Next Chapter Begins With CAR T-Cell Therapy in Myeloma

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?

The biggest challenge has been getting the CAR T-cell product. As of right now, we are still using the autologous CAR T-cell product. However, the time to generate CARs is approximately 4 weeks. That is from when we collect the cells from patients, send them to be generated, then get them back to patients. These are very sick patients who do not have many options, so our biggest challenge is how can we control their disease for the 4 weeks [while the CAR T-cell product is prepared]. Once we start doing CARs earlier on in the disease course, this is not going to be a problem because we will have options to bridge patients to get them to that level.

The other thing that we are thinking of is using off-the-shelf CARs as well, such as allogenic CAR products. Once we have those, there would be no waiting time. That is 1 of the biggest challenges right now.

What are the biggest concerns with toxicity?

We were afraid of going into the CAR T-cell space when we first started. We have been very pleasantly surprised in the context of myeloma. We have not seen a lot of toxicity with these CARs, and that may have to do with the costimulatory domain that we are using. It may also be using T cells that are not very potent, so they do not expand as much.

The 2 big toxicities that you have to worry about with CAR T-cell technology is neurotoxicity and cytokine release syndrome (CRS). What has happened, which we have learned from our lymphoma and leukemia colleagues, is that we are pretty good at picking up these toxicities, and we have the antidotes to treat them.

In general, I would say the toxicity of CAR T cells is way better than some of the toxicities of other cellular products, such as autologous stem cell transplant.

What are the advantages to using off-the-shelf CAR products?

The benefit is patients do not have to wait around for the cells to be manufactured. Because it is off-the-shelf, you can keep reusing these cells as well. I do not want to jump too far ahead, because we have to first figure out if these are efficacious and make sure they are safe, but we also have to make sure we can continue to give them again to patients. We are using most of these allogenic products from a few donors, and then you have to consider other problems when you are using donor-derived products. There is a lot we can do in the future.

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