Lentiviral CAR T Therapy Delivers Good Efficacy, Safety in R/R Multiple Myeloma

Article

Participants in the trial achieved a sustained response and experienced low-grade toxicity.

This article was originally published on our sister site, OncLive.

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 European Hematology Association (EHA) Annual Meeting, June 9-17, 2022, in Vienna, Austria and virtual.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).

For more coverage of EHA 2022, click here.

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
Recent Videos
Arun Upadhyay, PhD, the chief scientific officer and head of research, development, and Medical at Ocugen
Arun Upadhyay, PhD, the chief scientific officer and head of research, development, and Medical at Ocugen
Barry J. Byrne, MD, PhD, the chief medical advisor of Muscular Dystrophy Association (MDA) and a physician-scientist at the University of Florida
John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia
Chun-Yu Chen, PhD, a research scientist at Seattle Children’s Research Institute
Alexandra Collin de l’Hortet, PhD, the head of therapeutics at Epic Bio
David Dimmock, MBBS, on Accelerating Therapy Discovery and Approval With AI David Dimmock, MBBS, on Accelerating Therapy Discovery and Approval With AI
John Finn, PhD, the chief scientific officer of Tome Biosciences
David Dimmock, MBBS, on a Promising Case Study of Ultra-Rare, AI-Guided, ASO Development
Scott Jeffers, PhD, on The Importance of Precise Reproducibility of AAVs
Related Content
© 2024 MJH Life Sciences

All rights reserved.