Arlocabtagene autoleucel (arlo-cel) and anitocabtagene autoleucel (antio-cel) are emerging as promising therapies for patients with relapsed/refractory multiple myeloma, showcasing high response rates and manageable safety profiles in early clinical trials. These CAR T-cell therapies offer potential new options for patients who have exhausted standard treatment regimens.
Arlo-Cel: Targeting GPRC5D in Heavily Pretreated Patients
Arlo-cel, a GPRC5D-targeted CAR T-cell therapy, has demonstrated significant efficacy in heavily pretreated relapsed/refractory multiple myeloma patients. Data from the phase 1 CC-95266-MM-001 study, presented at the 2024 ASH Annual Meeting, showed that at the recommended phase 2 dose (RP2D) of 150 x 106 cells, arlo-cel elicited a 48% complete response (CR) rate. In 26 patients who received the RP2D, the overall response rate (ORR) was 91%. The median duration of response was 18.0 months (95% CI, 13.3-23.0), with responses observed regardless of high-risk cytogenetics or prior treatment with a BCMA-directed targeted therapy.
"Arlocabtagene autoleucel is a potential first in class GPRC5D-targeted autologous CAR T-cell therapy, which has been administered to patients with heavily pretreated multiple myeloma showing manageable safety and promising efficacy," said lead investigator Susan Bal, MD, University of Alabama at Birmingham. "There's promising preliminary efficacy with a high overall response rate. Notably, these responses and outcomes are not affected by exposure to prior therapies."
Across all doses, the ORR with arlo-cel was 87%, with a CR rate of 53%. Minimal residual disease (MRD) negativity was achieved in 85% of patients with a CR or better. The median progression-free survival (PFS) across all doses was 18.3 months (95% CI, 11.8-21.9).
The most common adverse events (AEs) were hematological, with grade 3/4 neutropenia occurring in 70% of patients. Grade 3/4 cytokine release syndrome (CRS) was observed in 4% of patients, and immune effector cell-associated neurotoxicity syndrome (ICANS) in 2%. Mild skin, nail, and oral AEs, related to the on-target but off-tumor effect on hard keratinized tissues, were also reported but were generally grade 1/2 in severity and resolved without intervention in 79% of cases.
Arlo-cel has received regenerative medicine advanced therapy designation from the FDA and is being explored in the phase 2 QUINTESSENTIAL study (NCT06297226) and the phase 3 QUINTESSENTIAL-2 study (NCT06615479).
Antio-Cel: Promising Results in Heavily Pretreated R/R MM
Anitocabtagene autoleucel (antio-cel) is another novel therapy showing promise in relapsed/refractory multiple myeloma. Preliminary results from the phase 2 iMMagine-1 trial (NCT05396885) indicate a 95% overall response rate (ORR) and a 62% complete/stringent response rate per International Myeloma Working Group (IMWG) criteria. Notably, 92% of eligible patients achieved minimal residual disease negativity.
The Kaplan-Meier-estimated 6-month progression-free survival (PFS) was 90% (95% CI, 77%-96%), and overall survival (OS) was 95% (95% CI, 85%-98%). The median follow-up was 10.3 months, and patients had received a median of 4 prior lines of therapy, with 69% being triple-class refractory and 34% penta-class refractory.
According to a press release, "Preliminary results from the first 58 patients in the phase 2 iMMagine-1 study demonstrate deep and durable responses and manageable safety in a high-risk fourth line or higher (4L+) [relapsed/refractory multiple myeloma] population including triple- and penta-class refractory disease. Notably, no delayed neurotoxicities, including no cranial nerve palsies, Guillain-Barré syndrome, or Parkinsonian-like symptoms have been observed with anito-cel to date."
The FDA had previously placed a clinical hold on the iMMagine-1 trial, which was later lifted after modifications to the trial's protocol regarding the prevention and management of adverse effects (AEs).
In terms of safety, most patients experienced either no cytokine release syndrome (CRS; 16%) or grade 1 CRS (64%). Grade 3 or higher AEs were primarily cytopenias, including neutropenia (36 patients), anemia (15), and thrombocytopenia (15).
More complete findings from the iMMagine-1 trial are expected to be reported at the 2024 American Society of Hematology Annual Meeting.
