Bispecifics vs CAR T-Cell Therapy: Which Is Better in Relapsed/Refractory Multiple Myeloma?

Saad Z. Usmani, MD

Newer treatment modalities are changing the landscape for patients with relapsed or refractory multiple myeloma who have received multiple prior therapies.

Chimeric antigen receptor (CAR) T-cell therapy is one such newer class of therapy to be introduced into the treatment paradigm for multiple myeloma, and bispecific antibodies are the expected next class of treatments to emerge in the clinic. As such, many questions remain about the optimal sequence and usage of these agents across the course of treatment, including: Which treatment type is better in this heavily pretreated population? Which one is safer, more effective? Are there particular patient populations that would benefit more from one method over the other? Which one should be used first, and would it prevent usage of the other?

“[We] have these effective treatments, and we don’t have a good idea of which patients benefit from one strategy vs the other,” Saad Z. Usmani, MD, MBA, FACP, explained to The SOHO Daily News prior to the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

Together, Usmani and Thomas G. Martin, MD, will attempt to answer some of these questions today in a debate entitled “T-Cell Engagers vs CAR T-Cell for RRMM,” with Usmani, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, New York, first defending bispecifics, and Martin, associate director of the Myeloma Program at University of California San Francisco and co-leader of the Cancer Immunology and Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center in San Francisco, California, defending CAR T-cell therapy.

The New Kid on the Block

Bispecific antibodies are antibodies that have 2 binding sites; Usmani explained that one binding site was directed at a surface marker on the cancer cell, and the other at a surface marker on an immune cell, to allow the T cell, or natural killer cell, to destroy the cancer cell.

Bispecifics are an area of great interest in multiple myeloma among clinicians and researchers; however, this interest has yet to be manifested as no agents are currently approved in the United States. There are at least 5 promising agents in development, with regulatory favor already being granted to some.

Teclistamab (Tecvayli®; Janssen), a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, was granted conditional marketing authorization from the European Commission in late August 2022 as treatment for patients with relapsed/refractory multiple myeloma who have underwent treatment with 3 previous therapies, including an immunomodulatory agent, a proteosome inhibitor, and an anti-CD38 antibody, as well as who have progressed on their last therapy.1 A biologics license application for the bispecific was also submitted to the FDA in December 2021.²

In the phase 1/2 MajesTEC-1 trial (NCT03145181 and NCT04557098), teclistamab demonstrated an overall response rate of 63.0%, including a complete response or better in 39.4% of patients with relapsed/refractory multiple myeloma after at least 3 prior lines of therapy, including triple-class exposure to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. The minimal residual disease negativity rate was 26.7%. Median duration of response was 18.4 months and the median progression-free survival was 11.3 months.³

Talquetamab, a GPRC5D x CD3 bispecific antibody, has been granted a breakthrough therapy designation and an orphan drug designation from the FDA as a treatment for adult patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy, including with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody.⁴

In the phase 1/2 MonumenTAL-1 study (NCT03399799 and NCT04634552), talquetamab demonstrated an overall response rate of 70%, with 57% achieving very good partial responses or better in heavily pretreated patients with relapsed/refractory multiple myeloma. The duration of response rate at 6 months was 67% in the lower dose cohort.⁵

“There’s a lot of competition in that space, and I think activity-wise, they’re going to be similar. Safety profile, route of administration, [and] frequency of administration will probably be different,” Usmani said when comparing the bispecifics currently in development.

“The sequencing question is something that we are all struggling with, but there are pros and cons to each of the sequencing strategies,” Usmani said. “You also have to pay attention to patient preference.”

He noted that anecdotal experience has shown that if someone receives a BCMA-directed CAR T-cell therapy and is relapsing after a year, then there’s no reason why they cannot receive a BCMA-directed bispecific antibody if they are still expressing BCMA. However, there is currently not much evidence for the opposite sequence, which may change once a bispecific drug is approved in the space.

Pros and Cons of Bispecifics

As bispecific antibodies are an off-the-shelf treatment, Usmani said that “if I see a patient today who needs a BCMA-directed treatment, I would be able to administer that drug to that patient very quickly,” which is not possible with CAR T-cell therapies.

Additionally, older patients with relapsed/refractory multiple myeloma or those with comorbidities may not be able to receive CAR T-cell therapy, but it may be easier for these patients to receive bispecific antibodies.

However, as no treatments have yet been approved in multiple myeloma, there is still a lot unknown about these agents once they do enter the clinic, so Usmani said that it will be a learning curve for the oncology community, and only academic centers may be able to administer these treatments in the near future.

Adequate T-cell collection is also an area of concern in order for bispecifics to work well, and the chance of infection can also be higher with bispecific antibodies. “But since we don’t have long-term follow-up with bispecifics, we don’t know the real magnitude of that infection risk, so we need some more clarity around that,” Usmani said.

The Case for CAR

Martin explained that CAR T-cell therapy is human T lymphocytes in which a gene has been inserted, typically using a retrovirus or adenovirus, and the gene has an extracellular domain that binds to the cell of interest, a transmembrane domain, and an intracellular signaling domain.

