CAR-T Paving New Path in Relapsed/Refractory Myeloma

Peter M. Voorhees, MD

Although novel immunotherapy approaches have not proven to be curative in heavily pretreated patients with relapsed/refractory multiple myeloma, the strategy is resulting in unprecedented responses and progression-free survival (PFS) benefits, according to Peter Voorhees, MD.

“You can look at [CAR T-cell therapy] from either a 'glass half full' or 'glass half empty' perspective,” said Voorhees. “Glass half empty [means]: It's not curative, patients are still progressing, and the median PFS with, say, idecabtagene vicleucel (ide-cel; bb2121), was 12 months. On the other hand, [if we look at it from a] glass half full [perspective], then: We've never seen anything like this before in this group of patients. A median PFS of 12 months in this patient population is unheard of.”

Topline results from the pivotal phase II KarMMA trial (NCT03361748) showed that treatment with ide-cel resulted in a 73.4% overall response rate (ORR) in patients with relapsed/refractory disease, meeting the trial’s primary endpoint.¹ Furthermore, the complete response (CR) rate with the BCMA-targeted CAR T-cell product was 31.3% and the median duration of response was 10.6 months.

Another notable BCMA-directed CAR T-cell therapy is JNJ-4528, which induced a 100% ORR with early and deep responses in patients with heavily pretreated, relapsed/refractory disease. Data from the phase Ib/II CARTITUDE-1 trial (NCT03548207) showed that the ORR included a 66% stringent complete response rate, a 3% complete response (CR) rate, a 17% very good partial response rate (VGPR), and a 14% partial response (PR) rate.²

Bispecific T-cell engagers (BiTEs) are also generating excitement in the space, according to Voorhees. Results from a phase I trial showed that treatment with AMG 420, when given at the maximum-tolerated dose (MTD) of 400 µg/day, led to an ORR of 70% in patients with relapsed/refractory disease.³ The ORR included 5 minimal residual disease (MRD)—negative CRs, 1 VGPR, and 1 PR.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Multiple Myeloma, Voorhees, a myeloma specialist at Levine Cancer Institute, of Atrium Health, provided an overview of the many developments made with CAR T-cell therapy in multiple myeloma, as well as the exciting research being done with bispecific antibodies.

OncLive: What is the hope for CAR T-cell therapy in multiple myeloma?

Voorhees: At this point, what’s very clear is that when you look at the BCMA-targeted CAR T-cell therapies in relapsed/refractory disease, we are seeing unprecedented response rates in heavily pretreated patients with disease that's refractory to a large number of different agents.

In that group of patients, we’re seeing response rates that we have never seen before and the depth of response with this therapeutic modality is also unprecedented.

It’s clear that [CAR T-cell therapy is] not a curative strategy in heavily pretreated patients with relapsed/refractory myeloma as it may be for patients with relapsed B-cell acute lymphoblastic leukemia (ALL) or those with diffuse large B-cell lymphoma.

We are all hopeful—intuitively and scientifically it makes sense—that as we move CAR T-cell therapy into earlier lines of treatment, we will see more durable results. Several ongoing studies are looking at the use of CAR T-cell platforms in the higher-risk patients who have had suboptimal response to initial therapy or experienced early relapse after frontline treatment.

Could you speak to the data that have been reported thus far with ide-cel?

The initial [studies with] CAR T-cell therapy in myeloma have been in relapsed/refractory disease. [Data with ide-cel have] been published in the New England Journal of Medicine. At CAR T-cell doses of 450 x 10⁶, we are seeing response rates of approximately 95%, at least in the initial phase I study; this is unheard of. A large proportion of these [responses] are CRs, and MRD-negative CRs. That's very exciting.

A press release on the phase II study, KarMMA, with [ide-cel was issued during the 2019 ASH Annual Meeting]. Not surprisingly, as you moved from phase I to phase II, there was a slight degradation in the signal of PFS. The median PFS [observed with the product] in the phase II study wasn't quite as good as it had been in the phase I trial, but it was still respectable for a heavily pretreated patient population.

What are some unanswered questions that remain with CAR T-cell therapy in myeloma?

It’s important to remember that this is not curative therapy. We need to better understand how we can produce durable remissions. For example, [maybe we can explore] different strategies to reengineer the CAR and find ways to manipulate the product as its in development to encourage a more stem cell—like T memory of cell populations. Can we re-dose?

