Lenalidomide

Abstract: Multiple myeloma (MM) is an incurable plasma cell dyscrasia that remains fatal. Despite efforts over the past 3 to 4 decades, the median survival of patients with MM does not exceed 3 to 4 years. Although patients receiving combination chemotherapy have higher response rates compared with those receiving oral melphalan and prednisolone, they have no survival advantage. High-dose chemotherapy followed by autologous stem cell transplantation has documented benefit over conventional treatment and is currently the accepted mode of treatment for symptomatic MM. Allogeneic transplantation is associated with high complete remission rates, but at the cost of high therapy-related mortality. Maintenance treatment with interferon-a shows benefit, albeit in a small fraction of MM patients. The use of bisphosphonates in patients with MM has clearly demonstrated benefit and reduced morbidity associated with bone disease. All of these measures have improved remission rates and survival, but all patients with MM ultimately relapse and succumb to their disease. Novel therapeutic strategies are therefore required to improve outcome of MM patients. The responses noted to thalidomide in MM are encouraging. Immune-based strategies, including both adoptive immunotherapy and vaccinations, are currently being investigated in the preclinical and clinical setting, with the goal of enhancing autologous and allogeneic anti-MM immunity for therapeutic applications.

Abstract: Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.

Abstract: Background Lenalidomide is a structural analogue of thalidomide with similar but more potent biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide plus dexamethasone in the treatment of relapsed or refractory multiple myeloma. Methods Of 351 patients who had received at least one previous antimyeloma therapy, 176 were randomly assigned to receive 25 mg of oral lenalidomide and 175 to receive placebo on days 1 to 21 of a 28-day cycle. In addition, all patients received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles and subsequently, after the fourth cycle, only on days 1 to 4. Patients continued in the study until the occurrence of disease progression or unacceptable toxic effects. The primary end point was time to progression. Results The time to progression was significantly longer in the patients who received lenalidomide plus dexamethasone (lenalidomide group) than in those who received placebo plus dexamethasone...

Abstract: Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide’s therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.