CART-ddBCMA generates profound responses in relapsed/refractory multiple myeloma

Matthew J. Frigault, MD, discusses the results of 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 shares insights additional research opportunities for CAR T-cell therapy.

CART-ddBCMA achieved 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 got responses that deepened over time, according to Matthew J. Frigault, MD.

Of those who responded to treatment, 94% had very good partial response or better than 94%, and 71% had complete response (CR)/severe 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% were still responding 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 a continuous response at 6 months and 69% were still responding at 12 months.

“CART-ddBCMA appears to be a very effective and long-lasting CAR T-cell therapy for highly refractory patients with high-risk characteristics,” said Frigault, executive director of Massachusetts General Hospital’s cell therapy department and assistant professor of medicine. at Harvard Medical School. “It was [well] tolerated, and the pivotal phase 2 study [NCT05396885] should hopefully recap the findings [we observed] of [the] stage 1.”

In an interview with Live®Frigault discussed the results of 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 CAR T-cell therapy.

Live®: 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-man, dose-escalation study, in which we investigated how CART-ddBCMA would work in relapsed/refractory multiple myeloma.

It was [done in] a patient population that should have been exposed to the 3 main classes of treatment for multiple myeloma: [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 dosage levels: 100 x 106 CAR-positive cells and 300 x 106 CAR-positive cells. The most impressive part of it all was that we saw an ORR of 100% [with the therapy] at both dose levels. This was exciting data, and we look forward to extending it to a pivot [phase 2] study.

What else do I need to know about the population examined in the trial?

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

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

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

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

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

What safety data have been reported with CART-ddBCMA?

Something encouraging was the fact that [CART-ddBCMA] was very well tolerated. A single 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]. SCR [cases] were all managed with tocilizumab [Actemra] and steroids.

Importantly, we found no atypical neurotoxicity, [like] the Parkinson-like syndrome that we see with some other BCMA-directed therapies. It is reassuring to note that this treatment was very well tolerated and appeared to be safe.

What are the next steps for CART-ddBCMA?

I hope the pivot [phase 2] the study can begin enrollment by the end of 2022. We have many patients who need highly effective BCMA-led therapies. Currently, there are not enough niches for manufacturing, and many patients would benefit significantly from CART-ddBCMA and other BCMA-led CAR T-cell therapies.

This product can have a significant impact on access and could improve outcomes for patients, many of whom die before they get their place. I am optimistic to be able to register [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(supplement 16):8003. doi:10.1200/JCO.2022.40.16_suppl.8003