New CAR T Therapy Shows Promise in Treating R/R Multiple Myeloma

Multiple myeloma cells: © David A Litman - stock.adobe.com

Durcabtagene autoleucel (PHE885), a BCMA-directed chimeric antigen receptor (CAR) T-cell therapy, produced high response rates with a manageable safety profile in patients with relapsed/refractory (R/R) multiple myeloma, according to interim phase 2 study (NCT04318327) results presented at the 2024 International Myeloma Society Annual Meeting.

In 94 patients who received 10 x 10⁶ CAR T cells, the overall response rate (ORR) was 89% as assessed by independent review committee (IRC), including 61% of patients with a stringent complete response (sCR)/CR, 20% with a very good partial response (VGPR), and 9% with a partial response (PR). These results met the primary end point of the study. Additionally, 10% of patients were classified as having an unknown response.

“These were patients who died prior to the initial evaluation time point or had discord in imaging techniques before and after infusion, therefore confounding interpretation of the results,” said Andrew Spencer, MD, professor at Alfred Hospital-Monash University, Melbourne, Australia, and study presenter.

Patients included in the study were heavily pretreated, with 82.8% (n = 120) triple-class refractory and 30.3% (n = 44) penta-class refractory. Further, 21.4% (n = 31) had high-risk cytogenetic abnormalities, and 53.8% (n = 78) were treated with bridging chemotherapy.

A second dose level of 5 x 10⁶ was also evaluated, and the ORR by investigator assessment in 34 patients was 100%, composed of a 62% sCR/CR rate, a 21% VGPR rate, and an 18% PR rate. The responses observed were durable, and the median duration of response was not reached in patients who achieved a CR at either dose.

A key secondary end point was minimal residual disease (MRD) negativity among the IRC efficacy-evaluable population. At the 10 x 10⁶ CAR T-cell dose, this was 39% (n = 37; 95% CI, 29%-50%), meeting this end point and rejecting the null hypothesis of MRD negativity ≤ 21%.

Regarding safety, there were 4 deaths reported within 30 days of infusion, all at the 10 x 10⁶ dose and adverse event (AE) related. Seventeen deaths occurred more than 30 days post infusion, with 4 at the 5 x 10⁶ dose and 13 at the 10 x 10⁶ dose. Here, 7 deaths were due to disease progression and 10 due to AEs.

In the lower-dose cohort, 100% (n = 34) of patients experienced cytokine release syndrome (CRS), with 8.8% (n = 3) experiencing grade 3 or higher and none experiencing grade 5. In the higher-dose cohort, 96.4% (n = 107) of patients experienced CRS, 5.4%(n = 6) were grade 3 or higher, and 1.8% (n = 2) were grade 5. Across all patients, the median time to CRS onset was 8 days with a median time to resolution of 4 days.

Immune effector cell associated neurotoxicity syndrome (ICANS) was observed in 5.9% (n = 2) of the lower-dose cohort and 16.2% (n = 18) of the higher-dose cohort, with grade 3 or higher events in 0% and 6.3% (n = 7) of patients, respectively. The median time to ICANS onset across all patients was 9 days with a median time to resolution of 5 days.

“While [the study] is not designed to compare between the 2 groups, there is the impression that there was a higher grade of AEs present in the 10 x 106 vs the 5 x 106 cohorts, [with] most deaths occurring subsequent to 30 days from infection and progressive disease,” Spencer concluded.

REFERENCE:

Spencer A, Raab M, Iida S, et al. Interim phase 2 study results of durcabtagene autoleucel (PHE885), a T-Charge™ manufactured BCMA-directed CAR-T cell therapy in patients with r/r multiple myeloma. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-12.