ONCAlert | Upfront Therapy for mRCC

Investigational CAR T-Cell Therapy in Relapsed/Refractory Multiple Myeloma

Targeted Oncology
Published Online:1:00 PM, Fri January 31, 2020

Nikhil C. Munshi, MD: So…we come to more specific CAR T-cell studies, such as the JNJ-4528 that was presented here by Dr Madduri. Would you like to update us, briefly, on what was mentioned? The first thing about this CAR T-cell study that would be important is that it targets 2 areas.

Parameswaran Hari, MD, MRCP: Yeah, exactly.

Nikhil C. Munshi, MD: So it’s a little bit different from the other one.

Parameswaran Hari, MD, MRCP: The bb2121 and several other CAR T cells that are in development right now. I think the most exciting part of this is that this was the CAR T cell that kind of woke us up 2 years ago, at ASCO [American Society of Clinical Oncology], when this construct done in China showed some amazing results. But at that time, the concern—at least in US physicians’ minds—was that those patients had not had as many treatments prior and as many relapses prior to getting CAR T-cell therapy as we see in our patients. They were patients with a little bit earlier relapse and potentially more likely to respond. So we were wondering how that would function for our US patients.

I think Dr Madduri’s presentation this morning suggests that the response rates are fantastic even in the United States population. I think the key is what you just pointed out. It’s a bivalent binding, and that may be causing more responses in these patients with a tighter bind. And one of the unknowns, which I don’t know the answer to, is the immunological synapse created between the CAR T cell and the target, and the distance between the molecule.

Nikhil C. Munshi, MD: Efficacy wise, it’s amazing. It’s close to 100% response.

Parameswaran Hari, MD, MRCP: Absolutely.

Nikhil C. Munshi, MD: Almost everybody responds.

Parameswaran Hari, MD, MRCP: All of them had a response.

Nikhil C. Munshi, MD: So I think that’s very, very encouraging. And this is in a setting where patients have had 5 or more lines of treatment.

Parameswaran Hari, MD, MRCP: Median was 5, and they were up to 11 or 13....

Nikhil C. Munshi, MD: So a heavily pretreated patient population. You and I know that these patients do not respond to anything else, so it is in a setting where any other treatment would have 2 months of response and the proportion of patients getting a response would be small. So that’s the good part. Toxicity. You mentioned your experience with CAR T-cell therapy in lymphoma and leukemia, so you’re very familiar with it. Lymphoma and leukemia are where we see quite a significant cytokine release syndrome. Also, we see more significant neurotoxicity. Myeloma looks a little bit different, and this particular drug…

Parameswaran Hari, MD, MRCP: Having worked with CAR T-cell therapy in the other settings, with this CAR T-cell therapy, again, as you saw in the presentation, they managed the cytokine release syndrome very well. Myeloma doctors can be proud that the [patients] who participated in this trial did exceptionally well. Ninety-one percent of patients ended up getting tocilizumab, the CRS [cytokine release syndrome]–protecting antibody. And 88% of patients got CRS, most of which was grade 1 and 2. So that was very good. And the neurotoxicity events were also in the single digits. So the fact that the CAR T-cell therapy is safe, and people have gained so much experience… Myeloma doctors are doing a really good job managing their patients who are getting CAR T cells.

Nikhil C. Munshi, MD: Any thoughts on managing the CRS? What are your thoughts on the use of tocilizumab and when one would or would not want to use steroids and other things? It is less frequent and less intense, so that’s the good news. But we still have to use, once in a while, the measures.

Parameswaran Hari, MD, MRCP: For sure, absolutely. The American Society of Transplantation and Cellular Therapy has come up with guidelines for grading CRS and the use of tocilizumab and other agents. They’re extrapolating from the lymphoma literature and the leukemia literature. Use of these agents does not seem to compromise the responses. So in this study that we saw, 90% got tocilizumab, but 100% responded. So I think it is a good sign that cells are expanding in the body and causing CRS, and it’s a very good sign that we are able to put a halt to it, very quickly, with tocilizumab. So I am an optimist in that regard.

