Background: Daratumumab (DARA) is a human IgG1 that binds to CD38 and kills tumor cells expressing CD38 through immune-mediated cytotoxicity. CD38 is expressed on plasma cells in multiple myeloma (MM), AL amyloidosis (AL) and on myeloid progenitor cells. Since SCT remains a standard therapy for MM and AL the effect of DARA on progenitor cells was evaluated. Ability of DARA to induce complement dependent cytotoxicity (CDC) of progenitor cells was assessed in progenitor cell assay (PCA). DARA-mediated antibody-dependent cytotoxicity (ADCC) of progenitor cells, its correlation with FcγRIIIA polymorphism and stem cell potential were examined using NK-cells from post-SCT patients (n = 10, n = 6 MM and n = 4 AL) as effectors against a MM target cell line. Methods: ADCC was performed with post-SCT NK cells and MM.1S cells in the presence of 100 ng/ml DARA or isotype control (ICA). DARA-mediated CDC was evaluated in PCA: unselected or CD34-selected mobilized cells were incubated in complement-rich serum with no antibodies, or DARA or anti-CD59 (BRIC 229) or both. The effects of these antibodies on CFU-GM and BFU-E were evaluated two weeks later. The results were analyzed by two-tailed paired t tests with P < 0.05 as significance level. Results: MedianADCC of MM.1S target cells by primary post-SCT NK cells was 39% and 7% using DARA or ICA, respectively (P < 0.05). Of the 10 NK donors, 6 were V/F or V/V and lysed 60% of targets, while 4 F/F lysed 17% (P< 0.05). In the PCA, there was no decrease in CFU-GM or BFU-E: with unselected mobilized cells, with CD34-selected cells with DARA, or with CD34-selected cells incubated with DARA (500 or 1000 ng/ml) +/- BRIC 229 indicating that DARA did not induce CDC on the CD34-selected progenitor cells. Conclusions: DARA is active in ADCC assays with post-SCT NK cells from patients with MM or AL and its activity correlates with FCGR3A-158V/F polymorphism. DARA did not inhibit progenitor cell growth by CDC in unselected or CD34-selected cells suggesting that administration of DARA may not cause undue harm to the progenitor cells after SCT. These findings support consideration of clinical trials of DARA consolidation post-SCT in MM and AL. CPC: MMRF fellow.