Arlo-Cel Generates Excitement, Moves Quickly to Phase 3 Studies for Multiple Myeloma

Susan Bal, MD

The GPRC5D-targeted CAR T-cell therapy arlocabtagene autoleucel (arlo-cel, BMS-986393) at the recommended phase 2 dose (RP2D) elicited a complete response (CR) rate of 48% for patients with heavily pretreated relapsed/refractory multiple myeloma, according to extended follow-up from part A and B of cohort A in the phase 1 CC-95266-MM-001 study presented at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California..

In 26 patients who received the RP2D of 150 x 10⁶, the overall response rate (ORR) with arlo-cel was 91% for patients with multiple myeloma who had received 3 or more prior lines of treatment. This response rate also included a very good partial response in 22% of patients. Across all doses examined, the median duration of response was 18.0 months (95% CI, 13.3-23.0). Responses were observed regardless of high-risk cytogenetics or prior treatment with a BCMA-directed targeted therapy. At the data cutoff following a median duration of follow-up of 16.1 months, 38% of responses were ongoing.

"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," lead investigator Susan Bal, MD, University of Alabama at Birmingham, said during a presentation of the results. "There's promising preliminary efficacy with a high overall response rate. Notably, these responses and outcomes are not affected by exposure to prior therapies."

Arlocabtagene autoleucel has received a regenerative medicine advanced therapy designation from the FDA, allowing for an expedited development. The cell therapy is currently being explored in the phase 2 QUINTESSENTIAL study for patients with multiple myeloma (NCT06297226). Additionally, the phase 3 QUINTESSENTIAL-2 study has been opened, although not yet recruiting, and will compare arlo-cel with standard regimens in patients with lenalidomide-refractory relapsed/refractory multiple myeloma following 1 to 3 prior lines of therapy (NCT06615479).

For the cell therapy, patients underwent leukapheresis prior to cells being sent for manufacturing. If required for disease control, bridging therapy was permitted during the manufacturing but was limited to a window between 19 and 28 days prior to infusion. Three days of lymphodepletion using fludarabine and cyclophosphamide was started 5 days prior to infusion. The cell therapy was successfully manufactured for all patients (n = 86).

The median age of patients was 63 years in both the full cohort and RP2D. High risk cytogenetics were present in most patients, with 31% having a del17p in the full cohort, which was 42% of those at the RP2D. Extramedullary plasmacytoma was present for 46% of those in the full cohort and for 35% treated with the RP2D. Approximately half of patients had received a prior BCMA-targeted therapy, at 49% in the full cohort and 46% for the RP2D. Twenty percent of patients in the full cohort were refractory to BCMA-targeted therapy and three-fourths were triple class refractory (76% for all patients, 85% for RP2D).

Across all doses in 79 efficacy evaluable patients, the ORR with arlo-cel was 87%, with a CR rate of 53%. Responses were seen across all high-risk subgroups, including an ORR of 87% in those with triple class refractory disease. In those with extramedullary disease, the ORR was 86% with arlo-cel. In those with high-risk cytogenetics, the ORR was 84%. The ORR was 79% for those who received a prior BCMA-targeted therapy. It was 81% in those who were refractory to a prior BCMA-directed agent.

"The responses were uniformly high and traditionally high-risk subsets such as extramedullary disease, high-risk cytogenetic abnormalities, as well as patients with triple class refractory disease," Bal said. "Additionally, the response was uniformly high for patients both with or without prior exposure, including patients who have previously refractory to BCMA-targeted therapy."

Minimal residual disease (MRD) was examined as an exploratory end point, with 57% of patients evaluable (n = 84). In this group, of those with a CR or better (n = 22), 85% were MRD negative (22 of 26).

The median progression-free survival (PFS) across all doses was 18.3 months (95% CI, 11.8-21.9). For those who received prior BCMA-directed therapy, the median PFS was 19.0 months. For those who did not receive prior BCMA-directed therapy, PFS was 18.3 months. The median overall survival (OS) across all treated patients was not yet reached. At 12 months, 90% of patients remained alive and at 18 months 87% of patients were alive. At month 21, the OS rate was 84%.

As with other CAR T-cell therapies, the most common adverse events (AEs) were hematological. A treatment-emergent AE (TEAE) was experienced by all patients in the study, with grade 3/4 TEAEs occurring in 86% of those across the full cohort and for 85% of those in the RP2D group. The most common grade 3/4 hematologic TEAE was neutropenia (70% in full cohort, 69% at RP2D). The most common non-hematological grade 3/4 TEAE were infections (19% in full group, 12% in RP2D).

Treatment-related adverse events (TRAEs) were generally low, Bal said. Across all patients, the rate of grade 3/4 cytokine release syndrome (CRS) was 4%, with any grade CRS seen in 82% of patients. Immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in 10% of patients, with 2% having grade 3/4 ICANS. Other neurotoxicity was seen in 12% of patients, of which 7% was grade 3/4, these consisted of dizziness, ataxia, dysarthria, and/or nystagmus, Bal noted. There were no cases of Parkinsonism, Guillain-Barré syndrome, or cranial nerve palsy.

GPRC5D is also associated with hard keratinized tissues, Bal noted, and there were mild skin, nail, and oral AEs associated with this on-target but off-tumor effect. These events were all grade 1/2 in severity, with skin events occurring in 30%, nail in 19%, and oral in 32% of patients treated with arlo-cel. "Due to the one-time nature of infusion, events were transient and 79% resolved without the need for additional intervention," Bal said.

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Reference
Bal S, Anderson LD, Nadeem O, et al. Efficacy and Safety with Extended Follow-up in a Phase 1 Study of BMS-986393, a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted CAR T Cell Therapy, in Patients (pts) with Heavily Pretreated Relapsed/Refractory (RR) Multiple Myeloma (MM). Presented at: ASH 2023 Annual Meeting & Exposition. December 7-10; San Diego, CA. Abstract #922.