Nikhil C. Munshi, MD: I totally agree. My focus has been in myeloma with CAR T-cell studies, but having also seen what our lymphoma colleague does, the myeloma CAR T-cell studies, in general, and this one, specifically, are relatively very well tolerated.

Parameswaran Hari, MD, MRCP: Exactly.

Nikhil C. Munshi, MD: So I think that’s a very good, important point. And so if we go back to the process of this particular study, patients got lymphodepletion. They got lymphodepletion with Cytoxan [cyclophosphamide] and fludarabine. And I think the combination of Cytoxan and fludarabine has its own toxicity. These are the old drugs we have used for 30-plus years, and the main problem is cytopenia. And I think one of the toxicities with this and every other CAR T-cell therapy has been prolonged cytopenia. We have to manage it, and managing cytopenia is not new to us. That’s part of oncology. However, this is a [patient with] very late-stage [disease] who could have more prolonged neutropenia, thrombocytopenia, and red cell requirement. So I think that’s important. So they get lymphodepletion, and then we infuse the CAR T cells. The doses of CAR T-cell therapy in this study were a bit different from what we are used to. They use more specific number of transfused cells, right?

Parameswaran Hari, MD, MRCP: Right. So they take the total T cells, and they calculate the percentage of transfused cells. Their goal is a weight-based dosing of 0.75 million cells. And that ends up in the ballpark of what we are doing with bb2121. But this is very specifically targeted to the number of transfused cells.

Nikhil C. Munshi, MD: And so overall response rate of 91%, or close to almost everybody responding, is a really important point for us. I just want to know your personal experience with this. Any anecdotes?

Parameswaran Hari, MD, MRCP: I have personal experience with this particular CAR T-cell therapy. I do a lot of allogeneic transplants for patients with late-stage myeloma. Somehow, everyone who ended up here was a patient who had an allotransplant. So they were in the very late stages. They had exhausted all available agents. I had seen them multiple times. They even had an allotransplant. We would just keep going until the next agent became available. I have also had all my patients with myeloma respond with very minimal CRS or any toxicity. And so far, fingers crossed, all patients are staying in remission at very early follow-up. I have to say the follow-up is less than 4 months for the shortest follow-up.

Transcript edited for clarity.

Nikhil C. Munshi, MD: So…we come to more specific CAR T-cell studies, such as the JNJ-4528 that was presented here by Dr Madduri. Would you like to update us, briefly, on what was mentioned? The first thing about this CAR T-cell study that would be important is that it targets 2 areas.

Parameswaran Hari, MD, MRCP: Yeah, exactly.

Nikhil C. Munshi, MD: So it’s a little bit different from the other one.

Parameswaran Hari, MD, MRCP: The bb2121 and several other CAR T cells that are in development right now. I think the most exciting part of this is that this was the CAR T cell that kind of woke us up 2 years ago, at ASCO [American Society of Clinical Oncology], when this construct done in China showed some amazing results. But at that time, the concern—at least in US physicians’ minds—was that those patients had not had as many treatments prior and as many relapses prior to getting CAR T-cell therapy as we see in our patients. They were patients with a little bit earlier relapse and potentially more likely to respond. So we were wondering how that would function for our US patients.

I think Dr Madduri’s presentation this morning suggests that the response rates are fantastic even in the United States population. I think the key is what you just pointed out. It’s a bivalent binding, and that may be causing more responses in these patients with a tighter bind. And one of the unknowns, which I don’t know the answer to, is the immunological synapse created between the CAR T cell and the target, and the distance between the molecule.

Nikhil C. Munshi, MD: Efficacy wise, it’s amazing. It’s close to 100% response.

Parameswaran Hari, MD, MRCP: Absolutely.

Nikhil C. Munshi, MD: Almost everybody responds.

Parameswaran Hari, MD, MRCP: All of them had a response.

Nikhil C. Munshi, MD: So I think that’s very, very encouraging. And this is in a setting where patients have had 5 or more lines of treatment.

Parameswaran Hari, MD, MRCP: Median was 5, and they were up to 11 or 13....

