CAR T-Cell Therapy Enters the Arena in Multiple Myeloma With Ongoing Research Ahead

Saad Z. Usmani, MD, FACP

The FDA approval of idecabtagene vicleucel (ide-cel; Abecma) has established a role for CAR T-cell therapy in heavily pretreated, relapsed/refractory multiple myeloma, with the product showing an unprecedented response rate and a generally favorable safety profile, said Saad Z. Usmani, MD, FACP.

However, with additional BCMA-directed constructs, allogeneic CAR T-cell products, and bispecific antibodies in the pipeline, ide-cel could become just 1 of many novel options the field. 

“BCMA-directed CAR T-cell therapy has good activity in heavily pretreated patients with multiple myeloma, including patients with triple-class refractory disease,” said Usmani. “Cytokine release syndrome [CRS], neurotoxicity, and low blood counts are [common], but patients [typically] recover from these adverse effects [AEs]. The timing of CRS and neurotoxicity could be different [between products], but we are seeing good activity [overall].”

On March 26, 2021, the FDA approved ide-cel as the first BCMA-directed CAR T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.¹

The regulatory decision was based on data from the phase 2 KarMMA trial, in which ide-cel elicited an overall response rate (ORR) of 72% and a stringent complete response (sCR) rate of 28% in patients with relapsed/refractory myeloma who had received at least 4 prior treatments.2

Another CAR T-cell product, ciltacabtagene autoleucel (cilta-cel) is currently in the myeloma pipeline, having demonstrated an ORR of 96.9% and an sCR rate of 67.0% in the phase 1b/2 CARTITUDE-1 trial.3 Notably, the median time to onset of CRS was 1 day with ide-cel compared with 7 days with cilta-cel.^2,3 In April 2021, Legend Biotech, the developer of cilta-cel, announced that a rolling submission of a biologics license application to support the approval of the drug for the treatment of patients with relapsed/refractory multiple myeloma has been completed.⁴

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on CAR T-cell therapy, Usmani, chief of Plasma Cell Disorders and director of Clinical Research in Hematologic Malignancies at the Levine Cancer Institute of Atrium Health, discussed the rapidly changing cellular therapy paradigm in relapsed/refractory multiple myeloma. 

OncLive^®: What key lessons were learned with ide-cel from the KarMMA trial?

Usmani: Ide-cel is a BCMA-directed CAR T-cell therapy that is the furthest along in terms of clinical development; we have the most follow-up with that particular construct. The key takeaway from the data [from the KarMMA trial], which were shared during the 2020 ASH Annual Meeting and Exposition, was that the initial signal of efficacy in the dose-escalation study did play out in the subsequent dose-expansion cohort. Longer-term follow-up [data have shown that] patients are getting minimal residual disease–negative complete responses; some patients who have been off of treatment are showing sustained remissions at 2 years and beyond.

There doesn’t appear to be any long-term safety concerns so far with [ide-cel]. The CRS and neurotoxicity that is seen is short term [and occurs] during the early parts of treatment, usually within the first month or so.

Importantly, an analysis [showed that] patients with high-risk cytogenetics [or] extramedullary multiple myeloma tended to have the same disease response with ORRs around 70% or higher. 

How could the other ongoing KarMMA trials answer some of the questions left with ide-cel?

KarMMA-2 [NCT03601078] has several different cohorts, including patients who are receiving ide-cel in earlier lines of treatment, patients who are receiving ide-cel with prior exposure to BCMA-directed therapy, and patients [who are receiving ide-cel] with high-risk disease, which will serve as a safety signal–generating cohort. 

[The KarMMA-2 trial] led to the development of the KarMMA-4 trial [NCT04196491], which is a frontline study for high-risk patients post induction.

The KarMMA-3 trial [NCT03651128] is another ongoing trial comparing ide-cel with standard triplet regimens in relapsed/refractory multiple myeloma. Some ide-cel studies [within] the Cooperative Group Setting were in the [Blood and Marrow Transplant Clinical Trials Network] looking at ide-cel after autologous stem cell transplant in high-risk patients [with multiple myeloma].

Could allogeneic CAR T-cell therapies overcome some of the logistical challenges of delivering autologous CAR T-cell therapies to patients?

The next endeavor that we are going to have as we are thinking about CAR–related products is how quickly we can give these therapies. Currently, it takes between 4 to 6 weeks from the time that we think about giving a patient CAR T-cell therapy to getting them on a trial, to [them undergoing] apheresis, and finally, getting the product back. Logistically, this can take up to 2 months on clinical trials. It would be ideal to have an off-the-shelf option, which is where the ALLO-715 concept is very important.

