CAR T-Cell Therapy ARI0002H Elicits Encouraging Responses in Relapsed/Refractory Multiple Myeloma

ARI0002H, a BCMA-directed CAR T-cell therapy, achieved promising response rates in patients with relapsed/refractory multiple myeloma, according to findings from a phase 1/2 trial (NCT04309981) presented at the 2022 EHA Congress.¹

At a median follow-up of 17.5 months (range, 5-23), ARI0002H elicited a response in 100% of patients (n = 30), including a complete remission (CR) in 63% of patients and a very good partial response (VGPR) or better in 93% of patients. Additionally, 96% of patients were minimal residual disease (MRD) negative at 28 days, and 92% were MRD negative at 100 days. At 6 months, 74% of patients were MRD negative, and at 12 months, 69% of patients were MRD negative.

“ARI0002H production is fast and feasible. We see 11 days in time of production. Patients achieved a sustained response with low-grade toxicity,” lead study author Carlos Fernández de Larrea, MD, PhD, a hematologist at the Hospital Clínic de Barcelona, and an associate professor at the University of Barcelona, said in a presentation of the data.

ARI0002H is an academic lentiviral autologous second-generation CAR T-cell therapy with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA.²

The phase 1/2 trial evaluated the safety and efficacy of ARI0002H in patients with relapsed/refractory multiple myeloma who received prior treatment with a proteasome inhibitor, an immunomodulatory drug, and/or an anti-CD38 monoclonal antibody.³

“Even though the prognosis has improved significantly in the last year, [patients with refractory multiple myeloma] don’t have a clear standard of care, and they have a poor survival,” Fernández de Larrea said.

The trial enrolled patients between the ages of 18 and 75 years with a diagnosis of multiple myeloma measurable by monoclonal component in serum and/or urine, or by free light chains in serum according to the eligibility criteria for clinical trials of the International Myeloma Working Group. Other eligibility criteria included at least 2 prior lines of treatment, being refractory to the most recent line of treatment, an ECOG performance status between 0 and 2, and a life expectancy of more than 3 months.

Key exclusion criteria included allogeneic stem cell transplant within 6 months prior to inclusion or graft-vs-host disease that required active systemic immunosuppressive treatment; an absolute lymphocyte count less than 0.1 x 10⁹/L; previous neoplasia, except in patients who have been in complete remission for more than 3 years, except for cutaneous carcinoma (non-melanoma); active infection requiring treatment; active infection of HIV, HBV, or HCV; previous diagnosis of symptomatic primary amyloidosis; and contraindication to receive conditioning chemotherapy.

Enrolled patients received conditioning chemotherapy consisting of 30 mg/m² of fludarabine per day and 300 mg/m² of cyclophosphamide per day, starting at 6 days prior to CAR T-cell infusion. At day 0, patients started fractionated dosing of ARI0002H at 0.3 x 10⁶/kg, followed by 0.9 x 10⁶/kg on day 3 and 1.8 x 10⁶/kg on day 7, for a total of 3.0 x 10⁶/kg CAR+ cells. From month 4 on, patients who achieved a response, did not progress, and did not experience complications to treatment were eligible for a second dose of ARI0002H, up to 3.0 x 10⁶/kg.

Prior data with ARI0001 showed that fractionated dosing reduced toxicity and maintained efficacy. In patients administered a single dose of 3.0 x 10⁶/kg CAR+ cells, cytokine release syndrome (CRS) of any grade occurred in 73.3% of patients compared with 43.5% of patients who received fractionated dosing. Instances of grade 3 or higher CRS occurred in 26.7% of patients who received a single dose of therapy vs 4.3% of patients who received a fractionated dose of treatment.

The primary end points of the trial were overall response rate (ORR) and safety, specifically the rate of CRS.

A total of 35 patients enrolled in the trial, and 30 patients received treatment. Four patients could not receive ARI0002H due to disease progression prior to apheresis (n =2) or study treatment (n = 2), and 1 patient died of a fungal infection.²

The median age of evaluable patients was 61 years (range, 36-74), and 18 patients were male. Additionally, 47%, 23%, and 23% of patients had heavy chain isotype of IgG, IgA, and Bence Jones, respectively, and 50% of patients each had light chain isotype of kappa and lambda. Furthermore, 47% of patients has plasmacytomas, including 20% with extramedullary plasmacytomas, and 33% had high-risk cytogenetics. The median serum M-protein was 12.5 g/L (range, 0-90), the median differential serum free light chains was 443 mg/L (range, 4-7325), the median urine M-protein was 0.08 g/24 hours (range, 0-19), and the median percentage of bone marrow plasma cells was 11% (range, 0%-100%).

