The efficacy and safety of isatuximab, an immunoglobulin G1 kappa monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells, were analyzed in a prospective, multicenter phase 2 study of previously treated patients with amyloid light-chain (AL) amyloidosis. Preliminary results from this analysis are reported here.
The primary objective of this study was hematologic response. Secondary objectives included safety, organ response, progression-free survival (PFS), and overall survival (OS). Eligible patients for this study were required to be at least 18 years of age, have relapsed or refractory systemic AL amyloidosis, have received ≥1 previous lines of therapy, have measurable disease activity (positive monoclonal serum immunofixation electrophoresis [IFE] or urine IFE, a serum free light chain [FLC] ratio outside the normal range [0.25-1.65], and a difference in the involved versus the uninvolved serum FLC of ≥4.5 mg/dL), have ≥1 involved organs, not be refractory to daratumumab, have an Eastern Cooperative Oncology Group performance status of 0 to 2, creatinine clearance ≥25 mL/min, and N-terminal pro-B-type natriuretic peptide ≤8500 pg/mL. Patients were treated with isatuximab intravenously 20 mg/kg weekly in the first 28-day cycle, followed by treatment every other week for cycles 2 to 24. The maximum number of cycles was 24.
A total of 43 patients were registered between March 2018 and September 2019 across 14 institutions (data cutoff, July 24, 2020). Among the 36 eligible patients, 35 received at least 1 dose of isatuximab. The median age of eligible patients was 70 years. Previous therapies included proteasome inhibitors (n = 32; 89%), high-dose therapy followed by autologous stem-cell transplant (17; 47%), immunomodulatory therapy (9; 25%), and anti-CD38 monoclonal antibody therapy (2; 6%). Single-organ involvement was found in 56% of patients, with the remainder having ≥2 organ systems involved. Sixteen (44%) of the patients had renal involvement, and 24 (67%) had cardiac involvement. Among patients with cardiac involvement, 29% had cardiac biomarker stage II and 38% had stage III disease as determined by the revised Mayo staging system. At data cutoff of November 12, 2020, 11 of 36 (31%) eligible patients were still receiving therapy. In the 19 (54%) patients who discontinued treatment, the most common reasons for discontinuation were adverse events (AEs; 21%), disease progression (26%), suboptimal response (11%), and concerns related to COVID-19 (11%). Median follow-up for this preliminary data analysis was 19 months. The most common AEs determined to be drug-related were infusion-related reactions (49%; majority [94%] being grade 1/2), anemia (26%; majority [89%] being grade 1), and lymphopenia (26%). The overall hematologic response rate was 77%. Of the patients receiving at least 1 dose of isatuximab, hematologic complete response, very good partial response (PR), and PR were observed in 3%, 54%, and 20% of patients, respectively. Median time to PR or better was 1.1 months, and 1-year estimated duration of response is 89%. One-year estimated OS is 97%, and 1-year estimated PFS is 85%.
The results of the preliminary analysis of this study showed encouraging efficacy for isatuximab use in patients with AL amyloidosis who were previously treated. The use of isatuximab among these patients was associated with a good safety profile, which was similar to other CD38 monoclonal antibodies.
Abstract 728. ASH 2020. December 7, 2020. A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients with Previously Treated AL Amyloidosis (SWOG S1702; NCT#03499808).