Questions Arise As CAR T-Cell Therapy and Bispecific Antibody Use Increase in Relapsed/Refractory Myeloma

With CAR T-cell therapies such as ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma) begin to move into earlier lines of therapy for the treatment of patients with relapsed/refractory multiple myeloma, several challenges have emerged, including patient access to CAR T-cell therapy and sequencing strategies between CAR T-cell therapy and bispecific antibodies, according to Prerna Mewawalla, MD.

In April 2024, the FDA approved cilta-cel for the treatment of patients with relapsed/refractory multiple myeloma who were treated with at least 1 line of therapy that included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and were refractory to lenalidomide (Revlimid).1 Data from the phase 3 CARTITUDE-4 trial (NCT04181827) trial supported the approval. At a median follow-up of 15.9 months (range, 0.1-27.3), the median progression-free survival (PFS) was not reached compared with 11.8 months (95% CI, 9.7-13.8) in the cilta-cel (n = 208) and standard of care (SOC; n = 211) arms, respectively (HR, 0.26; 95% CI, 0.18-0.38; P < .001).2

Furthermore, the FDA also approved ide-cel in April 2024 for the treatment of patients with relapsed/refractory multiple myeloma after 2 or more prior lines of therapy, including a PI, IMiD, and an anti-CD38 monoclonal antibody.3 The approval was based on findings from the phase 3 KarMMa-3 trial (NCT03651128).At a median follow-up of 18.6 months (range, 0.4-35.4), the median PFS was significantly longer in the ide-cel arm compared with the SOC arm, at 13.3 months (95% CI, 11.8-16.1) vs 4.4 months (95% CI, 3.4-5.9), respectively (HR, 0.49; 95% CI, 0.38-0.65; P < .001).4

“Although the data are exciting when it comes to bispecific antibodies and CAR T-cell therapy, it’s important to emphasize the need for individualized patient selection and improving access for patients to CAR T-cell therapy and bispecific antibodies,” Mewawalla explained in an interview with OncLive®. “If we can get bispecifics to the community, it’ll go a long way. It’s only a matter of time before it happens. The new REMS [Risk Evaluation and Mitigation Strategies] update is very promising for CAR T-cell therapy, where patients do not have to stay close to a CAR T-cell therapy center for 4 weeks. They can stay 2 weeks instead of 4 weeks, with a decrease in driving restrictions. All of these [aspects] will also improve access to CAR T-cell therapy for patients.”

In the interview, Mewawalla highlighted ongoing sequencing strategies with CAR T-cell therapies and bispecific antibodies, the clinical implications of CAR T-cell therapies moving into earlier lines of treatment, and toxicity management approaches for CAR T-cell therapies and bispecific antibodies in patients with relapsed/refractory multiple myeloma.

Mewawalla is an associate professor at Drexel University College of Medicine in Philadelphia, Pennsylvania, as well as the medical director of apheresis and a hematologist-oncologist in the Division of Hematology and Cellular Therapy at Allegheny Health Network in Pittsburgh, Pennsylvania.

OncLive: What is currently known about the optimal sequencing of CAR T-cell therapies and bispecific antibodies in multiple myeloma?

Mewawalla: That’s a moving target. [The International Myeloma Working Group] released its guidelines in July 2025, and they recommended, whenever possible, to use CAR T-cell therapies before bispecific antibodies because CAR T-cell therapies can offer a deeper, more durable response, and we would want to prioritize it as much as possible whenever it is feasible to do so.

However, bispecific antibodies are off-the-shelf. We have faster access to them and they are easy to use. For patients with rapid disease progression for whom we don’t have the luxury of waiting for a washout period waiting for the production of CAR T-cell therapy, bispecific antibodies might be the [right choice]. So far, there have not been prospective sequencing trials yet. Therefore, clinical judgment and individualized patient care still drives what we need to do.

What were the clinical implications of the April 2024 FDA approvals of cilta-cel and ide-cel in earlier lines of therapy?

For some background, cilta-cel has now been FDA-approved after 1 prior line [of therapy] and ide-cel has been approved after 2 prior lines of treatment, and they are no longer a last-ditch effort for [patients with] relapsed/refractory multiple myeloma. [These decisions] move CAR T-cell therapy into earlier lines, and in earlier lines patients also have better T-cell fitness, and their diseases are also better controlled. This is going to redefine the standard of care at first relapse for high-risk patients, and it also forces reevaluation of post CAR T-cell treatment strategies, because, so far, we have been using CAR T-cell therapies in later lines. If we do use CAR T-cell therapies earlier on, what treatments are available to us after?

What are the remaining unanswered questions regarding CAR T-cell therapy in earlier lines of therapy?

There are several. One, what happens after early CAR T-cell therapy relapse? Our current salvage options and sequencing after using early CAR T-cell therapy are not clearly defined. Do we go to bispecific antibodies later? Do we go to our traditional regimens after? This truly needs to be defined after [using] early CAR T-cell therapy. Secondly, there are trials [assessing whether] any maintenance therapy is required after some of these CAR T-cell treatments to get more durable responses. That’s another question that still needs to be answered. Thirdly, can we scale access to meet the growing demand [for CAR T-cell therapy], because these therapies are resource-intensive, and the infrastructure remains a limiting factor in many areas. How do we get CAR T-cell therapies to patients who live far away and don’t have access to an academic center or a transplant site that offers them? These are the big questions that need to be addressed.

What should be known about CAR T-cell therapy and bispecific antibody toxicity management?

The most common toxicities are cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] post CAR T-cell therapy, but as time has gone by and as we’ve been using CAR T-cell therapies for a while, we have become more comfortable with managing these toxicities and also using drugs like tocilizumab [Actemra] earlier in treating CRS. All of these treatment aspects have made CAR T-cell therapy more manageable than it previously was. Supportive care is also critical for [managing] infections and prolonged cytopenias. Recently, an update from CARTITUDE-4 did not show any new long-term neurotoxicities, which was promising.

With bispecific antibodies, we see CRS as well, and it’s very common. However, the good thing is that most of the time, it tends to be low-grade and an early-onset neurotoxicity. Compared with CAR T-cell therapy, [ICANS] is rare with bispecific antibodies. [Regarding CRS,] many data are coming out about using prophylactic tocilizumab for bispecific antibodies, which will enable patients to even receive a ramp-up of their bispecific antibodies outpatient by using prophylactic tocilizumab. That would [also help] increase access to these bispecific antibodies. The other unique [aspect] is that—especially BCMA bispecific antibodies—have a higher risk of infections. It’s very important to know all the prophylaxis we need to [have], including antiviral prophylaxis, CMV-IVIg prophylaxis when needed, and PJP prophylaxis. On the other hand, we also have talquetamab [Talvey], which has unique [adverse] effects [AEs], which are very different from our BCMA bispecific antibodies. When it comes to skin, nail, and taste changes, and weight loss, all of these AEs get better with time. We also have all gotten better with using talquetamab; however, recognizing these AEs and knowing how to prevent them, and educating patients on these AEs even before we start these therapies is just so important.

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 August 5, 2025. 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. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379
3. 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 August 5, 2025. 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
4. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614