Multiple Myeloma Mechanism of Action

The pathobiology of MM is complex and the root underlying cause of myeloma is the multistep genetic changes in the postgerminal center B cell. In addition, the bone marrow microenvironment plays a crucial role.[2] The interaction between myeloma cells and the microenvironment is mediated through adhesive interactions via cell-surface receptors, paracrine loops involving several cytokines, such as IL-6, VEGF and IL-10, and suppression of cell-mediated immunity.[2–4] IMiDs modulate many of these interactions leading to decreased myeloma cell growth and survival. Thalidomide was the first IMiD introduced to treat MM. It was initially synthesized in Germany in the late 1950s to treat insomnia and morning sickness. It was withdrawn from the market in 1961 because of its teratogenic effects. Its immunomodulatory properties were realized when it was observed to improve erythema nodosum leprosum, a painful immunologic reaction of leprosy, leading to its approval by the FDA in 1998 with tight prescribing and marketing regulations. Subsequent research showed the diverse mechanism of action of thalidomide including its immunomodulatory effect by inhibition of de novo IgM antibody synthesis,[5] modulation of the T-cell subset by increasing the T-helper cells, inhibitory effects on the TNF-α and antiangiogenic activity leading to its use in MM. Significantly higher response rates in combination with dexamethasone led to its approval in the treatment of newly diagnosed MM in 2006. Lenalidomide, a second-generation IMiD, was developed from the structural backbone of the thalidomide molecule by the addition of an amino group (NH2-) at position 4 of the phthaloyl ring and removal of the carbonyl group (C = O) of the 4-amino-substituted phthaloyl ring (Table 1).[6] In addition to immunomodulatory effects, other mechanisms of action have been described such as direct cytotoxicity via induction of apoptosis, inhibition of cell adhesion molecules and inhibition of growth signals that promote bone marrow angiogenesis