Improving Durability of Responses Is a Key Next Step for CAR T-cell Therapy in Myeloma

Although the BCMA-directed CAR T-cell therapies idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) have altered the treatment landscape for patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy, work remains to improve the durability of responses and address sequencing questions as other treatments emerge, according to Susan Bal, MD.^1,2

“We know that patients who have had BMCA-targeted therapy and go on to receive GPRC5D-targeted therapy do respond, so we need to find new targets and also work on the durability of responses to CAR T-cell therapies,” Bal explained.

In an interview with OncLive^®, Bal, an assistant professor of Hematology/Medical Oncology at the University of Alabama at Birmingham (UAB), UAB Health, O’Neal Comprehensive Cancer Center, discussed the data that supported the FDA approvals of ide-cel and cilta-cel, how the implementation of these agents has shifted how patients with later-line relapsed/refractory multiple myeloma are treated, and the challenges that still need to be addressed with CAR T-cell therapy.

OncLive: What have the addition of the CAR T-cell therapies ide-cel and cilta-cel meant for the treatment paradigm in multiple myeloma?

Bal: CAR T-cell therapy represents a remarkable advancement in the field of all hematologic malignancies, including multiple myeloma. Currently, there are 2 FDA-approved CAR T-cell products available: ide-cel and cilta-cel, which are approved for patients with later-line multiple myeloma.

These [CAR T-cell therapies] have shown response rates that exceed 80% and have shown durability of response, particularly in the context of triple-class refractory myeloma. However, what's even more exciting is the exploration of these therapies in earlier lines of [treatment] when patients are more fit and their immune system is hopefully more robust, to see how these responses could be improved.

Additionally, there are other targets on myeloma cells that are being explored [with other CAR T-cell therapies], including GPRC5D, which we hope will provide additional options, particularly for patients who have disease progression on approved [CAR T-cell] therapies and [those] in earlier lines [of treatment]. There are several approaches that we are working on to improve the constructs and the durability of responses [with] the CAR T-cell products that are currently available.

Could you expand on the data that led to the 2021 FDA approval of ide-cel?

The first anti-BCMA CAR T-cell [therapy] that was FDA approved was ide-cel. This is a second-generation CAR T-cell product. It has CD3 zeta as the T-cell activation domain and 4-1BB as the costimulatory domain. This product was approved by the FDA based on the phase 2 KarMMA trial [NCT03361748], which evaluated its safety and efficacy in dose ranges from 150 x 10⁶ to 450 x 10⁶ cells. In the study, a total of 140 patients were accrued, of which 128 received [ide-cel]. Most of these patients [84%] were triple-class refractory. The median age of this study population was a bit younger than our traditional [patients with] myeloma at 61 [years], and the median prior lines of therapy was 6.³

CAR T-cell [therapies] have some unique adverse effects [AEs], including cytokine release syndrome [CRS]. In this study, most patients [85%] experienced [any-grade CRS]. However, [the rate of] grade 3 or higher [CRS] was [9%]. There were also neurologic events that occurred, known as immune effector cell–related neurotoxicity syndrome [ICANS]. However, this was less common than what we have frequently seen in lymphoma, occurring in 18% of patients, with more serious grade 3 or higher toxicity occurring in a small minority at 3%.

The responses on the study were very exciting, particularly in this patient population, with an overall response rate [ORR] of 73% in the overall study. In patients who got the highest dose level, which was 450 x 10⁶ cells, the ORR was [81%], and 38% of these were complete responses [at the highest dose level], which was very exciting.

The median progression free survival [PFS] was 8.8 months for the entire study. In the highest dose cohort, [the median PFS was 12.1 months]. For the whole study, the median overall survival [OS] was [19.4 months].

What key findings supported the FDA approval of cilta-cel?

Cilta-cel is another second-generation anti-BCMA CAR T-cell [therapy]. This also has a CD3 zeta activation domain and 4-1BB as the costimulatory domain. However, it does have 2 BCMA-targeting single-chain variable fragments, which do increase its activity to and avidity to multiple myeloma. This is the only other FDA-approved CAR T-cell therapy [in multiple myeloma] other than ide-cel.

This was studied in the phase 1b/2 CARTITUDE-1 trial [NCT03548207] that enrolled 113 patients, and 97 went on to receive cilta-cel [between] phase 1b and phase 2. What was interesting was that there was a flat dosing of 0.75 x 10⁶ CAR-positive T cells/kg that was used on this study.⁴

The baseline characteristics of the patients in this study were very similar to KarMMA, with a similar median age of 61 years, and patients had received a median of 6 prior lines of therapy. Eighty-eight percent of the patients were triple-class refractory.

In this study, we saw a high [rate] of overall CRS [95%], but [only 4% had grade 3/4 CRS]. However, we saw a signal for ICANS and a signal for late-onset neurotoxicity, which were some peripheral neuropathies, as well as movement and neurocognitive changes that occurred in 12% of patients, [including 8% with grade 3/4 events]. This was a little bit different than what we had observed with ide-cel and definitely requires ongoing monitoring in these patients.

However, what was astounding was the ORR of 98%, with [78%] of the patients having a stringent complete response. A vast majority [93%] of those evaluable [n = 57] were minimal residual disease negative at 10^-5. That was impressive for any setting, particularly in this late-line setting. The [12-month] PFS [rate] for the whole study was [77%], and [this rate was 85%] when looking at just the patients who had had a complete response [or better]. The 12-month] OS [rate] was [89%].

What unmet needs remain to be addressed regarding CAR T-cell therapy in multiple myeloma?

One of the biggest things that we as a field need to improve upon is the durability of these responses. We see very early, quick responses [with] a lot of patients getting to a deep level of response [within] the first month. However, patients continue to relapse. There are still no plateaus on these PFS curves, and people are still progressing and dying from relapsed disease.

There is a lot left to be desired for CAR T-cell therapies in multiple myeloma. One of the other challenges ahead of us is [investigating other] targets. Both of the FDA-approved CAR T-cell therapies are against BCMA. What happens when patients relapse on these therapies? Exploring other targets on the myeloma cell will be of paramount importance, including GPRC5D, for which we have already seen some data at the 2022 ASH Annual Meeting.

Additionally, now we have teclistamab-cqyv [Tecvayli], which is a bispecific antibody that's FDA approved [after at least 4 prior lines of therapy] and also targets BCMA. We don't [yet] understand the kinetics of how patients do when they're first treated with a BCMA-directed CAR T-cell therapy vs a bispecific. Is there an appropriate sequence, or should there be a sequence at all? That is also going to be a point that will be hopefully clarified over time.

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 May 26, 2023. https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration
2. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. News release. FDA. February 28, 2022. Accessed May 26, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
3. Munshi NC, Anderson ND, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850
4. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8