Next Chapter Begins With CAR T-Cell Therapy in Myeloma

Published: Sunday, Mar 01, 2020

Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital

Noopur Raje, MD

After observing patients with relapsed/refractory multiple myeloma achieve minimal residual disease negativity with the first rendition of CAR T-cell therapy, Noopur Raje, MD, said it’s time to take the next steps with this treatment to make the responses more durable.

“It’s an exciting space to be in. It is up to us to move this forward in the appropriate patient population and to change the 1-year benefit we have been getting so far in this disease to make this more durable,” explained Raje. “The sky is the limit, and there is so much we can do in terms of manipulating these [CAR T cells] to make them more potent and make them more effective, as well as less toxic.”

While the most-developed CAR T cells mainly target BCMA, others with dual-targeting properties are gaining interest. Additionally, sequential CAR T-cell products, off-the-shelf CAR T cells, and CAR-engineered natural killer (NK) cells are also being eyed in the pipeline.

In an interview with OncLive during the 24th Annual International Congress on Hematologic Malignancies, Raje, director, Center for Multiple Myeloma, Massachusetts General Hospital, discussed the investigational CAR T-cell therapies and strategies in the multiple myeloma pipeline.

OncLive: What is the role of CAR T-cell therapy in multiple myeloma?

Raje: We have quite a lot of data now in the space of CAR T cells. We have several different CARs, all targeting BCMA and all showing durable and deep responses in very late-stage myeloma patients. There are newer targets that we will be considering and thinking about what we should be doing in terms of how to generate the next generation [of agents].

What new targets have emerged in the myeloma space?

The big thing with CARs right now is everyone is targeting BCMA. We have seen fantastic responses with that, so we are looking at moving that earlier on in the disease course, specifically in the high-risk myeloma patients. In these patients, we are looking at bringing up CARs at the time of diagnosis so that patients receive the induction treatment that has high-risk FISH cytogenetics. We would actually consider doing a CAR T-cell therapy here because, in general, the responses and durability of patients in that population are quite low.

In addition to considering the CARs that we have studied previously earlier on [in the disease course], we are looking at other CARs as well. We are looking at CARs that are dual-signaling or dual-targeting, that is, those that target BCMA and APRIL, for example. We are looking at CARs like the one from Janssen, which binds to 2 separate BCMAs, and we are seeing very deep responses with that CAR.

There are sequential CARs, which are being used at least by investigators in China, where they have used a CD20-directed CAR followed by the BCMA CAR. There are also several other different strategies for creating CARs. We are already in the space of using off-the-shelf CARs, and we will be opening up the first clinical trials using allogenic CAR T cells directed against BCMA. With this, we do not have to wait for the generation of CARs, and we will be studying those in the context of myeloma.

The other interesting things in the CAR T-cell space are NK cells. Along with the CARs that we are using today, if we can also target or activate NK cells, we might be able to get better responses. That is something we will be studying in the future.

How are the CAR NK cells different than the other CAR T-cell products that are futher along?

The downside of NK cells right now is that they do not live that long. They remain in circulation for about 10 days. The question is, “Can we use them in combination with something else to get a deep response?” Once we get the deep response, we won’t need the NK cells around. NK cells are just a different immune strategy; it’s still a cellular strategy. We have seen nice data, which have already been presented in leukemia, and we are working on it in myeloma. We just have to wait and see how this pans out.

What are the challenges in using CAR T cells in myeloma?

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