If we have an allogeneic product from a single donor, we can make 100 off-the-shelf products ready to go. If I need to give such a product to a patient, I can start lymphodepleting chemotherapy and give them CAR T-cell therapy [shortly thereafter].

ALLO-715 tried to do that and is being evaluated in a dose-escalation, early-phase study. The important thing [about ALLO-715] is that about 90% of patients were treated within 5 days of enrolling, which is a much shorter timeframe [compared with autologous CAR T-cell therapy]. Moreover, there appears to be clinical activity [with ALLO-715] at the highest [dose] of 320 million [cells]. Six out of 10 patients had a response with 4 out of 10 having a very good partial response or better. [The trial has] short follow-up in a small cohort of patients, but the data are encouraging.

How do you anticipate the field will utilize CAR T-cell therapy, assuming the data remain positive?

The early approvals will come in the relapsed/refractory setting for patients who have had exposure or refractoriness to PIs, IMIDs, and [monoclonal] antibodies. Most of our early usage once [CAR T-cell therapies] come to the clinic will be for those patients, and part of their usage will be dependent on how much capacity each transplant and cellular therapy center has. Having said that, we are probably going to have a little bit more flexibility in how we can bridge patients to CAR T-cell therapy. Getting patients to CAR T-cell therapy would be ideal, so we will try to do that for most patients. However, bispecific antibodies are also coming down the pike, so those will be good backup options too.

What other BCMA-directed products are in the pipeline and how do they differ from ide-cel?

The second most mature dataset we have is with cilta-cel from the CARTITUDE-1 trial, [showing] a very impressive 97% ORR. With [cilta-cel], the time to CRS onset and neurotoxicity events is a bit delayed compared with ide-cel. As we think operationally, if both products [become] available to us, maybe one [product could be] given in the outpatient setting vs monitoring patients in the inpatient setting early on. Every center will look at things in a little bit of a different way based on their resources, but it is a good problem to have more than 2 options for patients. 

We also have the bb21217 construct, which has the same construct as ide-cel. However, a PI3K inhibitor is utilized during the CAR T-cell expansion to push it toward more of a memory T-cell phenotype, [which could translate] to long-term remission for patients.

Then we have the LUMMICAR constructs, which are somewhat similar in terms of data and safety to ide-cel with lower-grade CRS. [With the investigational] PRIME-BCMA-101 [product], the CAR T cells do their job and then are out of the system quickly. There too, we are seeing low rates of CRS overall, as well as low [rates of] grade 3 or 4 CRS.

The efficacy and safety, as well as the vein-to-vein time, appear to be the keys [to getting CAR T-cell therapy into the clinic], but it is early. I’m curious to see how all of this evolves, especially with ide-cel and cilta-cel as frontrunners. 

Do the advantages of CAR T-cell therapy outweigh the disadvantages? Do you anticipate that bispecific antibodies or other therapeutic modalities will be given instead of CAR T-cell therapy if they receive FDA approval?

The advantages in favor of CAR T-cell therapies are that although it’s more labor intensive early on, they don’t require maintenance. Patients do enjoy that quality of life after having recovered from CAR T-cell therapy.

The disadvantages [include] production time and capacity of transplant centers, which play a role in discussing what may be the best option for patients. With the bispecific antibodies coming along, it is highly likely that we could see usage of antibody-drug conjugates and bispecific antibodies in the community setting even before patients come to see us for a CAR T-cell therapy consultation. There are a lot of nuances [to utilizing these products] that we will have to figure out once we have the therapies [available].

[Ultimately], the one-and-done approach that CAR T-cell therapy [provides] is quite unique and many patients will favor that.

Editor’s Note: This interview took place prior to the March 26, 2021, FDA approval of idecabtagene vicleucel in relapsed/refractory multiple myeloma. 

References

1. U.S. Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and bluebird bio. March 26, 2021. Accessed April 8, 2021. https://bwnews.pr/39jWjjd.
2. Munshi NC, Anderson Jr LD, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa results. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503
3. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor t cell therapy, in relapsed/refractory multiple myeloma. Presented at: 47th Annual Meeting of the EBMT; March 14-17, 2021; Virtual. Accessed April 8, 2021.
4. Form 20-F Legend Biotech Corp: Annual and transition report of foreign private issuers [sections 13 or 15(d)]. Accessed April 6, 2021. https://bit.ly/3fLKJ4h