The median prior lines of therapy for enrolled patients was 4 (range, 2-10), and 87% of patients received prior autologous stem cell transplant, 13% had prior allogeneic stem cell transplant, 100% of patients were triple exposed, and 67% of patients were triple refractory to a proteasome inhibitor (bortezomib [Velcade] or carfilzomib [Kyprolis]), an immunomodulatory drug (lenalidomide [Revlimid] or pomalidomide [Pomalyst], and an anti-CD38 monoclonal antibody (daratumumab [Darzalex]).

Twenty-four patients received the full fractionated dose of 3.0 x 10⁶/kg CAR+ cells at first infusion, and 6 patients received 1.2 x 10⁶/kg CAR+ cells. Additionally, 24 patients were administered a second dose, including 19 who received 3.0 x 10⁶/kg CAR+ cells, 3 who were given 1.8 x 10⁶/kg CAR+ cells, and 2 patients who had 1.2 x 10⁶/kg CAR+ cells.

Additional data showed that 73% of patients were still alive after 18 months, including 53% of patients without disease progression. The median progression-free survival (PFS) and overall survival (OS) were not reached.

In patients with plasmacytomas, the ORR was 93%, including a CR rate of 57% and a VGPR rate of 29%. One patient had a partial response, and 1 patient had progressive disease.

After the first infusion of ARI0002H, the median maximum peripheral blood expansion was 14 days (range, 7 days–6 months). At day 100, 6 months, and 12 months, the median rate of CAR+ cells in peripheral blood was 62%, 36%, and 20%, respectively. The median persistence of CAR+ cells was 5 months (range, 2–not reached). Notably, 33% of patients who relapsed (n = 3 of 9) had detectable CAR+ cells in peripheral blood.

Of the 24 patients who received a second dose of ARI0002H, 9 were given a lymphodepletion regimen. Notably, 58% of patients already had a stringent complete response at reinfusion, 25% had improved response after reinfusion, and 17% maintained response after reinfusion.

Regarding safety, 90% of patients experienced CRS, though no instances of grade 3 or higher events were reported. Specifically, 67% of patients experienced grade 1 CRS, and 23% had grade 2 CRS. The median time to onset of CRS was 8 days (range, 1-10), and the median duration of CRS was 4 days (range, 1-12). Notably, 74% of patients received tocilizumab (Actemra), primarily for persistent grade 1 CRS, and 10% received corticosteroids. No instances of CRS were reported in patients who received a second infusion.

Fernández de Larrea said there were no reported cases of neurotoxicity. Notably, 87% of patients experienced any grade of neutropenia, including 69% who had grade 3 or 4 events. The median duration was 9 months (range, 1-19). Additionally, 100% of patients had grade 3 or 4 thrombocytopenia with a median duration of 4 months (range, 0-14), and 90% of patients had anemia of any grade, including 52% that was classified as grade 3 or 4. The median duration of anemia was 5 months (range, 0-20). Notably, all patients presented with cytopenias at least 30 days after infusion (thrombocytopenia, 100%; neutropenia, 93%; anemia 93%).

Other notable adverse effects of any grade included macrophage-activation syndrome (n = 3), hepatitis B reactivation (n = 1), and colon cancer (n = 1).

Editor's Note: Article updated at 10am EST, following the presentation at 9:30am EST.

References

1. Fernández de Larrea C. Efficacy and safety of ARI0002H, an academic BCMA-directed CAR-T cell therapy with fractionated initial therapy and booster dose in patients with relapsed/refractory multiple myeloma. Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract S103.
2. Fernández de Larrea C, Gonzalez-Calle V, Cabañas V, et al. Results from a pilot study of ARI0002H, an academic BCMA-directed CAR-T cell therapy with fractionated initial infusion and booster dose in patients with relapsed and/or refractory multiple myeloma. Blood. 2021;138(suppl 1):2837. doi:10.1182/blood-2021-147188
3. Clinical trial using humanized cart directed against BCMA (ARI0002H) in patients with relapsed/refractory multiple myeloma to proteasome inhibitors, immunomodulators and anti-CD38 antibody. ClinicalTrials.gov. Updated February 4, 2022. Accessed June 11, 2022. https://clinicaltrials.gov/ct2/show/NCT04309981