Sequencing, Access, and Eligibility Drive CAR T-Cell Therapy Decisions in Early Relapse Myeloma

With CAR T-cell therapy and a bispecific antibody–based regimen approved by the FDA in the second-line setting for patients with relapsed/refractory multiple myeloma, further integrating these types of therapies earlier in the treatment course vs other standard-of-care (SOC) regimens is a key focus for the field, according to Peter Voorhees, MD.

“As long as a patient is getting a T-cell–redirecting therapy in the early relapse space, patients are winning the game,” Voorhees said in an interview with OncLive^®. “The key thing is to get these therapies out to all patients.”

With ciltacabtagene autoleucel (cilta-cel; Carvykti) and the combination of teclistamab-cqyv (Tecvayli) and daratumumab (Darzalex) both FDA approved for use as early as first relapse, Voorhees explained the rationale for utilizing T-cell–redirecting therapies earlier in the treatment course and how that could affect patient efficacy and safety outcomes.^1,2 In the interview, Voorhees also explained how he determines whether a patient is a candidate for CAR T-cell therapy, how to approach treatment decision-making with patients in the early relapse setting, and what these decisions mean for subsequent treatment sequencing.

Voorhees is a member of the Department of Hematology/Medical Oncology (Cancer) at Atrium Health and a professor of cancer medicine at the Wake Forest University School of Medicine, both in Charlotte, North Carolina.

OncLive: How are CAR T-cell therapies currently being integrated into earlier lines of treatment for patients with relapsed/refractory multiple myeloma?

Voorhees: The data [for CAR T-cell therapy] for early relapse are quite positive. Compared with existing SOCs, [we see] higher response rates, more meaningful responses, and deeper responses, and that has translated into clear improvements in progression-free survival [PFS] and overall survival, with regard to cilta-cel. We have a new SOC in the early relapse space for those patients who are eligible and have the logistical wherewithal to access CAR T-cell therapy.

From my perspective, from a safety standpoint, particularly when we think of cilta-cel, applying it in the early relapse space is a lot easier than using it in patients who are heavily pretreated and have disease that’s more resistant to numerous classes of drugs. That’s largely due to the fact that you’re much more easily able to control the disease [in the early relapse setting] prior to T-cell apheresis and during bridging therapy when the CAR T cells are being manufactured. [This can lead to] a lower disease burden going into the CAR T-cell infusion, translating into a lower risk of high-grade cytokine release syndrome [CRS], high-grade immune effector cell–associated neurotoxicity syndrome [ICANS], Parkinsonism, and prolonged, deep cytopenias. For many reasons from a safety standpoint, using these [CAR T-cell therapies] in early relapse is more advantageous than using them as a last-ditch effort in the heavily pretreated patients.

Additionally, in the [phase 1/2] CARTITUDE-1 trial [NCT03548207], for those [more heavily pretreated] patients who had the most durable remissions, their disease burden was lower going into the CAR T-cell infusion. Therefore, we think a lower disease burden going into the infusion not only is important from a safety standpoint, but it optimizes the effector-to-target ratio, and that translates into more durable remissions, as well.

You mentioned considering CAR T-cell therapy in the early relapse setting for patients who are eligible. What factors are you looking at in terms of determining if a patient is an ideal candidate for CAR T-cell therapy in this setting?

For frail patients, those who may be older, and certainly those with multiple comorbidities, you have to think carefully before you pursue CAR T-cell therapy. How would that patient fare if they experienced grade 2 or 3 CRS? How would that patient with cognitive impairment tolerate potential neurotoxicity associated with CAR T-cell therapy and the potential risk of ICANS? All of that has to be taken into consideration.

There’s also the logistical piece [to consider], and one of the biggest barriers that we oftentimes identify at our center is caregiver support. Especially if we want to try to [give CAR T-cell therapy] on the outpatient side, do [these patients] have access to reliable caregivers who can keep eyes on these individuals 24/7 during those initial critical 2 weeks of observation after the CAR T-cell infusion? How far away are they from the center? Do they have transportation issues or other issues that you need to mitigate in order to improve access? [Eligibility for CAR T-cell therapy] breaks down to comorbidities and then logistical considerations.

With access being a focal point for improvement since the introduction of CAR T-cell therapy to clinical practice, what strategies have helped more patients receive this type of treatment?

There are support services, [such as] coverage of local lodging, for patients who live further away from a CAR T-cell center, so that can address the costs of transportation and lodging. However, if a patient’s caregiver has a job that they can’t go away from because they’re going to be at risk of becoming unemployed, then you’ve got a problem on your hands. One of the other things that we’ll do for patients who don’t have as reliable caregiver support is admit those patients and just do those initial 2 weeks of monitoring on the inpatient side. Patients prefer to do this on the outpatient side, and that’s what we do in the majority of instances. However, if someone doesn’t have that 24/7 caregiver support, especially for those first 2 weeks, we’ll manage those patients in the hospital.

