Arlo-cel Elicits 87% ORR in Heavily Pretreated, Relapsed/Refractory Multiple Myeloma

Arlocabtagene autoleucel (arlo-cel; BMS-986393), a CAR T-cell therapy targeting GPRC5D, demonstrated encouraging antitumor activity and an acceptable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma, according to updated findings from a phase 1 trial (CC-95266-MM-001; NCT04674813) presented during the 2024 ASH Annual Meeting and Exposition.1

In the overall efficacy-evaluable population (n = 79), the overall response rate (ORR) was 87%, which comprised a 53% complete response (CR) rate, a 23% very good partial response (VGPR) rate, and an 11% partial response (PR) rate. In patients who were treated with the recommended phase 2 dose (RP2D) of 150 × 106 CAR T cells (n = 23), the ORR was 91%, the CR rate was 48%, and the VGPR and PR rates were both 22%. Forty-two percent of patients in the overall population and 35% of patients in the RP2D population achieved a stringent CR (sCR).

Additionally, no new safety signals were reported with the updated data presented at ASH. Any-grade treatment-emergent adverse effects (TEAEs) were reported in all patients, and grade 3/4 TEAEs occurred in 86% of all-treated patients (n = 84) and 85% of patients who received the RP2D (n = 26).

“Arlo-cel, a potential first-in-class, GPRCD-targeted, autologous CAR T-cell therapy administered to patients with heavily pretreated relapsed/refractory multiple myeloma, showed manageable safety and promising efficacy,” lead study author Susan Bal, MD, an associate professor at the University of Alabama at Birmingham, said in a presentation during the meeting.

Bal also noted that arlo-cel has been granted FDA Regenerative Medicine Advanced Therapy Designation.

Earlier data from the first-in-human, multicenter, open-label trial highlighted the agent’s unique safety profile as well as high, deep, and durable responses observed.2

The multicohort study was comprised of the following:1

• Part A + Part B (Cohort A): patients with heavily pretreated, relapsed/refractory multiple myeloma who had received at least 3 antimyeloma regimens, including a proteasome inhibitor, immunomodulatory drug (IMiD), anti-CD38 therapy, and autologous stem cell transplant (ASCT) unless they were ineligible. Patients in this cohort underwent lymphodepletion with fludarabine and cyclophosphamide before receiving a single infusion of arlo-cel in a dose-escalation and -expansion dose design of 25 to 450 × 106 CAR T cells.
• Part B (Cohort B): patients with heavily pretreated, relapsed/refractory multiple myeloma who received at least 3 antimyeloma regimens, including a proteasome inhibitor, IMiD, anti-CD38 therapy, and ASCT unless they were ineligible. Patients in this cohort received lymphodepletion with bendamustine and were then given the RP2D of 150 × 106 CAR T cells of arlo-cel.
• Part B (Cohort C): patients with relapsed/refractory multiple myeloma who had received 1 to 3 antimyeloma regimens, including a proteasome inhibitor, IMiD, and ASCT unless they were ineligible. Patients received lymphodepletion with fludarabine and cyclophosphamide and then received the RP2D of 150 × 106 CAR T cells of arlo-cel.

At the 2024 ASH Annual Meeting, Bal unveiled updated findings from cohort A that encompassed the first overall survival (OS) results with a median follow-up duration of 15.1 months.

Diving Into the Phase 1 Trial’s Criteria and Enrollment

Cohort A enrolled adult patients with relapsed/refractory disease who progressed within 12 months of their most recent regimen per International Myeloma Working Group (IMWG) criteria. Patients had an ECOG performance status of 0 to 1 and must have been previously exposed to at least 3 antimyeloma therapies. Prior BCMA-directed treatments were permitted and included CAR T-cell therapies.1

After screening, patients underwent leukapheresis followed by arlo-cel manufacturing at day –19; bridging therapy was optional and, if required for disease control, was limited to no more than 28 days and discontinued at least 19 days prior to infusion. All patients underwent lymphodepletion with fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 on days –5, –4, and –3. Following arlo-cel infusion, patients had their first posttreatment disease assessment on day 29 and a posttreatment follow-up at 24 months.

