Ide-cel Elicits Durable Responses in High-risk Myeloma After Inadequate ASCT Response

David Siegel, MD, PhD

The CAR T-cell therapy idecabtagene vicleucel (Abecma; ide-cel) generated frequent, deep, and durable responses in patients with relapsed/refractory high-risk multiple myeloma who experienced an inadequate response to first-line autologous stem cell transplant (ASCT), according to data from cohort 2C of the phase 2 KarMMa-2 trial (NCT03601078) presented at the 2022 ASH Annual Meeting.

At a median follow-up of 27.9 months (range, 24-32), the primary end point was met, with 74.2% (95% CI, 55.4%-88.1%) of patients experiencing a complete response or better with ide-cel (n = 31; P < .0001). The overall response rate achieved with ide-cel in this population was 87.1% (95% CI 70.2%-96.4%). Moreover, the median progression-free survival (PFS) was 30.7 months (95% CI, not evaluable [NE]-NE). The 12- and 24- month PFS rates were 90.1% and 83.1%, respectively.

“This is the very beginning of utilizing these kinds of products. It is not just CAR T-cell therapies; there are a lot of T-cell–redirecting therapies that are coming [down the pike],” said David Siegel, MD, PhD, who is the lead study author and chief of the Division of Multiple Myeloma at John Theurer Cancer Center of Hackensack Meridian Health in Hackensack, New Jersey. “[The question becomes:] Can we pick a subset of patients that will achieve extraordinarily durable remissions [with agents like ide-cel]? That is certainly the hope. The future is certainly looking brighter and brighter.”

In an interview with OncLive^®, Siegel discussed the evaluation of ide-cel in cohort 2C of the KarMMa-2 trial and what these data could mean for this population and others with multiple myeloma. He also shared other exciting data to come out of the 2022 ASH Annual Meeting.

OncLive^®: Please provide some background on the key objective of the KarMMA-2 study and the population of patients enrolled to cohort 2c.

Siegel: KarMMa-2 is a study of ide-cel, one of the many BCMA[-directed] CAR T-cell products that are in development or commercially available [for those with multiple myeloma. This analysis focused on a] subset of patients who were post [ASCT] and who did not achieve high-level remission, [meaning they] achieved something less than a very good partial response.

This is one of the more dynamic areas in myeloma clinical care. [We’re asking ourselves:] What do we do with those patients who don’t have excellent responses to their up-front therapy? Very often, these patients get put on lenalidomide [Revlimid] maintenance, but the expectations of durable remission are somewhat less than some of [those] who achieve a higher level of response.

What were the key findings from this cohort presented during the 2022 ASH Annual Meeting?

Patients [given ide-cel experienced] many high-level responses. Very durable responses were achieved in this population without any inordinate toxicity issues. One potential concern we have is that when we collect the lymphocytes for the creation of CAR T cells earlier on, the lymphocytes [may be] more active [than lymphocytes collected after more lines of therapy]. They’ve been subjected to less immunosuppressive therapies, and patients have not had enormous exposure to lymphotoxic agents. In the aftermath of high-dose melphalan–based ASCT, these patients go for extended periods of time without treatment.

There were no new toxicity signals, which is perhaps the most important [observation]. Although the long-term follow-up is not complete, these patients had very durable remissions—better than the [10.9-month responses] that had previously been reported [from the phase 2 KarMMa trial (NCT03361748)] in heavily pretreated patients [who received ide-cel] in very late lines of therapy. We are very excited about the potential to move CAR T-cell platforms to earlier lines of therapy.

If data continue to be positive, what could this mean for this patient subset?

We are hoping that we will cure a subset of patients. I do not know whether we can make those kinds of statements, but obviously, [curing patients] is the goal. Who are the right patients [to treat with ide-cel]? We picked a population that is more difficult [to treat]. Whether [these outcomes] are going to translate [to outcomes for] other populations with multiple myeloma [is unknown].

We are just starting to learn the biomarkers and the characteristics of patients who have the most durable responses. If we can select particularly susceptible subsets of myeloma, maybe we will be able to identify patient subsets that can predictably be cured, or at least have protracted remissions.

What additional data and trials stuck out to you at the 2022 ASH Annual Meeting?

With this meeting, at least from the from the perspective of myeloma, it is the [year of] BCMA. We heard a lot about different CAR T-cell platforms that have distinguishing features. [That said, we did not see] one [readout] that said that this is clearly the end where we can stop evolving these kinds of therapies.

T-cell engagers [were also discussed]. There were 5 or 6 different T-cell engagers being reported at the meeting. There is not anything that distinguishes one [product] from another other than where they are in their clinical development. We just got the first T-cell engager approved [by the FDA in October 2022 with teclistamab-cqyv (Tecvayli)]. There are going to be others that come along shortly, and these are very exciting.

Perhaps the most exciting thing to come from the meeting were the data on talquetamab [JNJ-64407564], which is a T-cell engager directed at [GPRC5D rather than] BCMA. There are a couple of other targets that are in development. The toxicity profile and some of the issues that concern us most, such as infections with both CAR T-cell therapies and maybe even more so with T-cell engagers, do not seem to be as much of a problem [with this drug].

It was a very exciting meeting in that we just got a [taste] of what’s going to be coming along next year and the following year. It won’t be that much longer before we get T-cell engagers and CAR T-cell [therapies] that are not BCMA directed.

Reference

Dhodapkar M, Alsina M, Berdeja J, et. al. KarMMa-2 cohort 2c: efficacy and safety of idecabtagene vicleucel in patients with clinical high-risk multiple myeloma due to inadequate response to frontline autologous stem cell transplantation. Blood. 2022;140(suppl 1):7441-7443. doi:10.1182/blood-2022-162615