Investigational Immunotherapies Elicit Unprecedented Responses in Relapsed/Refractory Myeloma

Nina Shah, MD

As novel immunotherapies such as CAR T-cell therapies and bispecific T-cell engagers emerge in the multiple myeloma treatment paradigm, more patients with heavily relapsed/refractory disease are able to achieve benefit, according to Nina Shah, MD, who added that additional efforts are being focused on making these therapies safer and more easily accessible.

The CAR T-cell product that is furthest along in the pipeline is idecabtagene vicleucel (ide-cel; formerly bb2121), according to Shah. In March 2020, a biologics license application (BLA) was submitted to the FDA for the agent’s use in patients with multiple myeloma who had received at least 3 prior therapies, including an proteasome inhibitor (PI), an immunomodulatory (IMiD) agent, and an anti-CD38 agent.

The BLA was supported by data from the phase 2 KarMMA trial in which the CAR T-cell product resulted in an overall response rate of 73.4% in patients with relapsed/refractory disease, meeting the trial’s primary end point.¹ However, in May 2020, the FDA issued a Refusal to File letter to Bristol Myers Squibb and bluebird bio, Inc, citing that additional information was needed for the Chemistry, Manufacturing, and Control module of the BLA.²

Beyond ide-cel, other promising agents have showed encouraging responses in heavily pretreated patients. For example, JNJ-4528 showed an ORR of 100% in the phase 1/2 CARTITUDE-1 trial,³ and the orvacabtagene autoleucel (JCARH125) showed an ORR of 92%.⁴

Bispecific T-cell engagers (BiTEs) are another exciting area of exploration, noted Shah. “This is an antibody-like substance or an antibody-like molecule that targets both BCMA and CD3 to bring them together so that the parent T cells can kill the target,” she said. “These T-cell engager options are really exciting because they don't require anyone to go and get their cells processed, which is required with CAR T-cell therapy. As such, these agents are really [available] off the shelf.”

In an interview with OncLive, Shah, who is also an associate professor of clinical medicine at UCSF, discussed the future of CAR T-cell therapy and bispecific antibodies in multiple myeloma.

OncLive: Could you shed light on where CAR T-cell therapy stands in the multiple myeloma space?

Shah: CAR T-cell therapy is still investigational because we’re still awaiting FDA approval for the first product. Because of that, and the way that these trials have been run, this modality is mainly being examined in patients with relapsed/refractory disease. When I say this, I mean patients who have very relapsed/refractory disease, who had received a median of 6-7 lines of treatment. However, this may not necessarily reflect how we will use this therapy in the future.

Inclusion criteria [for these trials] only requires 3 lines of prior treatment and patients must be progressing. However, most patients in clinical trials are already beyond that because it’s a clinical trial.

What are some of the key BCMA-targeted products in the pipeline?

Many of the CAR T-cell therapies [in this space] target BCMA. The products that are most advanced in their clinical trials are ide-cel and JNJ-4528. Ide-cel product targets BCMA with an antibody-like structure on the surface of the T cell that's specific for BCMA; it intracellularly signals to 4-1BB, which is very similar to JNJ-4528.

The difference is that the anti-BCMA aspect is from a llama, and it hooks onto 2 parts of the BCMA. As such, [ide-cel] is structurally different [than JNJ-4528] and it might explain some of the different connects between [the 2 products]. However, both of them are targeting BCMA. BCMA, as a category of a target or a target itself, is great for myeloma because it's expressed almost uniformly on these plasma cells, even at low levels. It turns out that, even [if a patient has] a low level of BCMA, [they can] still respond to the anti-BCMA CAR T-cell therapy.

Could you expand upon the data that have been reported with ide-cel?

Updated data with this agent were reported during the 2020 ASCO Virtual Scientific Program. This [agent] is for patients with relapsed/refractory myeloma who had previously received at least 3 lines of therapy, including PI, IMiD, and an anti-CD38 antibody; these are very heavily pretreated patients.

[In the KarMMA trial], investigators gave [ide-cel] to patients with actively progressive disease. This was a difficult population to enroll, but investigators were able to treat 128 patients with [the product]; results showed an overall response rate (ORR) of 73% [with] all doses. Just to clarify, they examined 3 dose levels, which were 150 x 10⁶, 300 x 10⁶, and 450 x 10⁶. The good news is, at the higher dose of 450 x 10⁶, the response rate was around 80% or higher and the median progression-free survival was about 12 months.

A biologics license application was recently submitted to the FDA for this product. If approved down the line, what would the clinical implications be?

Investigators are in the process of trying to get ide-cel approved. As physicians, we're hopeful that the approval will happen soon because many patients cannot access this product unless they are located near an institution with a clinical trial. Once this is approved, I believe there will be an additional therapy option for these patients.

I'm not saying that every single patient is going to receive CAR T-cell therapy, but for the patients who are fit and can make the trip to a center that administers these products, they may have another option. Notably, when CAR T-cell therapy works, it’s a 1-time treatment.

Patients don’t need an infusion every week; it's different from other therapies available. This is very important and exciting, especially with regard to quality of life.

What were the updated data with JNJ-4528?

The JNJ-4528 product is also very important; I’m looking forward to seeing further results from the CARTITUDE-1 trial with this agent. Again, this is a BCMA-targeting CAR T-cell product. This product is interesting because it targets 2 aspects of BCMA and as such, it might change some kinetics and how it interacts with the target myeloma cell.

