FDA-Approved CAR T-Cell Therapies Illuminate Advances in Multiple Myeloma

The FDA approvals of idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) are shifting the treatment paradigm for patients with relapsed/refractory multiple myeloma, according to Noopur S. Raje, MD, who also spoke about augmenting the landscape with off-the-shelf options such as BCMA-directed bispecific T-cell engagers (BiTEs).

“There is much excitement around CAR T cells; ide-cel and cilta-cel are our first foray into the CAR T-cell world,” Raje, director of the Center for Multiple Myeloma at Massachusetts General Hospital, said. “At [the 2021 ASH] Annual Meeting and Exposition, [many interesting data were presented that should compel us to create better treatment options].”

In an interview with OncLive^®, Raje discussed the presentation she gave at the 26th Annual International Congress on Hematologic Malignancies® on the CAR T-cell therapy product bb21217, other exciting myeloma treatments that were presented at ASH, and the need for increased treatment accessibility.

OncLive^®: The presentation you gave at ASH focused on the role of CAR T cells in multiple myeloma. Could you provide a brief overview of some of the topics you talked about?

Raje: CAR T cells are an exciting development in the treatment of patients with multiple myeloma. We now have 2 CAR T-cell therapy products approved. We have ide-cel, which was approved in March 2021, and more recently, we have cilta-cel, which was approved in March 2022. [These therapies are both indicated for patients] with relapsed/refractory multiple myeloma who have previously been exposed to many other drugs, including both immunomodulatory drugs [IMIDs], lenalidomide [Revlimid] and pomalidomide [Pomalyst], bortezomib [Velcade], and carfilzomib [Kyprolis].

Most of these patients [have also been treated with] a CD38 monoclonal antibody. [In my presentation,] I talked about data with the CAR product bb21217, which is similar to ide-cel. What we’re trying to do with all these strategies, many of which were presented at ASH, is find ways to improve upon what we already have with CAR T cells.

We know that ide-cel produces a complete response [CR] rate of close to 40%, which translates into a [progression-free survival (PFS)] of about 22 months. We want to know: Can we do better than that? That was the [focus of the] presentation I gave on bb21217. The idea with that product is to expose the CAR product ex vivo so that in vitro, you’re exposing it to a drug product called bb007, which is a PI3 kinase [PI3K] inhibitor. The goal is to enrich for a memory naïve-like phenotype, with the intent of having a longer duration of response.

How can these new CAR T-cell therapies help evolve the treatment landscape for multiple myeloma?

The good news is that these approvals are going to allow us access to [a broader treatment landscape]. The struggle is that these therapies are not treatments that are off-the-shelf and readily available to our patients, especially given that we are trying to do personalized, designer-specific therapy for each patient.

It’s not easy to get [treatment] slots; there are many bottlenecks involved in the production of CAR T cells. For example, you need to consider whether you have enough viral vector, and if you don’t, you’re not going to be able to create the CAR.

It is incumbent upon us as to how we can make them accessible, because on average, we’re able to take care of 1 or 2 patients with each of these drug products. In the relapsed/refractory multiple myeloma space, we have too many patients and very few slots.

Could you highlight any other intriguing ongoing trials and further research that are investigating CAR T-cell therapies within multiple myeloma?

The Fred [Hutchinson Cancer Research Center] presented [data on] a CAR product that includes [JSMD194] which is an upregulator for BCMA. BCMA is the target toward which all CAR T cells are directed. Using JSMD194, you can increase BCMA expression and thereby improve the response rates for these CARs. This data are early, so it’s difficult to speak to whether [this treatment is effective], but that’s step 2: trying to enhance responses.

There was data with other CAR products as well, such as those from a trial presented from our group at [Massachusetts General Hospital]. It was the Arcellx product, which is also directed against BCMA. The data look quite compelling, as they show a high response rate.

However, these results are in smaller numbers of patients, and the data are still early. We are seeing toxicity signals [that are comparable to other therapies], such as manageable [cytokine release syndrome (CRS)], manageable neurotoxicity, and high response rates. Additionally, patients are continuing to remain in response for close to 2 years. We don’t know what the average PFS is.

In general, these are exciting data, and our hope is that we can keep improving on what we already have with ide-cel and cilta-cel. The cilta-cel data were striking, in that we’re seeing a 97% response rate in the penta-refractory patient population. That’s exceedingly high, and the CR rate is 55%, with about 72% of these patients remaining progression-free at 2 years. [These data are unparalleled.]

What still needs to be addressed within this field in terms of CAR T-cell therapies?

The biggest thing that needs to be addressed is access [to treatment]. [I look forward to seeing] this access improve, because, as of right now, all these drug products are only approved in the very late relapsed/refractory state. Oftentimes, we have patients waiting for these drug products who cannot make it to that stage. Once [these CAR T-cell therapies are] approved in late-stage myeloma, we should move them up front, like we do with other drugs.

Up-front trials are already ongoing both with cilta-cel and ide-cel and some of the other drug products as well. Once we have the indication in the earliest stages of myeloma, even if patients must still wait to get the drug products they need, [treatment in this setting is] feasible, because you can bridge these products with [other therapies]. That is one of the biggest unmet needs.

Another unmet need in myeloma has to do with product-specific treatments. With cilta-cel, for example, we’re seeing extremely high response rates and sustained remissions. Our hope is that we continue to see no neurotoxicity, [the opposite of what] was seen in CARTITUDE-1 [NCT03548207]. The good news is that we have not seen neurotoxicity thus far with the mitigation strategies we’re using, but we need to follow patients in the long term [to confirm this].

The unmet need with ide-cel is that response rates are about 40%, and the PFS is about 20 months in the very refractory patient population. We must do better to increase response rates, and we must improve upon the duration of response as well.

Is there anything else you would like to highlight?

CAR T cells are one aspect of many exciting new developments in myeloma. In general, all immunotherapies have been extremely exciting in multiple myeloma. Some of the others that were highlighted at the ASH meeting included many BiTEs. The beauty of these is that they’re off-the-shelf, so patients don’t have a waiting period. They also do exactly what CARs do, which is engage the T cells and get the T cells to work against the tumor cell. The response rates with BiTEs are slightly lower than with CAR T cells. Nonetheless, we’re seeing [minimal residual disease (MRD)]–negative disease.

At the ASH meeting we also saw combination studies. With CAR T cells, we’re using IMIDs combined with CARs. With the [BiTEs], we are combining them with monoclonal antibodies, and other anti-myeloma drugs [and yielding] improved response rates.

The future is bright with all these immune therapies. Within the next 4 or 5 years, it’s our responsibility to figure out how best to combine these therapies, sequence them, and determine what should come first in the treatment paradigm. [Overall, getting these treatments to more patients is the key.]