Ide-Cel Displays Potential in Myeloma After Suboptimal Response to Frontline ASCT and Maintenance

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With several CAR T-cell therapies being further investigated in novel settings in the multiple myeloma space, the efficacy and safety displayed by idecabtagene vicleucel (ide-cel; Abecma) in patients with multiple myeloma who experienced suboptimal response to upfront autologous hematopoietic cell transplant (auto-HCT) and lenalidomide (Revlimid) maintenance therapy could point to another potential role for the treatment, according to Alfred L. Garfall, MD.

Topline data from the phase 2 BMT CTN 1902 trial (NCT05032820) presented at the 2025 Transplant and Cellular Therapy Meetings demonstrated that by 6 months after the infusion of ide-cel, 63% of evaluable patients (n = 38) had improved to a complete response (CR). At 6 months, 87% of patients also achieved minimal residual disease (MRD) negativity at 6 months, and 95% of patients achieved MRD negativity at any point.

“We saw our trial as a logical progression of those prior ideas to [assess] ways to integrate therapies that have been effective in relapsed myeloma into the first-line therapy [to] assess the basic safety, feasibility, and early evidence of efficacy,” Garfall said in an interview with OncLive®. “That's what we're doing with CAR T cells in this study.”

During the interview, Garfall discussed the rationale for investigating ide-cel in patients with suboptimal responses to standard first-line therapy, specific patient enrollment, key early efficacy and safety data, and the next steps in research.

Garfall is the director of Autologous Hematopoietic Stem Cell Transplantation, section chief of Myeloma and Hematology-Oncology, and associate professor of Medicine at the Hospital of the University of Pennsylvania, Penn Medicine, in Philadelphia

OncLive: What was the rationale for evaluating ide-cel in suboptimal response after upfront stem cell transplant in multiple myeloma?

Garfall: If you think about the history of first-line therapy for multiple myeloma, [we’ve] taken agents that have shown efficacy in the relapsed setting and considered the best place to add them into first-line therapy. We ultimately evaluate whether adding an agent in first-line therapy gives long-term benefits in phase 3 trials. We've seen an intensification of the initial induction therapy to include triplet and, more recently, quadruplet therapy with daratumumab [Darzalex]. Of course, ASCT has been tested extensively as part of first-line therapy, and then maintenance options after transplant have been added in multiple studies over time.

Two different CAR T-cell therapies, including ide-cel, have been approved, initially in very late-line therapy, and then in the intermediate line of therapy with patients receiving [CAR T-cell therapy as] second- or third-line therapy. We’re now asking whether there is evidence that [CAR T-cell therapy could] work as part of first-line therapy, and our study is one of several studies that has tested how CAR T cells work in the post-transplant setting in different populations and slightly different settings.

Before we started our study, there were some real open questions about how CAR T cells would integrate here. We had to consider whether somebody recovering after an ASCT could have their lymphocytes harvested and used to manufacture CAR T cells early after transplant. We wondered if patients could, from a hematologic standpoint, tolerate lymphodepleting chemotherapy in this early stage after transplant. We also wondered whether we could get patients back on the standard-of-care maintenance lenalidomide, which has been shown to improve overall survival, so we wouldn't want to deviate from that. We'd look to integrate CAR T cells with that and consider if it would be feasible to give patients CAR T cells and get them back on maintenance therapy, and also if CAR T cells attack myeloma very well in this setting.

These patients have a low burden of myeloma and a low target antigen burden, so do CAR T cells expand in vivo in this setting? Are they effective at targeting myeloma in the setting? These were some basic preliminary questions we looked to answer in this study.

How was the suboptimal response to ASCT defined to allow patients to enroll?

We required that patients were not in complete response [CR] after a standard induction regimen, ASCT, and at least 3 months of maintenance therapy. These patients all had pretty intensive therapy before they enrolled and still had some detectable disease, as indicated by not having achieved a CR. Patients’ responses when they came on the study were mostly very good partial responses [PR], so they had at least a 90% reduction in disease burden; however, almost half of the patients were even in a lower level of response—just a PR or a minimal response. Therefore, those patients are a high-need group after going through at least triplet or quadruplet induction, ASCT, and 3 months of maintenance therapy and still having had less than or just over a 50% reduction in their paraproteins.

What were the key early efficacy data regarding ide-cel and lenalidomide maintenance?

This was a phase 2 safety and feasibility study, so we wanted an end point that would read out relatively quickly and give us an initial sense of the efficacy; therefore, the primary end point was the [rate of patients who had an] improvement of response to a CR 6 months after the CAR T-cell infusion. We know that if patients don’t have a CR at this stage in their therapy, it's pretty unlikely that they will evolve to CR spontaneously over 6 months. It doesn't happen that often, but we projected from prior data that it would happen spontaneously less than 10% of the time. We set a bar for ourselves to see if we could increase that to at least 30%, and what we found was that we did even better than that by a good amount. We found that 63% of patients converted to CR, and another 24% upgraded their response in some other way, [meaning] a total of 87% of patients improved their response to some extent.

What were the key safety data?

[Safety data were] very encouraging. We did see a high rate of cytokine release syndrome [CRS]; 81% of patients, overall, developed CRS. That's reassuring in some ways because the CAR T cells are getting in there and expanding in vivo, even though there's not a lot of myeloma around to simulate them. However, all of the [instances of] CRS were low grade at grade 1 or 2, with most being grade 1. It was also reassuring that we saw no immune effector cell–associated neurotoxicity syndrome or neurologic toxicity at all, which is encouraging. this supports the safety of this approach—giving CAR T cells in a consolidation setting or the setting of lower disease burden that we do. This wasn’t a comparative study, but it seems to be a more favorable adverse effect profile than what we see in the relapsed setting.

What are the next steps in research and potential clinical implications?

There are other studies that have evaluated CAR T cells in the [frontline] setting. Another study with ide-cel investigated CAR T cells right after transplant but before patients had maintenance therapy. Then there was another small study that evaluated ciltacabtagene autoleucel [Carvykti] in a similar setting. Results of all these studies have come out over the last year or so, and they all give a similar message: CAR T cells are clinically active in [the frontline post-transplant] setting and have a reasonable safety profile.

The next step would be having a larger phase 3 randomized study. One study had been started with ide-cel, but it was unfortunately halted in the last several months due to low accrual globally, which is disappointing because we saw a lot of enthusiasm from patients for this approach on our study. Over time, it will be interesting to see if other studies are set up to evaluate this approach specifically in the post-transplant setting. This study and other smaller studies are building a general case for using CAR T cells in a consolidated setting with low disease burden in earlier lines of therapy. There are a number of other ongoing trials doing that as part of first-line therapy, but not necessarily in the post-transplant setting. There is the [phase 3] CARTITUDE-6 study [NCT05257083] evaluating transplant vs CAR T cell with the consolidation of induction therapy and these data support those ongoing randomized efforts and could be supportive of future randomized comparative studies to look at CAR T-cell therapy, specifically in the post-transplant setting.

Reference

Garfall AL, Pasquini MC, Bai L, et al. Phase II multicenter trial of idecabtagene vicleucel (ide-cel) followed by lenalidomide maintenance for multiple myeloma patients with sub-optimal response after an upfront autologous hematopoietic cell transplantation: top line results from the BMT CTN 1902 clinical trial. Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract LBA-1.