Data from a very small cohort of about 29 patients were originally presented at the 2019 ASH meeting. Results showed an ORR of 100%, which is really impressive—even for a small cohort. The preliminary data [showed similar promise] as well as the mature data that had also been seen in the Chinese study of the same product. [However, CARTITUDE-1 examined the agent in] an American population and, similar to the [ide-cel] study, these patients also had to have received 3 prior lines of therapy or at least have been exposed to a PI, an IMiD, and anti-CD38 antibody. The patient characteristics [between the trials] were very similar.

At this past ASCO, additional data were presented. Of course, they still showed an ORR of 100%. However, what I found to also be impressive was that 86% of patients had a complete response (CR) or a stringent CR; that’s extremely impressive for a patient population that is this pretreated with such advanced disease.

Evaluable data were not yet available with regard to progression free-survival (PFS). However, approximately 86% of patients at the 9-month mark had still not progressed. As such, I believe that [this agent] might possibly beat [the data that we saw at the] 12-month mark with the 450 x 10⁶ dosage of ide-cel; it’s possible but we don’t know. We don't like to compare trials against each other, but I think that’s one reason why these data are greatly anticipated.

Are any other products generating excitement?

Another product is the orvacabtagene autoleucel product that is being examined in the EVOLVE study. This is a slightly different product. It's similar to the other products in that it targets BCMA, but the way they culture the cells is a little bit different. Investigators provided some early phase 1 data showing an ORR of 92% [with this product].

I don't want to make too much of these data; however, I do want to say that the response rate is very impressive. It's hard to know because many different doses [of the product] are also being examined in this trial and there isn't very extensive, long-term follow up to understand the duration of response or PFS. Although, I believe this tells us that there are multiple options with regard to BCMA-targeted CAR T-cell therapies, which is great because that ultimately trickles down to the patient.

Beyond BCMA, are any other targetable agents currently under investigation in this space?

Aside from BCMA, other targets are being investigated [and products] are being developed. We're doing some clinical trials with antibody-drug conjugates against CD74 along with CD46, which is very exciting. Obviously, CD38 is always an exciting target because we know [it’s a good target].

There's also some early-development targets. GPRC5D, which was discovered at Memorial Sloan Kettering Cancer Center, is another target that might be good and specific to myeloma cells without getting into too many other cells; this would ultimately [be more safe]. Target discovery is huge, not just on plasma cells, but also on early B cells because we know that we're not getting rid of all the cells just by targeting BCMA; there’s not yet a plateau on these curves.

What is some of the work that is being done with BiTEs?

We learned from our leukemia colleagues that [these agents] can also cause cytokine release syndrome (CRS), although, it can be managed. Early data have been reported for 3 T-cell engagers. Initially, AMG 420 showed a response rate of approximately 70% but there were issues with continuous infusion; therefore, investigators have moved onto another product that is similar but is longer acting. I believe this new product is more patient friendly.

At this past ASH meeting, phase 1 data with Celgene’s CC-93269 product were also presented. Investigators showed that, with weekly dosing, then every-other-week dosing, and eventually every-4-week dosing, they were able to see an almost 90% response rate with the higher doses of the product, which is unprecedented. Again, this is an off-the-shelf therapy.

Another similar therapy is teclistamab (JNJ-64007957), from Janssen Pharmaceuticals. Data with this agent were presented at this past ASCO. Here, investigators showed phase 1 data with the agent. All these trials enrolled many patients with relapsed/refractory disease, which is challenging. Results showed that at higher doses, they were able to show a response rate that was approximately 67%; that’s difficult to do, so it’s very impressive. Right now, this molecule is being given in a weekly dosing, although dosing schedule or administration may change.

Importantly, this is also an off-the-shelf therapy, so there is no need for patients to go to a specialized cellular therapy institution. Even if there is CRS, it's easily managed at the first dose and it’s very rare that it would occur again. The other adverse effects are generally expected in patients who are this advanced, such as infection which is unavoidable because you are targeting a cell of the immune system. We're really excited about these off-the-shelf options for patients going forward. We are also looking forward to seeing some of them receive regulatory approval in the future, as well.

What is your take-home message to your colleagues?

We are very excited about the emerging molecules, cellular therapies, and immunotherapies that are coming to the myeloma space. I believe each will build upon the other and eventually

we will hopefully have combination therapies. I am so thankful to all of the myeloma and oncology practitioners who have sent their patients to clinical trials all over the world; we could not do it without them. We wouldn't know any of this without the participation of both patients and physicians alike. If anything, I hope that I can suggest clinical trials to anyone listening so that other patients can reap these benefits, as well.

References

1. Bristol Myers Squibb and bluebird bio announce submission of biologics license application (BLA) for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121) to FDA. News release. Bristol Myers Squibb and bluebird bio, Inc. March 31, 2020. Accessed August 17, 2020. https://bit.ly/2UtAxm6.
2. Bristol Myers Squibb and bluebird bio provide regulatory update on idecabtagene vicleucel (ide-cel, bb2121) for the treatment of patients with multiple myeloma. News release. Bristol Myers Squibb and bluebird bio, Inc. May 13, 2020. Accessed August 17, 2020. https://bit.ly/3bA5n1T.
3. Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505
4. Mailankody S, Jakubowiak AJ, Htut M, et al. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update on the phase 1/2 EVOLVE study (NCT03430011). J Clin Oncol. 2020;38(suppl 15):8504. doi:10.1200/JCO.2020.38.15_suppl.8504