All of these questions need to be answered. As I said before, we all believe that these products are going to perform much better in [patients with] early relapse and potentially as consolidation therapy, particularly in high-risk patients after initial treatment, [but we need to explore this to know for sure]. It’s still very early, but [all of this is] very exciting.

Also in the pipeline is the BCMA-directed CAR T-cell therapy JNJ-4528. Could you shed some light on the data from the phase Ib/II trial that were presented at the 2019 ASH Annual Meeting?

Yes, [data were presented on the] the Janssen product, which was examined in the phase I LEGEND-2 study that had been presented a couple of years ago. [Now], data from the CARTITUDE-1 study showed that at very low doses of cells, we're seeing very potent activity [with the product]. We’re also seeing very high response rates, the majority of which are MRD negative.

What do the safety profiles look like for some of these products?

It is important to recognize that CAR T-cell therapies are associated with the real risk of cytokine release syndrome (CRS). With ide-cel as well as with [JNJ-4528], CRS of some grade is expected. In the CARTITUDE-1 study, 1 death related to CRS was reported, so this remains a very important area. As we learn more about it and we [intervene] early, we will get better [at managing these adverse events (AEs)]. Similarly, neurotoxicity is a very real, potential AE.

Will CAR T-cell therapies be for everyone? Probably not. Perhaps for an older, frailer patient, going through [that type of therapy] might be a bit difficult, which is why some of these other approaches, such as the BiTEs or antibody-drug conjugates, are so interesting.

However, I will say that we are seeing CRS with the [BiTEs] as well, and, at the 2019 ASH Annual Meeting, 1 patient who had CRS did pass away, but other factors were also at play, such as myeloma progression and infection; it was a muddy story. Nonetheless, [those receiving] the [BiTEs] are potentially at risk of CRS as well. Notably, however, in the studies that have been presented to date, the vast majority of the CRS events that we have seen with the [BiTEs] have [ranged from] grade 1 to grade 2 [in severity].

What notable BiTEs are being examined in myeloma?

The BiTE space is very exciting, and it's going to be very interesting to see how [this area of research] plays out relative to [the work that’s being done with] CAR T-cell therapy. The majority of the work that has been presented or published thus far is looking at [BiTEs] that are directed against BCMA on plasma cells. They’re directed [against] BCMA on the one hand, and then on the other hand, [they are] engaging T cells through CD3 and activating T cells in the presence of myeloma.

The first-generation [BiTE] that was presented and now [has data] published is AMG 420; this was an agent that had to be given as a 4-week consecutive infusion—kind of like blinatumomab (Blincyto) in acute lymphoblastic leukemia. It’s given on a 4-weeks-on, 2-weeks-off schedule. Over the course of dose escalation, as investigators reached doses at which they started to see a signal, all of the sudden, they started to see CR rates. At that MTD, the ORR was about 70%; the vast majority of those responses were CRs, with MRD-negative CRs as well. Obviously, it's a challenging mode of administration, [but the responses are promising].

Are next-generation BiTEs being designed to overcome that administration challenge?

Some are now in development and they have longer half-lives, which allow you to dose them intermittently. Some, for example, are being dosed on a weekly basis; others that are in development are being dosed on an every-3-week basis. A lot of work is still being done as far as [determining the] optimal schedule of administration, but the first longer half-life BCMA-targeted [BiTE] that has been presented was the Celgene product at the 2019 ASH Annual Meeting.

As the investigators got to doses where they were starting to see a signal, the ORR was about 85% and the majority of these responses were CRs. Again, in many cases, they were MRD-negative CRs.

These are therapeutics that don't have to be taken out of the patient, manufactured, and then given back; these are right off the shelf and we're starting to see signals of activity that are very much in line with CAR T-cell therapy. All of [this work] is very early; the durability of these responses remains an open question, but I believe that there is a very real opportunity for these agents in this space.

References

1. Bristol-Meyers Squibb and bluebird bio announce positive top-line results from the pivotal phase 2 KarMMa study of ide-cel in relapsed and refractory multiple myeloma [news release]. Princeton, NJ, and Cambridge, MA: Bristol-Myers Squibb Company and bluebird bio, Inc; December 6, 2019. bit.ly/2DVej3e. Accessed January 31, 2020.
2. Madduri D, Usmani SZ, Jagannath S, et al. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). Blood. 2019;134(suppl 1): 577. doi: 10.1182/blood-2019-121731.
3. Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. J Clin Oncol. 2019;37(suppl 15; abstr 8007). doi: 10.1200/JCO.2019.37.15_suppl.8007.