Disease relevance of Revlimid

• Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma [1].
• We studied the toxicity and efficacy of lenalidomide in patients with AL [2].
• Findings from this trial indicate that lenalidomide can be effective in treating AL amyloidosis [3].
• The most common grade 3 or 4 adverse events at least possibly attributable to lenalidomide were neutropenia (45%), thrombocytopenia (27%), rash (18%), and fatigue (18%) [2].
• Lenalidomide therapy in myelofibrosis with myeloid metaplasia [4].
• Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m(2) [5].

High impact information on Revlimid

• Lenalidomide, especially in conjunction with dexamethasone, is highly active in patients with multiple myeloma [2].
• The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis [2].
• Here we show that lenalidomide (LEN), a novel thalidomide (Thal) analog, enhances antigen-specific expansion of NKT cells in response to the NKT ligand alpha-galactosylceramide (alpha-GalCer) in both healthy donors and patients with myeloma [6].
• We conclude that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities [4].
• Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications [6].

Chemical compound and disease context of Revlimid

• Moreover, this study provides new insights on the cellular pathways affected by lenalidomide and CC-4047, proposes new potential clinical uses, such as bone marrow regeneration, and suggests that the combination of lenalidomide or CC-4047 with certain HDAC inhibitors may elevate the therapeutic index in the treatment of hematologic malignancies [7].
• Initial phase II and III results with lenalidomide, a thalidomide analogue, have confirmed impressive response rates with a significantly more favorable toxicity profile [8].
• Lenalidomide is currently being tested in combination with both standard and novel agents, including bortezomib, for patients with relapsed/refractory multiple myeloma [9].
• Enoxaparin or aspirin for the prevention of recurrent thromboembolism in newly diagnosed myeloma patients treated with melphalan and prednisone plus thalidomide or lenalidomide [10].
• Early phase trials are also evaluating bortezomib in combination with other agents used in the treatment of multiple myeloma, including melphalan, prednisone, thalidomide, and lenalidomide [11].

Biological context of Revlimid

• Combining rapamycin and CC-5013 induced apoptosis of MM cells [1].
• Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response [4].
• Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma [12].
• In vitro exposure of ECs to thalidomide or its derivative CC-5013 inhibited gene expression of the receptors for transforming growth factor-beta and thrombin [13].
• Pretreatment with lenalidomide sensitized MM cells to SGN-40-induced cell death [14].

Anatomical context of Revlimid

• Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells [7].
• To better understand these clinical observations, we investigated and compared the effects of lenalidomide and a structurally related analogue, CC-4047, on the proliferation of two different human hematopoietic cell models: the Namalwa cancer cell line and normal CD34+ progenitor cells [7].
• Pretreatment of effector cells with lenalidomide augmented SGN-40-induced MM cell lysis, associated with an increased number of CD56(+)CD3(-) natural killer (NK) cells expressing CD16 and LFA-1 [14].
• CC-5013 has various immunomodulatory effects, including growth arrest or apoptosis of drug-resistant myeloma cell lines and inhibition of binding of myeloma cells to bone marrow stromal cells [15].
• Lenalidomide also enhanced AP-1 transcriptional activity in Namalwa, but not in the other cell lines tested [16].

Associations of Revlimid with other chemical compounds

• However, recent clinical trials enrolling patients with MDS have reported encouraging results with use of newer drugs, including lenalidomide, decitabine, and darbepoetin alfa [17].
• In the most lenalidomide-sensitive chromosome 5 deleted cell line, Namalwa CSN.70, the compound induced G0/G1 cell cycle arrest, inhibited Akt and Gab1 phosphorylation, and inhibited the ability of Gab1 to associate with a receptor tyrosine kinase [16].
• Thalidomide has been registered in the USA in combination with dexamethasone in newly diagnosed patients, but is not yet registered in the European Union. Its use is currently challenged by bortezomib and by thalidomide's analog lenalidomide [18].
• Therefore, allogeneic transplantation should be continued in clinical trials exploring new conditioning methods, the graft-versus-myeloma effect of new cell types, and its combination with new targeted drugs such as bortezomib and lenalidomide [19].
• We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with del(5)(q31) [20].
• In comparison with our previous study with thalidomide and rituximab in an analogous patient population, the responses achieved in WM patients with lenalidomide and rituximab appear less favorable [21].

Gene context of Revlimid

• Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40-mediated ADCC against CD40-expressing MM cells [14].
• The clinical relevance of this observation was confirmed by the elevation of serum TNF-alpha during REVIMID trade mark treatment of patients with advanced cancer [22].
• One patient was treated with lenalidomide (Revlimid) for multiple myeloma, 2 received infliximab, and 1 received etanercept for severe rheumatoid arthritis; the last patient was in a clinical trial of adalimumab for psoriatic arthritis [23].
• Finally, CC-4047 and lenalidomide had synergistic effects with valproic acid [a histone deacetylase (HDAC) inhibitor] by increasing the apoptosis of Namalwa cells and enhancing CD34+ cell expansion [7].
• Lenalidomide also up-regulated CD40L on CD56(+)CD3(-) NK cells, facilitating IL-2-mediated activation of NK cells [14].

Analytical, diagnostic and therapeutic context of Revlimid

• Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2) [24].
• The oral immunomodulatory drugs thalidomide and lenalidomide have produced major therapeutic responses in patients with MM when used in combination with oral steroids and chemotherapy, but a high incidence of VTE has been reported [25].
• Data from clinical trials of lenalidomide in MDS have shown erythropoietic- and cytogenetic-remitting activities that frequently result in transfusion independence, particularly in patients with 5q- deletion and lower-risk MDS [26].
• Lastly, based on the increased potency and reduced toxicity profile of CC-5013 compared with thalidomide, a study of CC-5013 in patients with relapsed/refractory disease following transplantation was initiated [27].
• As a single agent for post-transplant salvage therapy, lenalidomide 25 mg every 3 weeks has shown response rates as high as 44% [9].

References