CART-ddBCMA Generates Deep Responses in Relapsed/Refractory Multiple Myeloma

Matthew J. Frigault, MD

CART-ddBCMA elicited an overall response rate (ORR) of 100% in patients with previously treated relapsed/refractory multiple myeloma (n = 31), according to data from a phase 1 trial (NCT04155749) presented at the 2022 ASCO Annual Meeting.1 Notably, patients achieved responses that were found to deepen over time, according to Matthew J. Frigault, MD.

Among those who responded to treatment, 94% experienced a very good partial response or better rate of 94%, and 71% experienced a complete response (CR)/stringent CR (CR/sCR). Of the 24 patients who had a minimum follow-up of 6 months and a median follow-up of 13.3 months, 92% still responded to treatment at 6 months. Of the 16 patients who had a minimum follow-up of 12 months and a median follow-up of 17.7 months, 94% had an ongoing response at 6 months and 69% were still responding at 12 months.

“CART-ddBCMA appears to be a highly effective, durable CAR T-cell therapy for highly refractory patients with high-risk features,” said Frigault, who is the administrative director of Cellular Therapy Service at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School. “It was [well] tolerated, and the pivotal phase 2 study [NCT05396885] should hopefully recapitulate the findings [we observed] from [the] phase 1.”

In an interview with OncLive^®, Frigault discussed the findings from a phase 1 trial investigating the safety and efficacy of CART-ddBCMA in patients with multiple myeloma in whom all previous lines of treatment had failed and shared additional research opportunities for the CAR T-cell therapy.

OncLive^®: What was the design of the phase 1 trial evaluating CART-ddBCMA in patients with relapsed/refractory multiple myeloma?

Frigault: [At the 2022 ASCO Annual Meeting,] we presented data from the phase 1 trial of CART-ddBCMA; [this was] a first-in-human, dose-escalation study, where we we examined how CART-ddBCMA would work in relapsed/refractory multiple myeloma.

This was [done in] a patient population that had to have been exposed to all 3 major classes of multiple myeloma therapy: [a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody]. They had to have [received] at least 3 prior lines of therapy or be triple refractory, and they needed [to have] measurable disease at the time of treatment.

We [examined the therapy at] 2 dose levels: 100 x 10⁶ CAR-positive cells and 300 x 10⁶ CAR-positive cells. The most impressive component of all this was that we saw an 100% ORR [with the therapy] across both dose levels. These were exciting data, and we look forward to expanding this into a pivotal [phase 2] study.

What else should be known about the population examined in the trial?

This was a heavily pretreated group of patients. They had [received] a median of 5 prior lines of therapy, and they had multiple high-risk features, including high disease burden. In particular, something that we know [correlates with] a poor prognosis for durability of responses, is extramedullary disease; 39% of patients had extramedullary disease at the time of treatment. [Furthermore], 68% of patients were penta-refractory, meaning that they were refractory to all 3 major drug classes, including 2 drugs from 2 of those classes.

Could you expand on the efficacy data reported during the meeting?

We saw impressive findings. [I mentioned that the therapy elicited] an ORR of 100%, [which included] a 71% CR/sCR rate. The interesting thing [to note] is that these responses continued to deepen over time.

Although we had a median follow-up of 12.1 months for the total patient population, if you looked at patients who [had] beyond 12 months [of follow-up], the 16 patients with a median follow-up of 17.7 months, half of those patients had extramedullary disease, which is a higher-risk prognostic factor. Despite that, [69% of those] patients were still in an ongoing response.

We are still waiting for the data to mature, but [this] is promising for these patients.

What were the safety data reported with CART-ddBCMA?

Something that was encouraging was the fact that [CART-ddBCMA] was very well tolerated. Only 1 grade 3 event of immune effector cell–associated neurotoxicity syndrome [(ICANS) occurred in someone who received the therapy at 100 x 10⁶ CAR-positive cells], which is our recommended phase 2 dose. All [cases of] cytokine release syndrome [CRS] was grade 1 or 2 [at 100 x 10⁶ CAR+ cells]. CRS [cases] were all managed with tocilizumab [Actemra] and steroids.

Importantly, we did not see any atypical neurotoxicity, [like] the Parkinson-like syndrome that we are seeing with some other BCMA-directed therapies. It is reassuring that this treatment was very tolerated and appeared to be safe.

What are the next steps for CART-ddBCMA?

I am hoping that the pivotal [phase 2] study can begin enrollment by the end of 2022. We have a lot of patients who need highly effective BCMA-directed therapies. Currently, there are not sufficient slots for manufacturing, and there are many patients who would substantially benefit from CART-ddBCMA and other BCMA-directed CAR T-cell therapies.

This product can significantly impact access and could improve outcomes for patients, many of which are passing away prior to getting their slot allocation. I am optimistic to be able to enroll [patients to this] pivotal study and potentially see a new product on the block that can benefit patients.

Reference

Frigault MJ, Rosenblatt J, Cook D, et al. Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma. J Clin Oncol. 2022;40(suppl 16):8003. doi:10.1200/JCO.2022.40.16_suppl.8003