Daratumumab targets CD38-expressing myeloma cells through a variety of 
immune-mediated mechanisms (complement-dependent cytotoxicity, 
antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular 
phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also 
target nonplasma cells that express CD38, which prompted evaluation of 
daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood 
(PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 
daratumumab monotherapy studies were analyzed before and during therapy and at 
relapse. Regulatory B cells and myeloid-derived suppressor cells, previously 
shown to express CD38, were evaluated for immunosuppressive activity and 
daratumumab sensitivity in the myeloma setting. A novel subpopulation of 
regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more 
immunosuppressive in vitro than CD38-negative Tregs and were reduced in 
daratumumab-treated patients. In parallel, daratumumab induced robust increases 
in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab 
induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and 
increased memory T cells while decreasing naïve T cells. The majority of 
patients demonstrated these broad T-cell changes, although patients with a 
partial response or better showed greater maximum effector and helper T-cell 
increases, elevated antiviral and alloreactive functional responses, and 
significantly greater increases in T-cell clonality as measured by T-cell 
receptor (TCR) sequencing. Increased TCR clonality positively correlated with 
increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, 
which is associated with an increase in T-helper cells, cytotoxic T cells, 
T-cell functional response, and TCR clonality, represents possible additional 
mechanisms of action for daratumumab and deserves further exploration.