Anitocabtagene Autoleucel Elicits Deep Responses in Relapsed/Refractory Multiple Myeloma

Anitocabtagene autoleucel (anito-cel) demonstrated durable efficacy in patients with relapsed or refractory multiple myeloma, according to preliminary data from the phase 2 iMMagine-1 trial (NCT05396885) presented during the 2024 ASH Annual Meeting.1

At a median follow-up of 9.5 months, the therapy elicited an objective response rate (ORR) of 97% in evaluable patients (n = 86), which comprises a stringent complete response (sCR)/complete response (CR) rate of 62%, a very good partial response rate of 20%, and a partial response rate of 15%. The median time to response was 1.0 month (range, 0.9-7.3). Moreover, 93.1% of patients were minimal residual disease (MRD) negative at minimum of 10–5 sensitivity, and the median time to MRD negativity at 10–5 or lower was 1.0 month (range, 0.9-6.4).

The median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated PFS and OS rates at 6 months were 93.3% (95% CI, 84.4%-97.2%) and 96.5% (95% CI, 89.6%-98.9%); at 12 months, these respective rates were 78.5% (95% CI, 63.5%-87.9%) and 96.5% (95% CI, 89.6%-98.9%).

“Anito-cel demonstrated deep, durable responses in fourth-line or later relapsed/refractory multiple myeloma with a manageable safety profile, including no delayed or non–immune effector cell–associated neurotoxicity syndrome [ICANS] neurotoxicities,” Ciara L. Freeman, MD, PhD, of H. Lee Moffitt Cancer Center, in Tampa, Florida, said in a presentation of the data.

She added that anito-cel is a BCMA-targeting CAR with a CD3-zeta and 4-1BB costimulatory domain, that is unique from other products in its binding domain, which is a D-Domain. The construct facilitates high transduction efficiency and CAR positivity leading to a low total cell dose. Moreover, because of rapid folding, lack of disulfide bonds, and the hydrophobic core of the domain, the CARs are stable and do not have tonic signaling. Moreover, because the binder has a fast off-rate and high CAR surface expression, it is thought to allow for the killing of cancer cells without prolonged inflammation.

The therapy was initially evaluated in a phase 1 study (NCT04155749). At a median follow-up of 38.1 months (range, 25-56), the median PFS was 30.2 months (95% CI, 16.6-not evaluable [NE]) in evaluable patients (n = 38).2 Anito-cel elicited an ORR of 100%, with 79% of patients achieving a sCR/CR. In those who achieved a sCR/CR (n = 30), the median PFS was 34.3 months (95% CI, 24.2-NE). The median OS was not reached. Moreover, the toxicity profile was predictable and manageable. “This study informed the development of the phase 2 study,” Freeman noted.1

The phase 2 study enrolled patients with multiple myeloma who received 3 or more prior lines of therapy, including a prior immunomodulatory drug (iMiD), proteasome inhibitor, and CD38-targeted therapy, and were refractory to their last line of treatment. Patients were required to have an ECOG performance status of 0 or 1 and measurable disease.

After a screening period, patients underwent leukapheresis and received bridging therapy, if necessary, while anito-cel was being manufactured. They then received lymphodepleting chemotherapy comprised of 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine on days -5, -4, and -3. On day 0, anito-cel was infused, and the target dose was 115 x 106 CAR-positive T cells.

ORR by 2016 International Myeloma Working Group criteria served as the trial’s primary end point, and secondary end points comprised sCR/CR rate by the same criteria and ORR in patients limited to 3 prior lines of treatment per the same criteria.

A total of 129 patients were enrolled and leukapheresed. Eleven total patients discontinued due to withdrawn consent (n = 4), progressive disease (n = 4), intercurrent illness (n = 1), investigator decision (n = 1), or no longer being eligible due to myocardial infarction (n = 1). The remaining 118 patients underwent lymphodepletion, and 1 more patient discontinued after withdrawing consent. A total of 117 patients were dosed; 98 patients were evaluable for safety (minimum follow-up of 1 month), and 86 were evaluable for efficacy (minimum follow-up of 2 months). The data cutoff date for both sets was October 31, 2024.

In the efficacy evaluable patients, the median age was 65 years (range, 38-78), with 55% of patients aged 65 or older. More than half of patients were male (56%) and most were White (81%). Regarding ECOG performance status, 45% had a status of 0 and 55% had a status of 1. Fifteen percent of patients had extramedullary disease and 38% had high-risk cytogenetics.