The primary end point was safety and tolerability, specifically the maximum-tolerated dose and RP2D. Secondary objectives included ORR, CR rate, duration of response (DOR), time to response by IMWG, progression-free survival (PFS), and OS; exploratory end points were minimal residual disease (MRD)–negative status and pharmacodynamics.

As of the data cutoff date of August 23, 2024, 86 patients were enrolled and underwent leukapheresis and 57 received systemic bridging therapy. Two patients did not receive arlo-cel treatment due to study withdrawal and other reason (n = 1 each). Among the 84 patients in the dose-escalation and -expansion all-treated population, arlo-cel was given at 25 × 106 CAR T cells (n = 6), 75 × 106 CAR T cells (n = 24), the RP2D of 150 × 106 CAR T cells (n = 26), 300 × 106 CAR T cells (n = 17), and 450 × 106 CAR T cells (n = 8). Five patients were not evaluable for responses due to death before day 29 (n = 2), and lack of measurable disease after bridging therapy (n = 3), bringing the efficacy-evaluable population to 79 patients.

Baseline characteristics were reported for both the all-treated patients (n = 84) and those who received the RP2D (n = 26). Between both cohorts, the median age was 63 years (range, 39-80), and most patients were male (51% vs 54%, respectively) and were White (67% vs 73%). Additionally, patients had del(17p) mutations (31% vs 42%), had extramedullary plasmacytoma (46% vs 35%), and received prior BCMA-targeted therapy (49% vs 46%), respectively. Of those who were refractory to BCMA-targeted therapy (20% and 13%, respectively), 76% and 85%, respectively, had triple-class refractory status.

Further Data Observed With Arlo-cel

Responses were seen across patient subgroups of the efficacy-evaluable population, including in those with triple class–refractory disease (ORR, 87%; 95% CI, 75%-94%), extramedullary disease (86%; 95% CI, 71%-95%), high-risk cytogenetics (84%; 95% CI, 66%-95%), and in those who were refractory to prior BCMA-targeted therapy (81%; 95% CI, 54%-96%).

Bal added that in the efficacy-evaluable responders, soluble BCMA profiles suggested deep and sustained tumor clearance regardless of prior BCMA-targeted therapy received.

Additionally, 57% (n = 48/84) of patients were evaluable for MRD, and 46% were found to have MRD-negative disease and had achieved a CR or sCR. Among patients who were MRD-evaluable with a CR or higher, 85% were MRD-negative (n = 22/26).

At a median duration of follow-up of 16.1 months (range, 2.8-25.2), the median DOR was 18.0 months (95% CI, 13.3-23.0) with a median time to response of 1.0 month (range, 0.9-6.0). Thirty-eight percent of responses were ongoing at the time of the data cutoff (n = 26/69).

Furthermore, the median PFS in the efficacy-evaluable population was 18.3 months (95% CI, 11.8-21.9). When stratified by receipt of prior BCMA-targeted therapy, the median PFS was 19.0 months (95% CI, 8.9-not available) for those who did receive the therapy (n = 38) compared with 18.3 months (95% CI, 11.8-23.9) for those who did not (n = 41). OS was also measured in all-treated patients; here, the median OS was not reached. The 12-, and 18-, and 21-month OS rates were 90% (95% CI, 81%-95%), 87% (95% CI, 76%-93%), and 84% (95% CI, 72%-91%).

Spotlighting Safety and Next Steps With Arlo-cel

Additional safety data showed that hematologic TEAEs were the most common type of TEAE observed in both cohorts. In all-treated patients, these included neutropenia (any-grade, 74%; grade 3/4, 70%), anemia (50%; 32%), and thrombocytopenia (46%; 29%); in the RP2D cohort, these rates were similar with neutropenia (77%; 69%), anemia (50%; 42%), and thrombocytopenia (38%; 19%), respectively.

