Lenalidomide (trade name Revlimid) is a derivative of thalidomide introduced in 2004. It is an immunomodulatory agent with anti-angiogenic properties. Revlimid in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Also is indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. In addition, Revlimid is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. Recently was discovered, that protein cereblon (CRBN) is a proximate, therapeutically important molecular target of lenalidomide. Low CRBN expression was found to correlate with drug resistance in multiple myeloma (MM) cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by (immune-modulatory drugs) treatment. CRBN is also implicated in several effects of immunomodulatory drugs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the immunomodulatory drugs (IMiDs) are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance. Lenalidomide also inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.

CC-220 is a potent cereblon modulating agent that displays anti-proliferative, pro-apoptotic and immunomodulatory activity on sensitive and resistant multiple myeloma cell lines. CC-220 is currently under clinical investigation for systemic lupus erythematosus and multiple myeloma as a single agent, or in combination with dexamethasone in patients who may have previously been exposed to pomalidomide. Comparable to other Cereblon-binding agents, ex vivo treatment of CC-220 on B-cells, T-cells, and monocytes leads to the degradation of the hematopoietic transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). followed by disruption of the multiple myeloma promoting c-Myc/IRF4 axis.