Pomalidomide in the Management of Relapsed Multiple Myeloma

Abstract

Pomalidomide, a very potent member of the immunomodulatory drug family, is considered a standard of care for patients with relapsed and refractory myeloma, who have previously been treated with bortezomib and lenalidomide. Pomalidomide induces both direct myeloma cell death, and indirect antimyeloma response through its impact on the microenvironment (modulation of immune response, inhibition of angiogenesis, inhibition of bone resorption). Pomalidomide in combination with dexamethasone is an approved regimen in Europe and USA based on the results of a Phase III randomized trial. In order to improve response rate and patient survival, pomalidomide is currently being assessed in triplet combinations with other antimyeloma agents. The present review addresses current knowledge regarding the clinical use of pomalidomide in relapsed myeloma patients.

Therapeutic effect of the immunomodulatory drug lenalidomide, but not pomalidomide, in experimental models of rheumatoid arthritis and inflammatory bowel disease

“…12, 13, 14 The two first-in-class IMiDs with a favorable toxicity profile and increased efficacy are lenalidomide and pomalidomide, 7, 12 which are first-line treatments in several hematological malignancies. 14, 15 IMiDs are potent TNFα inhibitors and block signaling through NFκB and COX-2, and have T-cell co-stimulatory properties. 7, 16, 17, 18, 31, 32 Mechanistically, IMiDs bind to cereblon, a substrate receptor of the CRL4 E3 ubiquitin ligase, altering its substrate specificity that results in breakdown of intrinsic downstream proteins such as Ikaros and Aiolos.…”

“…12, 13, 14 The two first-in-class IMiDs with a favorable toxicity profile and increased efficacy are lenalidomide and pomalidomide, 7, 12 which are first-line treatments in several hematological malignancies including multiple myeloma and myelodysplastic syndromes. 14, 15 The postulated mechanisms of action for IMiDs include blocking signaling through nuclear factor-kappa B (NFκB), downregulation of TNFα and cyclooxygenase 2 (COX-2), and T-cell co-stimulatory properties, abolishing the requirement for secondary co-stimulation signals from antigen-presenting cells. 16, 17, 18 …”

Pomalidomide in multiple myeloma

“…Pomalidomide treatment downregulates proinflammatory cytokines, VEGF (an important prosurvival factor for MM cells), and enhances natural killer cell cytotoxicity. Cereblon, a molecular target of IMiDs [1], is expressed at very low levels in plasma cells from patients resistant to IMiDs (including pomalidomide). Pomalidomide through the downregulation of the transcription factor PU.1 allows reduction of bone resorption [1].…”

“…However, prognosis is poor for those who relapse or are refractory (RR) to lenalidomide and bortezomib [1]. Pomalidomide, a third-generation IMiD, was approved in 2013 by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in combination with low-dose dexamethasone for MM patients who have received at least two prior therapies, including both lenalidomide and bortezomib, and whose disease progressed after the last treatment.…”

Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

“…Pomalidomide [4-Amino-2-(2,6-dioxopiperidin-3-yl) isoindole-1,3-dione] is a potent second-generation IMiD [27][28][29][30][31][32][33][34]. Pomalidomide has direct antiproliferative, pro-apoptotic, and antiangiogenic effects, as well as modulatory effects on bone resorption and on the immune system.…”