New effective strategies are required that specifically address the challenges of multiple myeloma (MM) treatment, namely, disease recurrence, immunosuppression, and treatment-related toxicities. Recent preclinical and clinical findings suggest that the IMiDs® immunomodulatory compound lenalidomide has a dual mechanism of action, involving both a direct tumoricidal activity and immunomodulation, which may result in rapid and sustained control of MM, respectively. The tumoricidal effect of lenalidomide occurs through several mechanisms, including disruption of stromal support, induction of tumor suppressor genes, and activation of caspases. The immunomodulatory effects of lenalidomide, including T-cell and natural killer (NK)-cell activation, and increased expression of death effector molecules, lead to enhanced immune cell function and may explain the beneficial effects of this agent in the maintenance setting. Lenalidomide appears to be effective regardless of prior thalidomide treatment, which may reflect mechanistic differences - lenalidomide has greater immunomodulatory properties than thalidomide, whereas thalidomide has greater antiangiogenic activity. Recent studies also suggest that the concomitant use of dexamethasone may influence lenalidomide's direct and immunomodulatory effects. Lenalidomide in combination with dexamethasone synergistically inhibits proliferation and induces apoptosis; however, dexamethasone appears to antagonize the immune-enhancing effect of lenalidomide. A study has demonstrated that a regimen of lenalidomide in combination with an optimal dose and schedule of dexamethasone may increase survival by allowing synergistic antiproliferative effects, without affecting immunomodulatory activity. As preclinical and clinical research continue, additional insights into the dual mechanism of action of lenalidomide will help to further optimize the use of lenalidomide in MM.
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