ONCAlert | Upfront Therapy for mRCC

Types of BCMA-Directed Therapies in Relapsed and Refractory Multiple Myeloma

Targeted Oncology
Published Online:1:00 PM, Fri January 24, 2020

Nikhil C. Munshi, MD: Certainly, if we talk about BCMA-targeting ADC [antibody-drug conjugate]….

Parameswaran Hari, MD, MRCP: Belantamab.

Nikhil C. Munshi, MD: Belantamab. It’s one of the classes of drugs that we have evaluated in other settings before—CD19, CD56-targeted ADC, etcetera. This one is especially important for us because it targets BCMA, so there’s less risk. There’s great excitement about the drug because efficacy is very high.

Parameswaran Hari, MD, MRCP: Yeah.

Nikhil C. Munshi, MD: Do you want to discuss the efficacy and maybe say something about the toxicity that we should be looking after or taking care of?

Parameswaran Hari, MD, MRCP: In this context, too, we should talk about efficacy and toxicity and the risk balance, as you say. The unique toxicity of this drug that we have not seen with prior myeloma drugs is something called keratopathy, which is corneal damage that, thankfully, does not seem to be permanent damage. But a specific proportion of patients who are exposed to this drug developed dry eyes and deposition of the toxin in the cornea that leads to itching, and visual loss, and visual blurring, and, in extreme cases—a minority of cases, though—corneal laceration. It is thought that the cells that are taking up this toxin might wait and then get sloughed off in the normal process, and then the patient recovers if you hold the drug. This has led to some holds of this drug when you’re treating patients with this. And I’m sure that we will mitigate this as we go along and use risk-benefit discussions with patients who use this drug. But it is a toxicity that we, as physicians, should be aware of.

Nikhil C. Munshi, MD: The efficacy is quite encouraging.

Parameswaran Hari, MD, MRCP: Of course. Again, you have worked with this drug. It works in people who are refractory to the major 3 classes.

Nikhil C. Munshi, MD: Triple refractory…

Parameswaran Hari, MD, MRCP: Yes.

Nikhil C. Munshi, MD: And the response ends up being around 60% or higher.

Parameswaran Hari, MD, MRCP: Yeah.

Nikhil C. Munshi, MD: So that drug has great promise. The second class of drugs would be the T-cell engagers. There’s a lot of discussion about more than 1 different T-cell engager. Would you like to explain the concept of T-cell engagers and how they function? And what is your opinion on the 2 T-cell engagers that have gone to clinic so far?

Parameswaran Hari, MD, MRCP: Yes. Actually, this is a class of drugs that is used in other hematological malignancies. There is a drug that’s approved, called blinatumomab, against CD19 in pediatric leukemia, and another one called inotuzumab works against CD22. The concept, again, is to make a small antibody that has binding specificity towards CD3 on one end, which is a surface molecule on T-cells. And on the other end, it binds to a target that you wish to direct these T-cells toward, which, in this case, is BCMA.

So this antibody, when infused or injected into the patient, coats the surface of the plasma cells and brings T cells into contact with them. This creates an artificial, what they call an immunological synapse, which leads to the T cell killing the plasma cells or its target in other cases. But what do you think? Do you really think that this mechanism can also cause cytokine release syndrome or can sometimes lead to immunological memory because it recruits other T cells?

Nikhil C. Munshi, MD: Yeah, I think it’s a good immunological approach. It recruits the T cells to do the function we would like it to do, but it will bring about, or it does bring about, the same adverse effect profile that we would see with CAR T-cell type of approaches that we will talk about in a minute. It probably does not have neurotoxicity. There are 2 drugs in the market, and 1 was actually evaluated. It’s a drug called AMG 420. It was one of the first BCMA-targeting engagers that showed efficacy, and that was very important news for all of us—that these T-cell engagers do work. The concern was that myeloma is an immunosuppressed disease. Would the T-cell engager be good enough to bring those not functioning T cells? That was saddled by that drug. The problem with AMG 420 was that it is not easy to administer—to give continuous infusion for days and repeat it.

Parameswaran Hari, MD, MRCP: Yeah, very cumbersome.

Nikhil C. Munshi, MD: Very cumbersome. But I think it established the principle. And then we have a next-generation AMG molecule, ABP 710, that can be given quickly. It’s a short infusion time, and at least in a preclinical model, it looks very attractive.

Parameswaran Hari, MD, MRCP: Exactly. We don’t have an update on that yet at this meeting, but it’s based off AMG 420. I think that suggests that this molecule is probably going to be very active.

Nikhil C. Munshi, MD: But then there was a second, similar compound that does not have a name yet either, but it comes from…

Parameswaran Hari, MD, MRCP: It’s called CC28396.

