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)

Sanchorawala:Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena, AstraZeneca, Nexcella: Membership on an entity's Board of Directors or advisory committees; Celgene, Millennium-Takeda, Janssen, Prothena, Sorrento, Karyopharm, Oncopeptide, Caelum, Alexion: Research Funding; Pfizer, Janssen, Attralus, GateBio, Abbvie, BridgeBio: Consultancy. Landau:Abbvie, Immix Biopharma, Legend Biotech, Alexion, Prothena: Consultancy; Janssen, Alexion, Protego, Prothena: Research Funding. Kapoor:Loxo Pharmaceuticals: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Ichnos: Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Keosys: Consultancy. Neparidze:Janssen: Consultancy, Research Funding; GSK: Research Funding. Girnius:Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Servier: Honoraria; Amgen: Speakers Bureau. Scott:Janssen: Current Employment, Current holder of stock options in a privately-held company. Orlowski:AbbVie Inc, Adaptive Biotechnologies Corporation, Asylia Therapeutics Inc, BioTheryX Inc, Bristol Myers Squibb, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Therapeutics, Oncopeptides, Pf: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; DEM BioPharma, Inc., Karyopharm Therapeutics, Lytica Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Myeloma 360, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sporos Bio: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb, CARsgen Therapeutics, Exelixis Inc, Heidelberg Pharma, Janssen Biotech Inc, Sanofi, Takeda Pharmaceuticals USA Inc; Laboratory Research Funding: Asylia Therapeutics Inc, BioTheryX Inc, Heidelberg Pharma: Research Funding; Asylia Therapeutics Inc.: Current equity holder in private company, Patents & Royalties; Sanofi, Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Isatuximab is an IgG1 kappa monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. It is currently approved in treatment of relapsed refractory multiple myeloma, but not in AL amyloidosis. The trial describes the use of isatuximab in relapsed refractory AL amyloidosis.