Natural killer cells from patients relapsing on daratumumab therapy express an exhausted-associated phenotype

The monoclonal antibody daratumumab can induce antibody-dependent cellular cytotoxicity (ADCC) via CD16 expressed by natural killer (NK) cells. Prior studies have shown that the number of NK cells decreased after initiation of daratumumab treatment. We used flow cytometry to evaluate the expression of immune checkpoint receptors on NK cells from patients with newly diagnosed multiple myeloma (NDMM) compared to myeloma patients progressing during treatment with daratumumab (DRMM). In accordance with prior studies, we found that the percentage of NK cells was significantly lower in the DRMM group compared to the NDMM group. In addition, the percentage of the cytotoxic CD56dim NK cell subset was lower in the DRMM group, and a lower portion of these NK cells expressed CD16, the receptor mediating ADCC. There was no difference in the expression of the inhibitory receptor PD-1, but the NK cells from DRMM patients expressed an exhausted-associated phenotype with a lower expression of the stimulatory receptor DNAM-1 and a higher expression of the inhibitory receptor TIGIT. Dysfunctional NK cells have been observed in other patients progressing on daratumumab. Our data show that patients progressing on DARA-containing regimens display NK cells with an inhibitory-skewed phenotype. Whether this reflects a driver, biomarker, or consequence of resistance requires further functional and longitudinal investigation.