Nikhil C. Munshi, MD: Yeah. And so that has clinical results now available to early stage, right?

Parameswaran Hari, MD, MRCP: At this meeting, both of us heard these results that are, I would say, very promising. At least the patients treated at goal dose in a phase I study, which was about 6 mg or higher, almost 100%, actually 89% of these patients ended up having a response.

Nikhil C. Munshi, MD: I think it was quite well tolerated. Some patients did require tocilizumab. But it was efficacious, and at the same time, toxicities were quite manageable. It’s quite exciting. And then the third compound to the BCMA-directed treatment, which probably is the most exciting compound, and, so far, with vast experience, is CAR T-cell therapy.

Parameswaran Hari, MD, MRCP: Absolutely.

Nikhil C. Munshi, MD: CAR T cells stands for “chimeric antigen receptor–expressing T cells,” and the concept is very simple. The T cells are genetically modified. They express, on their surface, an antibodylike molecule. So now the T cell will be able to target or recognize a tumor cell and bind to it. And then that same molecule has a tail inside the cell that makes a T cell get activated. So it functions better and starts proliferating. This is how CAR T cells work. But there are some different varieties of CAR T cells—the CAR T-cell variety with single epitope–targeting T cells and dual-epitope targeting. And the bb2121 is a single epitope–targeting CAR T cell, but the JNJ molecule is dual targeting. It targets BCMA, but on the 2 different load sizes, and might have a different thing. What do you think about these CAR T cells, in general? We’ll go into more detail on each of them, and JNJ in a minute. But in general, what’s your feeling about all of the enthusiasm with CAR T cells?

Parameswaran Hari, MD, MRCP: I think I am as excited as you and everyone else are about CAR T cells. We have 2 approved products in different diseases—lymphoma and ALL [acute lymphocytic leukemia]—which suggests that they are capable of getting out of clinical trials and into the commercial world to become accessible to all patients. Right now, with our CAR T-cell trials in myeloma, hundreds of patients have been treated on various CAR T-cell trials, both in the United States and in China, and some in Europe too. And I think in the BCMA-targeting world, we have shown with multiple CAR T cells that they induce responses. The length of responses is variable, and they can sometimes get patients into minimal residual disease–negative status. I think all of these are exciting. But the space, again, is a very immature space at this point, and we still have to go some ways before we discuss where they fit in and how we use them, I think.

Nikhil C. Munshi, MD: I totally agree with you.

Transcript edited for clarity.

Nikhil C. Munshi, MD: Certainly, if we talk about BCMA-targeting ADC [antibody-drug conjugate]….

Parameswaran Hari, MD, MRCP: Belantamab.

Nikhil C. Munshi, MD: Belantamab. It’s one of the classes of drugs that we have evaluated in other settings before—CD19, CD56-targeted ADC, etcetera. This one is especially important for us because it targets BCMA, so there’s less risk. There’s great excitement about the drug because efficacy is very high.

Parameswaran Hari, MD, MRCP: Yeah.

Nikhil C. Munshi, MD: Do you want to discuss the efficacy and maybe say something about the toxicity that we should be looking after or taking care of?

Parameswaran Hari, MD, MRCP: In this context, too, we should talk about efficacy and toxicity and the risk balance, as you say. The unique toxicity of this drug that we have not seen with prior myeloma drugs is something called keratopathy, which is corneal damage that, thankfully, does not seem to be permanent damage. But a specific proportion of patients who are exposed to this drug developed dry eyes and deposition of the toxin in the cornea that leads to itching, and visual loss, and visual blurring, and, in extreme cases—a minority of cases, though—corneal laceration. It is thought that the cells that are taking up this toxin might wait and then get sloughed off in the normal process, and then the patient recovers if you hold the drug. This has led to some holds of this drug when you’re treating patients with this. And I’m sure that we will mitigate this as we go along and use risk-benefit discussions with patients who use this drug. But it is a toxicity that we, as physicians, should be aware of.

Nikhil C. Munshi, MD: The efficacy is quite encouraging.

Parameswaran Hari, MD, MRCP: Of course. Again, you have worked with this drug. It works in people who are refractory to the major 3 classes.

Nikhil C. Munshi, MD: Triple refractory…

Parameswaran Hari, MD, MRCP: Yes.

Nikhil C. Munshi, MD: And the response ends up being around 60% or higher.

Parameswaran Hari, MD, MRCP: Yeah.

Nikhil C. Munshi, MD: So that drug has great promise. The second class of drugs would be the T-cell engagers. There’s a lot of discussion about more than 1 different T-cell engager. Would you like to explain the concept of T-cell engagers and how they function? And what is your opinion on the 2 T-cell engagers that have gone to clinic so far?

