A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients with Previously Treated AL Amyloidosis (SWOG S1702; NCT#03499808)
Authors: Parker Terri L. , Rosenthal Adam , Sanchorawala Vaishali , Landau Heather J , Campagnaro Erica , Kapoor Prashant , Neparidze Natalia , Hagen Patrick , Sarosiek Shayna , Scott Emma C. , Hoering Antje , Durie Brian G.M. , Usmani Saad Z. , Orlowski Robert Z. 
Published: February 2021

Background: Isatuximab (SAR650984) is an IgG1k monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in AL amyloidosis. It has been shown to be efficacious and well tolerated in relapsed and refractory multiple myeloma as a single agent and in combination. Here we report on the preliminary results of a prospective multi-center, 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 (defined as a positive monoclonal serum immunofixation electrophoresis (IFE) or urine IFE, a serum free light chain ratio outside of the normal range (0.25-1.65), and a difference in the involved versus the uninvolved serum free light chain of ≥ 4.5 mg/dL), at least one organ involved, not refractory to daratumumab, ECOG performance status 0-2, creatinine clearance ≥25 mL/min as measured by 24-hour urine collection or as estimated by Cockcroft and Gault formula, 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: At data cut-off (July 24, 2020), 43 patients were registered from March 2018 to September 2019 at 14 institutions. Thirty six patients were eligible with 35 patients receiving at least one dose of isatuximab. Of the eligible patients, the median age was 70 (range 40-81). Prior therapies included proteasome inhibitors in 32 patients (89%), high dose therapy followed by autologous stem cell transplant in 17 patients (47%), immunomodulatory therapy in 9 patients (25%), and anti-CD38 monoclonal antibody therapy in 2 patients (6%). Single organ system involvement was seen in 19 patients (53%), ≥ 2 organ systems in 17 patients (47%), 16 patients (44%) had renal involvement, and 24 (67%) had cardiac involvement. For those with cardiac involvement, 7 patients (29%) had cardiac biomarker stage II and 9 patients (38%) had stage III disease using the Revised Mayo Staging (Kumar S et al., J Clin Oncol, 2012). A total of 17 patients remain on therapy. The median duration on treatment for eligible patients is currently 11.8 months (current range, 0.3-22.1). Of the 19 patients who discontinued treatment, the most common reasons included adverse events in 5 patients (26%), disease progression in 4 patients (21%), sub-optimal response in 2 patients (11%), and concerns related to COVID-19 in 2 patients (11%). The current median follow up is 16.3 months. The most common drug-related AEs were infusion related reactions in 18 patients (50%) with the majority (16/18) being grade I or II, anemia in 9 patients (25%) with the majority (8/9) being grade I, and lymphopenia in 8 patients (22%). Patient characteristics and preliminary safety data were previously presented at the International Symposium on Amyloidosis. The overall hematologic response rate was 77%. Hematological complete response (CR) was observed in 1 of 35 evaluable (completing at least 1 dose) patients (3%), very-good-partial response (VGPR) in 19 patients (54%), and partial response (PR) in 7 patients (20%).
Conclusions: Isatuximab demonstrates encouraging efficacy in previously treated patients with AL amyloidosis. The administration of isatuximab in these patients is associated with a good safety profile similar to other monoclonal antibodies against CD38. The data will be updated at the meeting.

Disclosures
Sanchorawala: Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Janssen: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Takeda: Research Funding; Celgene: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding. Neparidze:GlaxoSmithKline: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member . Sarosiek:Spectrum: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Usmani:Incyte: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; Celgene: Other; Seattle Genetics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Isatuximab is FDA approved for relapsed refractory myeloma in combination with pomalidomide and dexamethasone. Isatuximab is not FDA approved for AL amyloidosis.