OAB-005: Update of safety and efficacy of Isatuximab short-duration fixed-volume infusion plus Bortezomib, Lenalidomide, and Dexamethasone combined therapy for NDMM ineligible/with no immediate intent for ASCT

Introduction One standard-of-care treatment for patients with newly diagnosed multiple myeloma (NDMM) not eligible for autologous stem cell transplant (ASCT) is the combination of bortezomib (V), lenalidomide (R), and dexamethasone (d). Isatuximab (Isa), a monoclonal antibody targeting a specific epitope of CD38, is approved in combination with pomalidomide/carfilzomib plus d for the treatment of adults with relapsed/refractory multiple myeloma. The objective of this study was to evaluate the efficacy and safety of the approved short-duration fixed-volume infusion of Isa, combined with VRd (Isa-VRd) in patients with NDMM ineligible/with no immediate intent for ASCT. Methods In Part A of this Phase 1b study (NCT02513186), a weight-based infusion of Isa-VRd was effective and well tolerated (median infusion duration at first infusion, 3.7 hours). Here, we present results from Part B, where Isa (10 mg/kg) was administered as a fixed-volume infusion of 250 mL with standard doses of VRd (Ocio Blood 2020). The primary endpoint is the complete response (CR) rate of Isa-VRd. Results Of 46 patients in Part B, 30 (65.2%) were receiving study treatment at data cutoff (March 17, 2021). Median patient age was 70.0 years (range, 49–87), and 8 (17.4%) had high-risk cytogenetics. There were 13 (28.3%) patients eligible, but with no immediate intent, for ASCT; of these, 7 (53.8%) proceeded to mobilization and 6 (46.2%) performed apheresis (median 8.1×106 CD34+ cells/kg collected). The median duration of Isa infusion decreased to 1.3 hours from the third infusion onward. The overall response rate was 97.8%, including a CR/stringent CR (sCR) rate of 35.6% and very good partial response rate of 55.6%. After implementation of the SEBIA Hydrashift Isa immunofixation assay assessing serum M-protein without Isa interference, the adjusted CR/sCR rate increased to 53.3%. Investigation of minimal residual disease (MRD) negativity by combined next-generation flow cytometry or sequencing methods at a threshold of 10-5 revealed 23/45 (51.1%) of response-evaluable patients with MRD negativity. All patients experienced ≥1 treatment-emergent adverse event (TEAE), 32 (69.6%) had Grade ≥3 TEAEs, 20 (43.5%) had serious TEAEs, and 6 (13.0%) had TEAEs leading to death. Infusion reactions were observed in 13 (28.3%) of patients; none were of Grade ≥3. The most frequently reported TEAEs were constipation (69.6%), asthenia (67.4%), diarrhea (56.5%), and peripheral sensory neuropathy (50.0%). The most common Grade ≥3 hematologic abnormalities were lymphopenia (76.1%) and neutropenia (41.3%). Conclusions These results confirm the feasibility, efficacy, and safety of the approved short-duration fixed-volume infusion method of Isa in combination with VRd in patients with NDMM ineligible/with no immediate intent for ASCT. Isa-VRd is under investigation in ongoing Phase 3 studies. Funding Sanofi.