Myeloma
bone disease is a major complication in
multiple myeloma affecting quality of life and survival. It is characterized by increased activity of osteoclasts, bone resorbing cells. Myeloma microenvironment promotes excessive osteoclastogenesis, a process of production of osteoclasts from their precursors, monocytes. The effects of two anti-myeloma drugs,
melphalan flufenamide (
melflufen) and
melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study. In line with previous research, differentiation of monocytes was associated with increased expression of genes encoding DNA damage repair
proteins. Hence monocytes were more sensitive to DNA damage-causing
alkylating agents than their differentiated progeny, osteoclasts. In addition, differentiated progeny of monocytes showed increased gene expression of immune checkpoint
ligands which may potentially create an immunosuppressive microenvironment.
Melflufen was ten-fold more active than
melphalan in inhibiting proliferation of osteoclast progenitors. Furthermore,
melflufen was also superior to
melphalan in inhibition of osteoclastogenesis and
bone resorption. These results demonstrate that
melflufen may exert beneficial effects in patients with
multiple myeloma such as reducing
bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis.