Isatuximab in Relapsed AL Amyloidosis: Results of a Prospective Phase II Trial (SWOG S1702)

Background: Isatuximab is an IgG1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in light chain (AL) amyloidosis. Anti-CD38 antibodies have shown efficacy alone and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. Here we report the final analysis of a multi-center, cooperative group prospective phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included: age ≥18 years, relapsed or refractory systemic AL amyloidosis, ≥1 prior line of therapy, measurable disease, ≥1 organ involved, not refractory to daratumumab, Eastern Cooperative Oncology Group performance status ≤2, creatinine clearance ≥25 mL/min, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28-day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: Forty-three patients were registered, with 35 patients being eligible for response. The median age of the evaluable patients was 70 years (range, 40.1-79.5) with the majority (66%, n=23) having a lambda clonal plasma cell dyscrasia. The most common cytogenetic abnormality using fluorescence in situ hybridization was translocation t(11;14) observed in ten patients (29%). The most common prior treatment was a proteasome inhibitor (94%, n=33) while 46% (n=16) had undergone autologous stem cell transplant. Eighteen patients (51%) had single organ involvement while 17 (49%) had multiple organs involved. The distribution of organ involvement was typical for AL amyloidosis with cardiac involvement in 25 patients (71%) and renal involvement in 14 (40%). As of December 30, 2022, no new safety concerns were identified. The most common treatment related grade ≥3 adverse events included lymphopenia (n=3, 8.5%) and infection (n=2, 6%). The overall hematologic response rate was 77.1% with a rapid median time to partial response or better of 1.1 months. Two patients (6%) achieved a hematological complete response (CR), 18 (51%) had a very good partial response (VGPR), and 7 (20%) had a partial response (PR). At 24 months from hematologic response, the rate of patients still in response was estimated at 81% (95% confidence interval (CI): 67, 96). The 24-month estimated overall survival was 85% (95% CI: 73%, 97%). Renal response occurred in 50% (7/14) of patients with renal involvement with a median time to response of 18.5 months. Cardiac response occurred in 56% (14/25) of patients with cardiac involvement with a median time to response of 16.6 months. Conclusions: Isatuximab monotherapy resulted in high rates of hematologic response in relapsed AL amyloidosis which translated into organ responses. Treatment appears safe and was well tolerated. Support: NIH/NCI/NCTN grant awards U10CA180888, U10CA180819, CA180820, and CA180821; and in part by Sanofi-Aventis (Sanofi US)