All were refractory to their last line of therapy, 86% were triple refractory, and 43% were pentarefractory. The median prior lines of therapy received was 4, with a range of 3 to 8; 43% of patients had received 3 prior lines of therapy. Most patients previously underwent transplant (74%) and had received bridging therapy (71%).

“Eight percent of patients were treated as an outpatient, and at the time of this data cut, this will increase as more of us became more comfortable toward the end of the study to treat patients on an outpatient basis,” Freeman noted.

Regarding safety, 83% of the safety-evaluable patients (n = 98) experienced cytokine release syndrome (CRS) of any grade, and the median onset was 4 days (range, 1-17) and the median duration was 3 days (range, 1-9). CRS occurred at grade 1 (68%) and grade 2 (13%); 17% of patients did not experience any CRS. One grade 5 CRS event occurred in a 76-year-old patient who experienced rapid disease progression between screening and baseline and did not receive bridging therapy.

“Management per protocol was in line with standard practice, and for those who developed early onset CRS within 48 hours, a single dose of dexamethasone was recommended to be administered in conjunction with the tocilizumab [Actemra],” Freeman said. “But two-thirds of the patients who received dexamethasone only received a single dose. No prophylactic tocilizumab or dexamethasone was administered on this study.”

Sixty-three percent of patients with either no CRS or CRS had their event resolve by 7 days after infusion; 92% had their event resolve by 10 days after infusion, and 98% had their event resolve by 14 days after infusion. Supportive measures included tocilizumab (72%), dexamethasone (65%), anakinra (Kineret; 8%), siltuximab (Sylvant; 4%), vasopressor (1%), and intubation or mechanical ventilation (1%).

Nine percent of patients experienced ICANS of any grade, and all cases resolved. The median time to onset was 7 days (range, 2-10) and the median duration was 4 days (range, 1-10). Supportive measures included tocilizumab (3%), dexamethasone (6%), anakinra (1%), and siltuximab (1%). No delayed or non-ICANS neurotoxicities were reported, including no instances of Parkinsonism, cranial nerve palsies, and Guillain-Barré syndrome. These effects were not observed in the phase 1 study either, according to Freeman.

The most common grade 3 or higher adverse effects were neutropenia (54%), anemia (22%), thrombocytopenia (20%), fatigue (2%), hypophosphatemia (2%), headache (2%), hypokalemia (2%), upper respiratory tract infection (2%), urinary tract infection (2%), nausea (1%), diarrhea (1%), hypogammaglobulinemia (1%), and COVID-19 (1%). No secondary primary malignancies of T-cell origin or hematological malignancies were reported, although follow-up is short, Freeman noted.

“There were 3 deaths that occurred on the study, the first involved a 65-year-old patient who also had significant disease progression occur between collection and lymphodepletion, and unfortunately presented for cell infusion with circulating plasma cells and evidence of plasma cell leukemia,” Freeman shared. “This patient had very high inflammatory markers and developed an inflammatory storm and is the only enrolled patient who developed hemophagocytic lymphocytosis at the current time. A bone marrow [biopsy] was performed to demonstrate the presence of hemophagocytosis in the setting of coagulopathy, and unfortunately, the patient suffered a massive retroperitoneal hemorrhage. It was one grade 5 CRS event, as I’ve discussed, and a death from invasive fungal infection.”

The global, phase 3 iMMagine-3 study (NCT06413498) is comparing the safety and efficacy of anito-cel with standard of care in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy, including an iMiD and an anti-CD38 therapy. The trial will enroll approximately 450 patients at about 130 clinical sites.

Disclosures: Dr Freeman disclosed receiving honoraria from Bristol Myers Squibb (BMS) and research funding from Roche/Genentech, Janssen, and BMS. She serves in a consultancy role for Amgen, AbbVie, Seattle Genetics, Janssen, ONK Therapeutics, Celgene, BMS, Sanofi, and Incyte.

References

1. Freeman CL, Dhakal B, Kaur G, et al. Phase 2 registrational study of anitocabtagene autoleucel for the treatment of patients with relapsed and/or refractory multiple myeloma: preliminary results from the iMMagine-1 trial. Blood. 2024;144(suppl 1):1031. doi:10.1182/blood-2024-198499
2. Bishop MR, Rosenblatt J, Dhakal B, et al. Phase 1 study of anitocabtagene autoleucel for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM): efficacy and safety with 34-month median follow-up. Blood. 2024;144(suppl 1):4825. doi:10.1182/blood-2024-201080