Lenalidomide in the treatment of multiple myeloma: a review

Abstract

Lenalidomide is an immunomodulatory drug derived from thalidomide. It was developed to maximize the anti-inflammatory and anti-neoplasic properties of thalidomide and to reduce its toxicity. The molecular mechanism of action of lenalidomide is unclear, but its therapeutic activity is mainly due to its well defined antiinflammatory, immunomodulatory, anti-proliferative and anti-angiogenic properties. In relapsed or refractory multiple myeloma (MM), lenalidomide, combined with standard dose dexamethasone, is superior to dexamethasone alone in terms of time to progression, response rate and overall survival. The most commonly reported adverse events include haematological toxicity with manageable neutropenia and thrombopenia. Lenalidomide does not trigger the limiting toxicities of thalidomide: somnolence, neuropathy and constipation. Lenalidomide, in combination with dexamethasone, is indicated for the treatment of MM patients who have received at least one prior therapy and is administered orally at the dose of 25 mg q.d. for 21 days of 28-day cycles. The drug is being investigated for the treatment of newly diagnosed MM. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical trial data on lenalidomide.

The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study

“…The addition of cyclophosphamide in this study increased the overall response rate (CR + VGPR + PR) to 81%, which is superior to that reported for lenalidomide alone (17-23%) (Armoiry et al, 2008) or in combination with dexamethasone (48-51%) (Wang et al, 2008). These responses were observed despite a median number of lines of prior therapy of 3 (range 1-6), used in this study compared to that seen in the MM009 and MM010 trials where up to one-third of patients were treated at first relapse.…”

Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab

“…1,2 Perhaps the best example of such an agent is lenalidomide (LEN), [3][4][5] a structural analog of thalidomide with similar but more potent immunomodulatory activities. [6][7][8] Since its approval by the FDA, lenalidomide has demonstrated impressive results in patients with newly-diagnosed and relapsed multiple myeloma 9,10 and also improved graft versus multiple myeloma effects after allogeneic stem cell transplantation. 11 In several initial studies, lenalidomide has been frequently used alone or in combination with other chemotherapeutical agents.…”

Design, synthesis and biological assessment of novel N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines and 3-substituted 2,6-dioxopiperidines for TNF-α inhibitory activity

“…In addition to thalidomide ( 1 ), 3 is a credible TNF-α inhibitor, 11a,b and is both approved for and effective in the for treatment of multiple myeloma and specific myelodysplastic syndromes. 12a–f Herein, compounds 9 , 12 , 14 and 16–18 possessed more potent TNF-α inhibitory activity than that of revlimid ( 3 ) as well as thalidomide ( 1 ) in our assay model, which has now been extensively characterized. 6c Indeed, compounds 9 , 14 and 16 not only showed the most potency as TNF-α inhibitors amongst all eleven assayed compounds (contrasting markedly with revlimid ( 3 )) but appeared well tolerated, albeit 14 was associated with a mild decline in cell viability at 30 μM.…”