Many Factors Influence Selection of CAR T Therapy, Bispecifics in Myeloma

"The first thing [to consider] when we talk about sequencing is that we have non-BCMA options. The mechanism of action, the duration of therapy, and the treatment-free interval to the apheresis of CAR T are important [factors], as well as the fusion of the CAR T product," according to Ajai Chari, MD.

Disease resistance mechanisms, adverse effect (AE) profiles, and other factors should be considered when selecting and sequencing treatment for patients with relapsed/refractory multiple myeloma, as suggested by Ajai Chair, MD in a presentation at the 2023 Society of Hematologic Oncology (SOHO) Annual Meeting.¹

“It’s remarkable in phase 1 studies, where we’re never usually supposed to talk about efficacy, we’re now getting 60% to 100% response rates,” Chari, director of the Multiple Myeloma Program and a professor of clinical medicine at the University of California, San Francisco, said during the presentation. “We’re [also] seeing these amazing [figures regarding] progression-free survival [PFS] and duration of response [DOR]. The question is, ‘we have such great tools, how do we use them thoughtfully and sequentially?’”

Available agents for relapsed/refractory multiple myeloma include CAR T-cell therapies and bispecific antibodies. Both classes of agent can target B-cell maturation antigens (BCMAs), and bispecific antibodies can also be directed towards G-protein–coupled receptor class 5 member D (GPRC5D), Fc receptor-homolog 5 (FcRH5), and CD3.

In terms of CAR T-cell therapy, in March 2021, idecabtagene vicleucel (ide-cel; Abecma) became the first BCMA-directed engineered tehrapy to be approved by the FDA for relapsed/refractory multiple myeloma. The agent is indicated for patients who had received at least 4 prior lines of therapy, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.² In February 2022, ciltacabtagene autoleucel (cilta-cel; Carvykti), also a BCMA-directed CAR T-cell therapy, was approved for the same patient population as ide-cel.³

The approval of ide-cel was supported by findings from the phase 2 KarMMa study (NCT03361748) and results from the phase 1/2 CARTITUDE-1 trial (NCT03548207) supported the indication for cilta-cel.^2,3

“We have these amazing CAR Ts, what’s the right place to use them?” Chari said. “Do we need to wait for patients to have 5 to 6 lines of therapy or might there be benefit from moving them earlier? Theoretically there could be benefit because of less T-cell exhaustion and better fitness [because of] less microenvironment inhibition, as well as [fewer] tumor alterations that come with repeated treatments.”

Chari then highlighted cohort 2a (n = 37) of KarMMA-2, which is evaluating ide-cel in patients with high-risk multiple myeloma who received 1 prior line of therapy and relapsed within 18 months of their initial treatment. The cohort met its primary end point, with 45.9% of patients achieving a complete response (CR) or better. Additionally, the overall response rate (ORR) was 83.8% (95% CI, 68.0%-93.8%). At a median follow-up of 21.5 months (range, 2-31), the median PFS was 11.4 months (95% CI, 5.6-19.6) and the median overall survival (OS) was not yet reached, with OS event-free rates of 88.0% (standard error [SE] ± 5.64%) and 84.7 % (SE ± 6.31%) at 12 and 24 months, respectively.⁴

Similarly, in cohort B (n = 19) of the phase 2 CARTITUDE-2 trial (NCT04133636) patients with progressive multiple myeloma following early relapse after treatment with a PI and an IMiD were treated with cilta-cel. The CAR T-cell agent displayed an ORR of 100% (95% CI, 82.4%-100.0%), including a 21% CR rate. The 18-month PFS rate was 83% (95% CI, 55.9%-94.3%) and the 18-month OS rate was also 83% (95% CI, 55.7%-94.2%).⁵

“The challenge here is we don’t have a lot of lot of historical data to put [these findings] into context,” Chari noted. “[However], this really is very encouraging and exciting for these early relapse patients.”

Next, Chari transitioned to speaking on bispecific antibodies, first spotlighting the BCMA/CD3-targeted agents teclistamab (Tecvayli) and elranatamab-bcmm (Elrexfio). Both agents have gained accelerated approval from the FDA for the treatment of patients with relapsed/refractory multiple myeloma.¹

In the phase 2 MajesTEC-1 trial (NCT04557098), patients with relapsed/refractory multiple myeloma who received teclistamab (n = 165) achieved an ORR of 63%, including 39.4% who had a CR or better. The median PFS was 11.3 months (95% CI, 8.8-17.1) and the median DOR was 18.4 months (95% CI, 14.9-not estimable [NE]).⁶

Findings from the phase 2 MagnetisMM-3 (NCT04649359) showed that patients with relapsed/refractory multiple myeloma who received at least 3 prior lines of therapy and received elranatamab (n = 123) experienced an ORR of 61%, including 35.0% with a CR or better. Notably, the median PFS and median DOR were both NE at 12 months.⁷

“There are some preclinical differences, some [BCMA-directed agents] have 2 binding domains to BCMA, some have lower affinity that might translate into less cytokine release syndrome [CRS],” Chari said. “The toxicities do have some ramifications for dosing and combinations.”

