Immunomodulatory drugs or IMiDs are structural and functional analogs of thalidomide and potent modulators of the immune system. The two leading examples of IMiDs are pomalidomide and lenalidomide. Lenalidomide is currently available as a multiple myeloma therapy and both of the drugs are currently undergoing evaluation as potential therapies for other haematological malignancies.
Thalidomide was the first agent to be approved for the treatment of multiple myeloma but its use is associated with significant toxicity, especially in older patients. Thalidomide’s immunomodulatory effects were first realized when it was shown to reduce symptoms in a painful complication of leprosy called erythema nodosum leprosum.
Further research showed that the drug’s effect included inhibition of de novo IgM synthesis, stimulation of T-helper cell production and inhibition of tumor necrosis factor–α. In addition, it showed anti-angiogenic effects, inhibiting the ability of tumors to form new blood vessels to support their growth. This led to starvation of the tumors which eventually killed them.
Studies showed that in relapsing and refractory multiple myeloma, thalidomide could produce response rates that were superior to any other single anti-cancer agents. In new cases of the disease, thalidomide alone and in combination with the steroid dexamethasone produced satisfactory results. As a result, the drug was approved for use in combination with dexamethasone for multiple myeloma in 2006. Examples of maintenance therapies with thalidomide-containing regimens included:
Thalidomide, adriamycine and dexamethasone
Bortezomib, melphalan, prednisone and thalidomide (VMPT)
Melphalan, prednisone and thalidomide (MPT)
Vortezomib, thalidomide and dexamethasone (VTD)
Thalidomide and dexamethasone (TD)
However, adverse effects were commonly associated with the use of thalidomide and included tiredness, constipation, bloating, fluid retention, rash, venous thromboembolism and peripheral neuropathy.
Lenalidomide and pomalidomide are IMiDs that have enhanced immunomodulatory and anticancer properties over thalidomide as well as fewer side effects. These agents are promising future therapies for several immune cell cancers including multiple myeloma.