (Blenrep), that targeted BCMA.

The important insights, for example, from the teclistamab study were that patients who were previously treated either with ADCs – a drug like Blenrep, for example – so they’re ADC- exposed. Versus CAR T-exposed – BCMA CAR T-treated – they actually still worked. The overall response rate in those patients was about 50 to 55%. So that’s really important. That’s an excellent indicator. And then if you actually combined the analysis into those that were either treated with CAR T or ADC, the response was still in the 50s. And there were some deep responses actually. Most of those responses were, in fact, VGPR or better. So that gave us confidence that if for some reason, patients were treated with CAR T, or Blenrep, or ADC drugs, they can still actually probably derive benefit from getting treatment with a bispecific antibody like teclistamab.

And then, as I mentioned earlier, a drug like alrenactomab is also a medicine that has been tested in patients that were previously treated with some sort of BCMA treatment. And in this bispecific therapy as well, we were able to see an activity signal in patients who were previously treated with BCMA agents. So, at least so far, in two different bispecifics, we know that they can actually work after previous exposure to other things. We still have to learn a lot more, right? How do CAR T-cells work after you give them a bispecific? Well, previously, that wasn’t a common situation because these bispecifics were only part of clinical trials.

Now, as we have one available, they’re going to be treated more and more standard of care, and we’re going to be creating situations where maybe some patients would’ve gotten the bispecific first, and then maybe, a CAR T later, or an ADC later. And then we’ll be able to have a chance to learn what is the response like if the bispecific is first, for example, and not CAR T-cell or ADC.

And another important point is also that BCMA is not the only target that’s being developed by these various CAR T-cells or ADCs, and also, especially, bispecific antibodies. There are also targets such as GPRC5D, so we had a recent report on CAR T-cells that are targeting GPRC5D. We also have multiple antibodies that are actually bispecific antibodies, that are targeting GPRC5D, and there are also targets like FCRH5.

So we are increasingly developing these bispecific antibodies that can actually target things other than BCMA. So, hopefully, if those drugs survive, and are safe and efficacious, and if and when they come to market and are available as standard of care, then the question would also not necessarily only be “Well, can I use some of these other BCMA drugs?” It would be “Well, let’s use a different drug with a different target.” And then the question will be “Well, should we be using a BCMA target first, or a GPRC5D first, or an FCRH5 first?” It’s going to get even more complex.

And this goes back to what I was saying earlier. We are increasingly advancing these powerful drugs earlier in the lines of treatment, and we are rapidly generating patient groups for which we don’t know what the best thing is to do right now. The good news is we have multiple potent drugs. And the idea is to try to expose them to different mechanisms of action and different targeting medicines, compared to what they have previously seen. So, at least, you have hope that with a different agent, a different target, and a different mechanism, the response chance would be higher that way.

Yolanda Brunson-Sarrabo: Right. It’s a new day. It really is. I’m excited. I hope a lot of the patients out here are excited. I know, again, it’s a new day from 10 years ago when I started – over 10 years ago, actually, some years in.

But, as we close, I wanted to ask you. What can you tell someone who is newly diagnosed today that you couldn’t have told them 10 years ago, as I just said?

Dr. Baljevic: Yeah. That’s a good question. And let me put that in the perspective of how far we’ve come, okay?

So, our audience and our wonderful patients will recognize some of these medicines, right? So thalidomide is perhaps not the most common immunomodulatory drug that we use. We use lenalidomide a little more. But thalidomide is used in Europe and Asia. Lenalidomide is not equally available everywhere in all corners of the world. But if you look at, for example, thalidomide or even lenalidomide, the success rate of single agents – when these drugs were developed – as a single drug given to patients, the overall response rate was 25% for both thalidomide and lenalidomide. And then pomalidomide, right, is their cousin – a newer drug – the overall response rate in single agent pomalidomide was 18%. So those are some of our agents. Let’s talk about some of the protease inhibitors. Everybody recalls bortezomib, right? We give it under the skin.

So the bortezomib drug, when it was developed, as a single agent, the overall response rate was 35%, right? Kyprolis, or carfilzomib, that’s a cousin. A newer-generation protease inhibitor, IV. The overall response rate was 24% when it was developed. So then we come to Darzalex, right, daratumumab, one of our early blockbuster drugs. One of the earliest immune drugs that were developed for myeloma patients. The single agent in response to daratumumab was about 31%.

And then the drug like selinexor (Xpovio), for example, came. An oral medicine. And selinexor was initially tested in a really difficult-to-treat patient population, pentarefractory. So that means two PIs, two [inaudible 00:43:50], and one CD38 antibody. So the overall response rate of selinexor was 26%.

And then, lastly, one of these drugs – immune drugs – belantamab, or Blenrep, was approved in August 2020, that was also tested in difficult-to-treat patient groups, and the overall response of Blenrep was also 32%. So that’s the baseline. That’s the benchmark that we have established over the last few decades, right?

And now, where are we? We are in the unprecedented era of immunotherapies, including CAR T-cells and bispecific antibodies. So where have we come now? We’ve come to the point where the overall response rates of CAR T-cells are not in the 20s and 30s and 40s. They are in the 80 to 90% range, right? And when you look at the bispecific antibodies, the response rates are in the high 60s to 70s, even for some of them, 80s. And keep in mind, those response rates are in even tougher patient populations than were used for the development of these earlier drugs. So when Darzalex was developed, we weren’t developing Darzalex in pentarefractory patients. We were developing it in patients that were less exposed to a lesser amount of drugs.

So we are in an incredible time for multiple myeloma. You can even say the future is “BCMA-bright,” right?

Yolanda Brunson-Sarrabo: Mm-hmm (affirmative).

Dr. Baljevic: There are so many BCMA drugs. But I would argue, the future is “immunotherapy bright” rather than just BCMA. Because, as we mentioned, there are drugs targeting other proteins on the surface of myeloma cells other than BCMA, like GPRC5D, FCRH5, and even other medicines, a newer generation of immunomodulatory drugs, these [inaudible 00:45:42]. You have molecular inhibitors. The Bcl-2 inhibitors had an early snag in development. But we’re increasingly developing them in targeted patient populations, which have 11;14 translocations, or Bcl-2 overexpression, because we know that they’re preferentially going to respond better to these molecular inhibitors, and the safety profile was better there from the earlier trials that were done. So we’re working on developing the first molecularly-targeted therapies in myeloma as well.

And lastly, we are at a point where we have learned that quadruplets are perhaps better than triplets at the beginning, right? So we’re giving patients maybe four-drug combinations at the beginning, with all three mechanisms: immunomodulatory drugs, protease inhibitors, and antibodies to CD38. So, after one line of therapy, when patients get worse, they will be technically considered refractory to these three groups of drugs.

So these BiTEs and these CAR T-cells are really ushering in a new era. They’re giving new hope to our patients. Patients need to be informed about them. They need to talk to their physicians about them. They need to ask them. And they need to start talking early; not waiting until the disease starts progressing rapidly so that the time is not available for us to consider some of these powerful options.

Yolanda Brunson-Sarrabo: Wonderful. This was such a wonderful conversation. I hope everybody was able to absorb everything that was said today. We want to thank you, again, for our special guest, Dr. Baljevic. What a wonderful conversation. Thanks for joining us today. And remember, knowledge is the key and the best medicine of all.