In MajecTEC-1, any-grade CRS (0.6%), infections (45%), and neutropenia (64%) were all reported.6 In MagnetisMM-3, no CRS was reported; any-grade infections and neutropenia occurred at rates of 35% and 48%, respectively.⁷

“With the single-arm studies, when you see deaths, it’s hard to know what they are from,” Chari said. “Is that because of the disease or the treatment? One concern that’s coming up here is that we’re seeing a fair amount of nonprogression deaths. With teclistamab there were 68 deaths, of which 41 were due to progression, and with elranatamab there were 21 deaths, 11 of which were due to progression. This is why [with] these drugs, [although] very, very powerful, we still need to do a lot of work to mitigate these infectious complications.”

Chari then referenced the bispecifc antibody talquetamab (Talvey), which has also received accelerated approval from the FDA, but differs from teclistamab and elranatamab in that it targets GPRC and CD3. Talquetamab was evaluated for patients with multiple myeloma who were intolerant to standard therapies and had received at least 3 prior lines of treatment in the phase 1/2 MonumenTAL-1 trial (NCT04634552).⁸

In MonumenTAL-1, talquetamab was administered to patients in 3 dosing groups: 0.4 mg/kg weekly (n = 143); 0.8 mg/kg every 2 weeks (n = 145); and either dose (n = 51). The respective ORRs were 74%, 72%, and 65%. The median PFS was 7.5 months, 14.2 months, and 5.1 months, respectively, and the median DOR was 9.5 months, not yet reached, and 11.3 months, respectively.⁸

GPRC-directed bispecific antibodies have generally led to less deaths, infections, and neutropenia, compared with BCMA-targeted bispecifics, Chari said. However, he noted that the safety profile of talquetamab differs from that of the BCMA-directed bispecifics, as it has led to more taste, skin, and nail AEs, which is something that clinicians need to weigh when determining which bispecific antibody their patient will receive. Chari also emphasized that combination regimens with GPRC-directed agents can be easier to build, since they don’t overlap with current drugs.¹

According to Chari, when sequencing BCMA-directed agents, either CAR T or bispecific, clinicians must be aware of the affect that prior treatments can have on the efficacy of the next agent. In CARTITUDE-1, patients who received cilta-cel achieved a median PFS of 34.9 months; however, in CARTITUDE-2, patients who received a previous BCMA-directed bispecific antibody or antibody-drug conjugate experienced a median PFS of 5.3 months and 9.5 months, respectively.¹

“This is really important and should give us pause when we think about treating our patients,” Chari said. “The first thing [to consider] when we talk about sequencing is that we have non-BCMA options. The mechanism of action, the duration of therapy, and the treatment-free interval to the apheresis of CAR T are important [factors], as well as the fusion of the CAR T product. [Additionally], you can have more protein and genomic loss of target at the time of progression, particularly with bispecifics that are repeatedly targeting the same antigen, as opposed to the more one-and-done CAR Ts.”

Chari also emphasized that a major consideration for clinicians choosing between CAR T-cell therapies and bispecific antibodies is the safety profiles of each class of agent. CAR T-cell agents lead to more high-grade CRS and immune effector cell–associated neurotoxicity syndrome, thus patients must be able to tolerate these AEs. Chari noted that bispefics could be advantageous in terms of managing AEs because therapy with these drugs can be paused or stopped based on AEs. Most disease factors favor CAR T-cell therapies; however patients who are experiencing rapid progression may benefit more from a bispecific antibody because manufacturing slot availability can be an issue with CAR T, he said.¹

“If we had to pick between CAR Ts and bispecifics, I think we all want that Rolls Royce Phantom [CAR T],” Chari said in conclusion. “But Phantoms are hard to get and until that it’s the [bispecifics] that make the world go round. In the short term, bispecifics will probably be more broadly applicable. If you have a rapidly progressing patient, consider a bispecific, and if you have an indolent patient [then consider] CAR T, but eventually we're going to need to sequence all of these.”

References

1. Chari A. BCMA/GPRC5D/FcRH5—CARs/BsAbs—how to choose. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.
2. US 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 September 8, 2023. https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-and-bluebird-bios-Abecma-idecabtagene-vicleucel-the-First-Anti-BCMA-CAR-T-Cell-Therapy-for-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
3. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Accessed September 8, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma
4. Usmani S, Patel K, Hari P, et al. KarMMa-2 cohort 2a: efficacy and safety of idecabtagene vicleucel in clinical high-risk multiple myeloma patients with early relapse after frontline autologous stem cell transplantation. Blood. 2022;140(suppl 1):875-877. doi:10.1182/blood-2022-162469
5. Einsele H, Cohen AD, Delforge M, et al. Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in lenalidomide (len)-refractory patients (pts) with progressive multiple myeloma (MM) after 1–3 prior lines of therapy (LOT): CARTITUDE-2, cohort A. J Clin Oncol. 2023;40(suppl 16):8020. doi:10.1200/JCO.2022.40.16_suppl.8020
6. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478
7. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. Published online August 15, 2023. doi:10.1038/s41591-023-02528-9
8. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from MonumenTAL-1. Blood. 2022;140(suppl 1):384-387. doi:10.1182/blood-2022-159707