Following bb2121, Novel CAR T-Cell Product Shows Potential in Myeloma

Nina Shah, MD

The efficacy and safety observed with the CAR T-cell product bb21217 could help physicians get patients with heavily pretreated relapsed/refractory multiple myeloma on the path towards a cure, according to Nina Shah, MD.

According to preliminary data from the phase I CRB-402 trial (NCT03274219), presented at the 2018 ASH Annual Meeting, the anti-BCMA therapy bb21217 was safe, tolerable, and showed promising clinical activity in this patient population.

Results showed that the objective response rate was 83.3%, with a very good partial response or better rate of 75%. Responses continued to deepen over time, with complete remissions (CR) achieved out to 10 months after infusion. The CR or stringent CR rate was 25%, and the minimal residual disease (MRD)-negativity rate was 100%.¹

Two-thirds (67%) of the cohort (n = 12) developed cytokine release syndrome (CRS), with 1 patient demonstrating a grade 3 event. The median time to CRS onset was 4.5 days. Neurotoxicity occurred in 25% of patients. However, the safety profile seems to be consistent with known toxicities of other CAR T-cell therapies, said Shah, who is the lead study investigator.

The bb21217 CAR T-cell is an enhancement of the bb2121 CAR construct, which had previously shown a median progression-free survival of 11.8 months and a median duration of response of 10.8 months in patients with multiple myeloma. Further, the CR or stringent CR rate was 50% and 36.4% of patients had a VGPR.²

OncLive: What is the mechanism of action of bb21217?

What was the design of this study?

Could you highlight the patient population and the preliminary findings?

In an interview with OncLive, Shah, an associate professor of Medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, discussed the promise of bb21217 in the complex treatment paradigm of relapsed/refractory multiple myeloma.Shah: The CAR T-cell therapy bb21217 targets BCMA as an antigen, but is different from other CAR T-cell therapies in the way it is cultured. It uses the same construct as bb2121 but is cultured like a PI3K inhibitor, so as to increase the proportion of memory-life or central-memory T cells in the infused product.The bb21217 trial is a phase I trial with endpoints of safety and tolerability. It is a standard 3+3 dose-escalation trial. The results that were presented at the 2018 ASH Annual Meeting only looked at the 12 patients treated in the first-dose cohort. That is 150 million cells as a flat dose. Those data were presented to look at the safety and preliminary efficacy.It was a relapsed/refractory multiple myeloma population. They had to have at least 3 prior lines of therapy and had been exposed to immunomodulatory agents and a proteasome inhibitor. They also had to have at least 50% BCMA expression in their bone marrow plasma cells. This is a hard-to-treat population.

Thus far, we have treated 12 patients and the safety [profile] is what we would expect to see with this type of therapy. Two-thirds of the patients had CRS; most of [these events] were grade 1 or 2, but one patient had a grade 3 event. Regarding neurotoxicity, there were 3 patients who presented with this event. This led us to expand the dose level, and we actually ended up treating another 6 patients with [the expanded] dose level. The reason for that is, we wanted to see how much high or low tumor burden impacted the safety. Do patients with >50% plasma cells in their bone marrow have a higher chance of toxicity? It turns out that [neurotoxicity] looked to be an isolated event.

Regarding efficacy, it looks like we have 83% of patients responding to bb21217. Remember that this is the first dose being tested. Some of these responses took a while to develop, so over time, they deepened. In addition, the longest followed-up patient in our group remains in remission for greater than 1 year.

What are the next steps for this research?

One thing that was interesting about this study was [determining whether] T cells cultured in a different way would last longer. Indeed, when you look at the early data coming out with T-cell persistence, it looks like there are T cells detected even 9 months out. We have shorter follow-up for other patients, and we hope to see more mature data in the next few months.We will go to the next dose level. We are already enrolling patients at the 300 million [cells] dose level. We will determine if that is safe and then potentially escalate to the next dose level. One of the other steps that we are looking forward to is following these patients out for a longer period of time, so we can understand how many become MRD-negative.

In summary, bb21217 is a novel CAR T-cell therapy developed for multiple myeloma. Thus far, it seems safe and consistent with previous CAR T-cell trials. The efficacy looks promising as well. I think this therapy will be another addition to this landscape that helps us get patients on the plateau towards a cure.

References

1. Shah N, Alsina M, Siegel DS, et al. Initial results from a phase 1 clinical study of bb21217, a next—generation anti BCMA CAR T therapy. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 488.
2. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).