Achieving Deep Responses With CART-ddBCMA in Relapsed/Refractory Multiple Myeloma


Matthew J. Frigault, MD, discussed safety and efficacy findings on CART-ddBCMA.

This content originally appeared on our sister site, OncLive.

Patients with previously treated relapsed/refractory multiple myeloma treated with CART-ddBCMA had an overall response rate (ORR) of 100%, according to data from a phase 1 trial (NCT04155749).

These data, from 31 patients, were presented at the 2022 ASCO Annual Meeting. Notably, patients achieved responses that deepened over time.

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 chimeric antigen receptor (CAR) T-cell therapy for highly refractory patients with high-risk features,” Frigault, administrative director, Cellular Therapy Service, Massachusetts General Hospital and assistant professor, Medicine, 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.”

OncLive spoke to Frigault about 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. He 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.

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
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