Nikhil C. Munshi, MD: So a heavily pretreated patient population. You and I know that these patients do not respond to anything else, so it is in a setting where any other treatment would have 2 months of response and the proportion of patients getting a response would be small. So that’s the good part. Toxicity. You mentioned your experience with CAR T-cell therapy in lymphoma and leukemia, so you’re very familiar with it. Lymphoma and leukemia are where we see quite a significant cytokine release syndrome. Also, we see more significant neurotoxicity. Myeloma looks a little bit different, and this particular drug…

Parameswaran Hari, MD, MRCP: Having worked with CAR T-cell therapy in the other settings, with this CAR T-cell therapy, again, as you saw in the presentation, they managed the cytokine release syndrome very well. Myeloma doctors can be proud that the [patients] who participated in this trial did exceptionally well. Ninety-one percent of patients ended up getting tocilizumab, the CRS [cytokine release syndrome]–protecting antibody. And 88% of patients got CRS, most of which was grade 1 and 2. So that was very good. And the neurotoxicity events were also in the single digits. So the fact that the CAR T-cell therapy is safe, and people have gained so much experience… Myeloma doctors are doing a really good job managing their patients who are getting CAR T cells.

Nikhil C. Munshi, MD: Any thoughts on managing the CRS? What are your thoughts on the use of tocilizumab and when one would or would not want to use steroids and other things? It is less frequent and less intense, so that’s the good news. But we still have to use, once in a while, the measures.

Parameswaran Hari, MD, MRCP: For sure, absolutely. The American Society of Transplantation and Cellular Therapy has come up with guidelines for grading CRS and the use of tocilizumab and other agents. They’re extrapolating from the lymphoma literature and the leukemia literature. Use of these agents does not seem to compromise the responses. So in this study that we saw, 90% got tocilizumab, but 100% responded. So I think it is a good sign that cells are expanding in the body and causing CRS, and it’s a very good sign that we are able to put a halt to it, very quickly, with tocilizumab. So I am an optimist in that regard.

Nikhil C. Munshi, MD: I totally agree. My focus has been in myeloma with CAR T-cell studies, but having also seen what our lymphoma colleague does, the myeloma CAR T-cell studies, in general, and this one, specifically, are relatively very well tolerated.

Parameswaran Hari, MD, MRCP: Exactly.

Nikhil C. Munshi, MD: So I think that’s a very good, important point. And so if we go back to the process of this particular study, patients got lymphodepletion. They got lymphodepletion with Cytoxan [cyclophosphamide] and fludarabine. And I think the combination of Cytoxan and fludarabine has its own toxicity. These are the old drugs we have used for 30-plus years, and the main problem is cytopenia. And I think one of the toxicities with this and every other CAR T-cell therapy has been prolonged cytopenia. We have to manage it, and managing cytopenia is not new to us. That’s part of oncology. However, this is a [patient with] very late-stage [disease] who could have more prolonged neutropenia, thrombocytopenia, and red cell requirement. So I think that’s important. So they get lymphodepletion, and then we infuse the CAR T cells. The doses of CAR T-cell therapy in this study were a bit different from what we are used to. They use more specific number of transfused cells, right?

Parameswaran Hari, MD, MRCP: Right. So they take the total T cells, and they calculate the percentage of transfused cells. Their goal is a weight-based dosing of 0.75 million cells. And that ends up in the ballpark of what we are doing with bb2121. But this is very specifically targeted to the number of transfused cells.

Nikhil C. Munshi, MD: And so overall response rate of 91%, or close to almost everybody responding, is a really important point for us. I just want to know your personal experience with this. Any anecdotes?

Parameswaran Hari, MD, MRCP: I have personal experience with this particular CAR T-cell therapy. I do a lot of allogeneic transplants for patients with late-stage myeloma. Somehow, everyone who ended up here was a patient who had an allotransplant. So they were in the very late stages. They had exhausted all available agents. I had seen them multiple times. They even had an allotransplant. We would just keep going until the next agent became available. I have also had all my patients with myeloma respond with very minimal CRS or any toxicity. And so far, fingers crossed, all patients are staying in remission at very early follow-up. I have to say the follow-up is less than 4 months for the shortest follow-up.

Transcript edited for clarity.
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