Parameswaran Hari, MD, MRCP: Yes. Actually, this is a class of drugs that is used in other hematological malignancies. There is a drug that’s approved, called blinatumomab, against CD19 in pediatric leukemia, and another one called inotuzumab works against CD22. The concept, again, is to make a small antibody that has binding specificity towards CD3 on one end, which is a surface molecule on T-cells. And on the other end, it binds to a target that you wish to direct these T-cells toward, which, in this case, is BCMA.

So this antibody, when infused or injected into the patient, coats the surface of the plasma cells and brings T cells into contact with them. This creates an artificial, what they call an immunological synapse, which leads to the T cell killing the plasma cells or its target in other cases. But what do you think? Do you really think that this mechanism can also cause cytokine release syndrome or can sometimes lead to immunological memory because it recruits other T cells?

Nikhil C. Munshi, MD: Yeah, I think it’s a good immunological approach. It recruits the T cells to do the function we would like it to do, but it will bring about, or it does bring about, the same adverse effect profile that we would see with CAR T-cell type of approaches that we will talk about in a minute. It probably does not have neurotoxicity. There are 2 drugs in the market, and 1 was actually evaluated. It’s a drug called AMG 420. It was one of the first BCMA-targeting engagers that showed efficacy, and that was very important news for all of us—that these T-cell engagers do work. The concern was that myeloma is an immunosuppressed disease. Would the T-cell engager be good enough to bring those not functioning T cells? That was saddled by that drug. The problem with AMG 420 was that it is not easy to administer—to give continuous infusion for days and repeat it.

Parameswaran Hari, MD, MRCP: Yeah, very cumbersome.

Nikhil C. Munshi, MD: Very cumbersome. But I think it established the principle. And then we have a next-generation AMG molecule, ABP 710, that can be given quickly. It’s a short infusion time, and at least in a preclinical model, it looks very attractive.

Parameswaran Hari, MD, MRCP: Exactly. We don’t have an update on that yet at this meeting, but it’s based off AMG 420. I think that suggests that this molecule is probably going to be very active.

Nikhil C. Munshi, MD: But then there was a second, similar compound that does not have a name yet either, but it comes from…

Parameswaran Hari, MD, MRCP: It’s called CC28396.

Nikhil C. Munshi, MD: Yeah. And so that has clinical results now available to early stage, right?

Parameswaran Hari, MD, MRCP: At this meeting, both of us heard these results that are, I would say, very promising. At least the patients treated at goal dose in a phase I study, which was about 6 mg or higher, almost 100%, actually 89% of these patients ended up having a response.

Nikhil C. Munshi, MD: I think it was quite well tolerated. Some patients did require tocilizumab. But it was efficacious, and at the same time, toxicities were quite manageable. It’s quite exciting. And then the third compound to the BCMA-directed treatment, which probably is the most exciting compound, and, so far, with vast experience, is CAR T-cell therapy.

Parameswaran Hari, MD, MRCP: Absolutely.

Nikhil C. Munshi, MD: CAR T cells stands for “chimeric antigen receptor–expressing T cells,” and the concept is very simple. The T cells are genetically modified. They express, on their surface, an antibodylike molecule. So now the T cell will be able to target or recognize a tumor cell and bind to it. And then that same molecule has a tail inside the cell that makes a T cell get activated. So it functions better and starts proliferating. This is how CAR T cells work. But there are some different varieties of CAR T cells—the CAR T-cell variety with single epitope–targeting T cells and dual-epitope targeting. And the bb2121 is a single epitope–targeting CAR T cell, but the JNJ molecule is dual targeting. It targets BCMA, but on the 2 different load sizes, and might have a different thing. What do you think about these CAR T cells, in general? We’ll go into more detail on each of them, and JNJ in a minute. But in general, what’s your feeling about all of the enthusiasm with CAR T cells?

Parameswaran Hari, MD, MRCP: I think I am as excited as you and everyone else are about CAR T cells. We have 2 approved products in different diseases—lymphoma and ALL [acute lymphocytic leukemia]—which suggests that they are capable of getting out of clinical trials and into the commercial world to become accessible to all patients. Right now, with our CAR T-cell trials in myeloma, hundreds of patients have been treated on various CAR T-cell trials, both in the United States and in China, and some in Europe too. And I think in the BCMA-targeting world, we have shown with multiple CAR T cells that they induce responses. The length of responses is variable, and they can sometimes get patients into minimal residual disease–negative status. I think all of these are exciting. But the space, again, is a very immature space at this point, and we still have to go some ways before we discuss where they fit in and how we use them, I think.

Nikhil C. Munshi, MD: I totally agree with you.

Transcript edited for clarity.
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