To date, 2 CAR T-cell therapy products have been approved for use in relapsed/refractory multiple myeloma: idecabtagene vicleucel (ide-cel; Abecma®; Bristol Myers Squibb) and ciltacabtagene autoleucel (cilta-cel; Carvykti™; Janssen). Both of these agents target BCMA, which is a target of great interest in multiple myeloma as it is highly expressed on malignant plasma cells.

Ide-cel was first approved on March 26, 2021, for the treatment of adult patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.⁶

The approval was based on the results of the phase 2 KarMMa trial (NCT03361748). In the study, 128 patients with relapsed/refractory multiple myeloma who had received a median of 6 prior lines of therapy (range, 3-16), received varying doses of ide-cel. After a median follow-up of 13.3 months, 73% of patients had achieved a response from any of the 3 dose levels. Thirty-three percent of patients achieved a complete response or stringent complete response, and of these patients, 79% also had minimal residual disease negativity. In patients who achieved the highest dose level, the response rate was 81% and the complete response/stringent complete response rate was 39%.⁷

The updated median progression-free survival was 8.6 months, and the median overall survival was 24.8 months.⁸

Next, cilta-cel was approved on February 28, 2022, for adult patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.⁹

Supportive findings came from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which both Martin and Usmani were involved in, showing a very high response rate in a similarly heavily pretreated patient population as in the KarMMa trial. In CARTITUDE-1, all patients had received 3 or more prior lines of therapy or were double-refractory to a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody. Overall, the 97 eligible patients had received a median of 6 lines of prior therapy (range, 4-8). The overall response rate was 97% and stringent complete responses were reported in 67%.¹⁰

Updated 2-year survival findings for the trial showed that both the median progression-free survival and median overall survival still had not been reached.¹¹

“These data are unprecedented and demonstrated the deep and durable responses achieved following CAR T-cell therapy,” Martin said. “No other FDA-approved agent has shown such promise in the relapsed and refractory (also known as triple-class refractory) space, and thus these agents are preferred for eligible patients.”

“Unfortunately, the demand for these therapies has outpaced the supply, and many who may be eligible don’t have access, even when 2 different CAR T-cell products are available,” Martin added.

Pros and Cons of CAR T-Cell Therapy

Martin explained that one of the benefits of CAR T-cell therapy is that it is a onetime treatment, whereas bispecifics are longer-term treatments, with the drug often needing to be administered over a period of a year or more. This results in an improved quality of life, which is important to the patient.

Additionally, CAR T-cell therapy induces a robust immune response and early on. Many patients are able to avoid subsequent treatment for many months to years.

On the other hand, Martin noted that “CAR T-cell therapy is not off-the-shelf, and a patient has to have significant family and caregiver support, including the ability to travel to a CAR T-cell therapy center and remain there for approximately 1 month,” in part due to the lengthy time required to manufacture the T cells. These demands are not made with bispecific antibody treatments.

Cytokine release syndrome, while also seen with bispecific antibodies, is more of a concern with CAR T-cell therapies, but mitigation strategies are actively being investigated.

Where They Agree

Usmani and Martin agreed that perhaps both bispecific antibodies and CAR T-cell therapies can be used in patients over time and over the full course of treatment for patients with multiple myeloma.

“Ideally, I would like some sort of an optimal sequencing strategy where we can utilize these therapies for our patients. What we don’t want is taking one treatment and then seeing [that] patients may not qualify for the others. We want our patients to get the benefit from each of these strategies,” Usmani said.

Martin suggested that if, when used together, each agent could target a different cell surface protein, then it could potentially be a curative approach.

_REFERENCES:

_{1. Janssen marks first approval worldwide for TECVAYLI (teclistamab) with EC authorisation of first-in-class bispecific antibody for the treatment of patients with multiple myeloma. News release. Janssen. August 24, 2022. Accessed August 30, 2022. https://bit.ly/3wsRYFP}

_{2. Janssen submits biologics license application to U.S. FDA seeking approval of teclistamab for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. December 29, 2021. Accessed August 30, 2022. https://bit.ly/3x3uO9k}

_{3. 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}

_{4. Janssen announces U.S. FDA breakthrough therapy designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. News release. Janssen. June 29, 2022. Accessed August 30, 2022. https://bit.ly/3x18bSS}

_{5. Minnema MC, Krishnan AY, Berdeja JG, et al. Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): updated results from MonumenTAL-1. J Clin Oncol. 2022;40(suppl 16):8015. doi:10.1200/JCO.2022.40.16_suppl.8015}

_{6. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. Updated March 29, 2021. Accessed August 29, 2022. https://bit.ly/3RnN71g}

_{7. Munshi NC, Anderson LD, 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}

_{8. Anderson LD, Munshi NC, Shah N, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: updated KarMMa results. J Clin Oncol. 2021;39(suppl 15):8016. doi:10.1200/JCO.2021.39.15_suppl.8016}

_{9. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. Updated March 7, 2022. Accessed August 29, 2022. https://bit.ly/3cQ1exd}

_{10. 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}

_{11. Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti–B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-Year follow-up. J Clin Oncol. Published online June 4, 2022. doi:10.1200/JCO.22.00842}