Feasibility of Co-Administration of Autologous NK Cells and Anti-CD38 Monoclonal Antibody Isatuximab, in Multiple Myeloma Post-Autologous HSCT in a Randomized Phase 2 Clinical Trial

Background: Autologous natural killer (NK) cells have been administered as consolidation therapy in multiple myeloma patients following autologous hematopoietic stem cell transplantation (HSCT). Our primary aim was to evaluate the detectability and phenotypic characteristics of transferred NK cells, with a specific focus on CD38 expression. Methods: NK cells were isolated, expanded as previously described (https://doi.org/10.1016/j.xcrm.2022.100508), and infused into multiple myeloma patients post-HSCT. Phenotypic analysis was performed to assess CD38 expression on the transferred NK cells. Results indicated retention of reduced CD38 expression on the infused NK cells. Based on initial findings, a clinical trial was initiated to investigate the co-administration of autologous NK cells with isatuximab. To date, 18 patients have been enrolled in which 8 patients received a combination therapy of isatuximab and NK cells and 10 patients received isatuximab only. NK cells were administered in three consecutive doses, every other week during every other week isatuximab administration regimen. First two NK cell doses were 30 million cells/kg, and the last dose was up to 100 million cells/kg. Isatuximab treatment was initiated within 103 days after autologous stem cell transplantation (Range 54-103 days). The retention and phenotype of NK cells following anti-CD38 mAb administration was monitored. Results: Transferred NK cells were detectable in all patients and characterized by low CD38 expression (MFIR: 0.2) This suggested potential compatibility with anti-CD38 mAb therapy. In this clinical trial, co-administration of autologous NK cells with anti-CD38 mAb was well tolerated in all included patients. NK cells were retained up to one month after administration, indicating that the anti-CD38 mAb did not adversely affect infused autologous NK cells' persistence. Only one patient had a grade 3 treatment emergent adverse event, hemolysis, that was attributed to COVID and RSV infections. Infused cells retained their proliferative capacity with a fluctuating receptor profile, including CD16, following isatuximab administrations. Conclusion: The co-administration of autologous ex vivo expanded and activated NK cells and Isatuximab is feasible and does not result in the loss of NK cells. These findings support further exploration of this combination therapy to enhance consolidation treatment in multiple myeloma patients post-HSCT.