Noopur Raje, MD, Talks Anti-BCMA CAR-T Therapy for Relapsed/Refractory MM

In this podcast, Noopur Raje, MD, Professor of Medicine, Harvard Medical School; Director of the Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, discusses the clinical significance of anti-BCMA CAR-T therapy with bb2121 in patients with relapsed or refractory multiple myeloma (MM).



I am Noopur Raje. I am a Professor of Medicine at Harvard Medical School and the director of the Multiple Myeloma Center at Massachusetts General Hospital in Boston. I am here today, and I am going to review some of the data, which is exciting data, in the context of myeloma with respect to cellular therapy, specifically CAR T‑cells, in the context of myeloma.

We have had several meetings this year, unfortunately all virtual. Nonetheless, we have had some very interesting data presented at both the American Society of Clinical Oncology and then the European Hematology Association meeting.

We have seen updates on some of the cellular therapy products that we have in the context of myeloma. As you all know, the target in the context of cellular therapy in multiple myeloma is BCMA, which also stands for B‑cell maturation antigen.

As well‑known to everybody now working on myeloma, BCMA is an antigen which is essentially present on generally all plasma cells, and specifically higher proportion of the tumor cells. We also know, over the course of the last few years, that BCMA has functional relevance in the context of myeloma in that it helps multiple myeloma cells survive much longer.

Therefore, it seems like an ideal target for both cellular therapy, as well as targeted approaches in the context of myeloma. Most of the clinical trials which are ongoing in the context of cellular therapy are using cellular products targeting this antigen, which is BCMA. The products which are furthermost in development is what I will allude to right now.

We have bb2121, also known idecacabtagene vicleucel, ide‑cel. This is a CAR T‑cell product targeting BCMA. It uses 41bb as the cross‑tumorlatory domain, and it also uses CD3 zeta, as do most CAR T‑cells. We have the phase I data, which has already been now published.

Most recently, the phase II pivotal trial, or the KarMMa trial, was presented both at ASCO and EHA. This is probably one of our biggest experiences with CAR T‑cells in the context of multiple myeloma, and it's included 128 patients who actually received the cellular drug product.

All of these patients had been prior exposed to both imids, which lenalidomide and pomalidomide, and generally both proteasome inhibitors, including bortezomib and carfilzomib, as well as a CD38 monoclonal antibody, either isatuximab or daratumumab.

The majority of these patients were actually refractory to some of these prior lines of therapy. This was a dose escalation trial wherein patients were treated from 150 million cells all the way up to 450 million cells, and 450 million cells is supposedly the target dose for ide‑cel in the future.

What was seen is a remarkably high response rate, in excess of 70 percent. One you get to the target dose of 450, it was in excess of 80 percent. This translated into a progression‑free survival benefit of close to about nine months or so.

If you look at the target dose, it was 12 months, and if you look at patients who achieved a CR or a stringent CR, their median progression‑free survival was 20 months. The overall survival data is still immature, and therefore, at least the PFS data in patients achieving a stringent CR or a CR are quite remarkable.

I think the other really important feature here is the fact that this is a well‑tolerated product. The most common toxicities associated with CAR T‑cells includes neurotoxicity as well as cytokine release syndrome.

CRS was seen in about 60 percent of patients, but most of the CRS was manageable, of grade one and two, and very few patients experienced grade three, or very few, in fact, experienced grade four. As far as neurotoxicity is concerned, again, very few patients experienced anything greater than a grade three neurotoxicity.

You could literally count them on your fingers. Maybe one patient had that kind of a toxicity. The bb2121 product, based on the KarMMa is actually quite, the data looks very, very encouraging. Our hope is that this will probably be the first product which will be approved for the treatment of multiple myeloma patients.

There were several other drug products which were presented at these international meetings as well. There was the product from Janssen which was presented, and although the experience with that one is relatively smaller, the phase I data with close to about 30 patients was presented.

The response rates are quite remarkable, with a very high response rate, translating into a progression‑free survival at a nine‑month follow‑up. Most of the patients who achieved a response remained progression‑free.

Obviously, the data here is a little less mature, and we have to wait and see what this pans out in terms of longer‑term follow‑up. Another product, which is a JCR product, was also presented at this year's meetings. This is also known as Orbucell.

The difference between these different cellular drug products is that the starting point for these CAR T‑cells was an equal ratio of CD4 and CD8 cells. They all use the same backbone of 41bb as the cross‑tumorlatory domain.

Once patients, about 60‑plus patients, were treated with this product, and most of these patients had a remarkable response rate, with over 90 percent of patients responding. Again, the follow‑up in the study is a lot smaller, and therefore, we do not have a median progression‑free survival.

Again, a word on toxicities. All of these products have had very comparable toxicity with very little in terms of CRS with very high grades ‑‑ that is grade four ‑‑ and nobody had grade five CRS. Neurotoxicity also was extremely manageable.

In conclusion, I think we are at the threshold where we are going to have several drug products, the cellular drug products, which will be approved in the context of myeloma. bb2121 is probably the first one in line for that approval. This will be a huge advance in patients with multiple myeloma who are refractory to most of what is available today.

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