That said, the following 2 weeks [during] the first month after CAR T-cell infusion are also important, where you’re on the lookout for potential later toxicities of the infusion. [Patients] still need reliable caregiver support, and [they need] the ability to travel back and forth to the CAR T-cell center, even after those first initial 2 weeks. That’s going to be an important consideration [when considering CAR T-cell therapy for a patient].

In 2026, teclistamab–based treatment and a CELMoD-based combination have both been approved for use as early as the first-relapse setting.^2,3 With multiple options, how to you weigh these potential approaches vs CAR T-cell therapy?

When it comes to the phase 3 data that we have now with CAR T-cell therapy and the bispecific antibodies in early relapse, the key take-home point is that patients deserve a chance at T-cell–redirecting therapy, and the discussion comes down to CAR T-cell therapy vs bispecific antibody therapy.

[For instance], if we have a frail patient with multiple comorbidities, there are risks associated with bispecific antibodies in that patient population, as there are with any therapy in a frailer patient population, but I think the bispecific antibodies are easier to navigate for a frailer patient population with more comorbidities. If you have a patient who has some of those logistical access issues, it’s a bit easier to navigate those barriers with bispecific antibody therapy than it is with CAR T-cell therapy. [Patients] don’t need 24/7 monitoring for 2 weeks with a bispecific antibody, so that’s an important consideration.

Otherwise, patient preference is incredibly important, and the discussion I have now with patients in first relapse is very long. You have to explain the logistics of the 2 different approaches: [CAR T-cell therapy and a bispecific antibody]. You have to explain the risks associated with the 2 different approaches and come to a decision. We might have a young, fit patient who thinks that a 0.5% risk of Parkinsonism with cilta-cel is unacceptable, and they may choose teclistamab and daratumumab for that reason. It’s a shared decision-making process, and you have to outline the logistics and the safety profiles of the different choices to help them navigate that decision.

When I am having that discussion with patients, the sequencing piece of this becomes critically important. When you’re thinking about CAR T-cell therapy vs bispecific antibodies, thinking about the patient’s age and risks is incredibly important. If you have a patient who’s, say, 83 years old and is relapsing for their first time, teclistamab plus daratumumab may be the last line of therapy they ever need. The sequencing issue doesn’t even really come into the discussion [for these older patients, but] you have to think about the long game when you’re making these decisions with patients.

When you are projecting later lines of therapy and how regimens will be sequenced, how do you weigh using sequential T-cell–redirecting therapies vs sandwiching another type of regimen between them?

All the data on sequencing T-cell–redirecting therapies are in the heavily pretreated population in that late-relapse space. How this all applies to early relapse remains to be seen, and we have to do all those real-world analyses. However, what we know from the late-relapse space is that CAR T-cell therapy followed by a bispecific antibody does seem to be a more effective strategy. That said, when you look at BCMA-directed CAR T-cell therapy and BCMA-directed bispecific antibody therapy, if a patient received a BCMA bispecific antibody before BCMA-directed CAR T-cell therapy, the BCMA-directed CAR T-cell therapy [produces worse outcomes] than a BCMA-directed CAR T-cell therapy without a prior BCMA-directed bispecific antibody. The same holds true the other way around: a BCMA-directed bispecific antibody does not perform as well in a patient whose disease has relapsed after BCMA-directed CAR T-cell therapy.

The best data on sequencing, with very small patient numbers, is probably with talquetamab-tgvs [Talvey] following relapse with BCMA-directed CAR T-cell therapy. In a subset of patients from the phase 1/2 MonumenTAL-1 study [NCT03399799], the median PFS for patients [who received prior BCMA-directed CAR T-cell therapy] was similar to that of the overall population.⁴ Probably the best argument for sequencing would be BCMA-directed CAR T-cell therapy, and then the GPRC5D-directed bispecific antibody talquetamab at that relapse.

For a lot of reasons, [such as] antigen escape, T-cell fitness, etc., doing the CAR T-cell therapy first, followed by the bispecific antibodies, makes the most sense. As we start talking more about limited-duration therapy with the bispecific antibodies, those considerations may be less problematic in the future.

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 lease one prior line of therapy. News release. Johnson & Johnson. April 6, 2024. Accessed August 27, 2026. 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. FDA grants third approval under the national priority voucher program. FDA. March 5, 2026. Accessed August 27, 2026. https://www.fda.gov/news-events/press-announcements/fda-grants-third-approval-under-national-priority-voucher-program
3. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. FDA. August 13, 2026. Accessed August 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone
4. Rasche L, Schinke C, Touzeau C, et al. Talquetamab in patients with relapsed/refractory multiple myeloma: 3-year follow-up of the phase 1/2 MonumenTAL-1 study. Blood. Published online August 6, 2026. doi:10.1182/blood.2025031994