Non-hematological TEAEs that occurred in at least 30% of patients included infections (all-treated patients: any-grade, 55%; grade 3/4, 19%; RP2D: any-grade, 50%; grade 3/4, 12%), hypokalemia (all-treated patients: 45%; 5%; RP2D: 46%; 8%), hypocalcemia (all-treated: 35%; 2%; RP2D: 27%; 0%), headache (all-treated: 37%; 1%; RP2D: 35%; 0%), hypophosphatemia (all-treated: 33%; 2%; RP2D: 42%; 4%), nausea (all-treated: 31%; 1%; RP2D: 31%; 4%), fatigue (all-treated: 33%; 2%; RP2D: 46%; 4%), dysgeusia (all-treated: 31%; 0%; RP2D: 35%; 0%), and diarrhea (all-treated: 30%; 1%; RP2D: 38%; 4%).

Cytokine release syndrome (CRS) predominantly occurred at grade 1/2 (any-grade, 82%; grade 3/4, 4%) in all-treated patients, Bal noted. One patient had grade 5 CRS at the 450 × 106 dose level. Any-grade and grade 3/4 immune effector cell-associated neurotoxicity syndrome occurred in 10% and 2% of patients, respectively. Additionally, 79% of patients with skin, nail, and/or oral on-target off-tumor toxicities did not need intervention. Five patients experienced weight loss following arlo-cel treatment.

Neurotoxicity events (any-grade, 12%; grade 3/4, 7%)—none of which were grade 4/5—including dizziness, ataxia, neurotoxicity, dysarthria, and/or nystagmus occurred in patients treated between the 150 × 106 and 450 × 106 dose levels. The median time to onset of these events was 30.5 days. Furthermore, no cases of Parkinsonism, Guillain-Barré syndrome, or cranial nerve palsy have been reported, according to Bal.

Other studies are active or are already exploring arlo-cel in relapsed/refractory multiple myeloma, including a phase 1 trial (NCT06121843),3 the phase 2 QUINTESSENTIAL trial (NCT06297226) of arlo-cel in quadruple class–exposed patients,4 and the phase 3 QUINTESSENTIAL-2 trial (NCT06615479) of arlo-cel vs standard therapies in patients with lenalidomide (Revlimid)-refractory disease who received 1 to 3 prior lines of therapy.5

Disclosures: Dr Bal cited receiving honoraria from MJH Life Sciences and research funding from AbbVie, Beigene, Fate Therapeutics, and Bristol Myers Squibb. She also has membership on an entity’s board of directors or advisory committee with Bristol Myers Squibb and consulting roles with Janssen, AbbVie, AstraZeneca, and Bristol Myers Squibb.

References

1. 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). Blood. 2024;144(suppl 1):922. doi:10.1182/blood-2024-201356
2. Bal S, Htut M, Nadeem O, et al. BMS-986393 (CC-95266), a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): updated results from a phase 1 study. Blood. 2023;142(supplement 1):219. doi:10.1182/blood-2023-181857
3. A study to evaluate the safety, effectiveness and tolerable dose of bms-986393 in novel combinations in participants with relapsed and/​or refractory multiple myeloma. ClinicalTrials.gov. Updated September 19, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT06121843
4. Study of BMS-986393 a GPRC5D-directed CAR T cell therapy in adult participants with relapsed or refractory multiple myeloma (QUINTESSENTIAL). ClinicalTrials.gov. Updated November 22, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT06297226
5. A study to compare the efficacy and safety of BMS-986393 versus standard regimens in adult participants with relapsed or refractory and lenalidomide-refractory multiple myeloma (QUINTESSENTIAL-2). ClinicalTrials.gov. Updated November 22, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT06615479