Weighing the Benefits and Limitations of CAR T-Cell Therapy and Bispecific Antibodies in Multiple Myeloma

The use of idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (Carvykti; cilta-cel) in earlier lines of therapy continues to lead to deep responses in patients with relapsed/refractory multiple myeloma. Despite this, the limitations of this drug class continue to impede their widespread implementation and benefit, according to James Ignatz-Hoover, MD, PhD, who added that the next-generation products may mitigate these concerns.

“The next generation of CAR T products are addressing some of those vein-to-vein issues, cost issues, and [seeking to] improve efficacy,” said Ignatz-Hoover, who is a hematologist/oncologist at the University Hospitals Seidman Cancer Center, in Cleveland, Ohio. “Especially given the recent FDA expansion of both ide-cel’s and cilta-cel’s [respective] labels, the myeloma space is becoming more and more interesting and complex each day.” In the meantime, bispecific antibodies offer an alternative, off-the-shelf therapy for patients who require immediate treatment, and are generally better tolerated than CAR T-cell therapies, Ignatz-Hoover noted.

On April 5, 2024, the FDA expanded the indication for cilta-cel to include adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody, and are refractory to lenalidomide (Revlimid).¹ This regulatory decision was concurrent with the FDA’s label expansion for ide-cel to include patients with relapsed/refractory multiple myeloma after 2 or more prior lines of therapy.²

In an interview with OncLive®, Ignatz-Hoover discussed the latest advancements in managing multiple myeloma, focusing on bispecific antibodies and CAR-T cell therapy. Specifically, he shed light on the expansion of the later-line treatment arsenal with the approvals of teclistamab-cqyv (Tecvayli), elranatamab-bcmm (Elrexfio), and talquetamab-tgvs (Talvey); the impact of moving ide-cel and cilta-cel into earlier treatment lines; and efforts to overcome practical barriers to achieving benefit with CAR-T cell therapy.

OncLive: Which bispecific antibodies are changing the field in multiple myeloma?

Ignatz-Hoover: The cup runneth over in myeloma. We have agents that target BCMA: those are elranatamab and teclistamab. Then we have talquetamab, which targets GPRC5D. These [have] all [received] accelerated approvals for patients who have previously received 4 lines of therapy and are triple-class exposed. Patients must have received at least 1 PI, 1 CD38 inhibitor and 1 iMID.

With this expanded arsenal, what factors do you consider when selecting treatment?

Treatment selection is really challenging right now because the FDA indications for these agents are all the same. Their profiles, according to data from the [respective] trials supporting their accelerated approvals, are all very similar. They all are generating an approximately 60% overall response rate, with a significant portion of patients achieving very good partial response or better. The median progression-free survival is very similar amongst these different agents. However, we don’t have head-to-head comparisons, so we can’t say which one is better.

There are some differences potentially in adverse effect [AE] profile that talquetamab has, including hair, nails, and oropharyngeal AEs, that teclistamab doesn’t. In theory, teclistamab has a [bit higher] risk of infection, but they both are associated with infection risks. [Their use] will end up [being decided based on] local practice patterns—at least initially, until we learn a little more about how these specific agents work in different treatment settings.

What questions remain regarding the optimal sequencing of CAR T-cell therapies and bispecific antibodies? What are the advantages of bispecific antibodies vs CAR T in this space?

That’s a very important clinical discussion and an active area of research. How do we sequence these agents? In general, cilta-cel and ide-cel both [induce] wonderfully deep responses in patients who are heavily pretreated. You do need to be ready for an extended vein-to-vein time to perform leukapheresis in your patients, send the cells out to the pharmaceutical company, transduce, expand the cells, and then give them back to your patient. Extended vein-to-vein time is an issue.
[With] next-generation CAR T cells, [we] are trying to change this. A lot of academic centers, including our own, are developing in-house CAR T cells and rapid manufacturing protocols will lower this vein-to-vein time.

However, right now, bispecific antibodies offer an off-the-shelf therapy for a patient who needs therapy [right away] and can’t wait up to 4 to 6 weeks for the CAR T product to come. Bispecific antibodies are also generally well tolerated and are better tolerated than a CAR T-cell therapy. CAR T-cell therapies themselves are better tolerated than autologous transplant. It is all on a spectrum of options that we could be offering older and frailer patients [with multiple myeloma].

References

1. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed May 24, 2024. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy
2. US FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb and 2seventy bio, Inc. April 4, 2024. Accessed May 24, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibb-and-2seventy-bios-Abecma-for-Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma-After-Two-Prior-Lines-of-Therapy/default.aspx