Immunomodulatory drug lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA in USA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Studies have shown that lenalidomide exert anti-tumor activity probably by various mechanisms in hematologic malignancies, such as immunomodulation, anti-angiogenesis and effects on signal transduction. In this article, the progresses of study on these problems are reviewed.
Hematologic Neoplasms ; immunology ; Humans ; Immunologic Factors ; Thalidomide ; analogs & derivatives ; pharmacology

OBJECTIVE: To explore the effects of different concentration of pomalidomide on human multiple myeloma cell line MM1.S and the expression of CRBN. METHODS: CCK-8 method was used for detecting inhibition effect of promalidomide on proliferation of MM1.S cells. Apoptosis rate of MM1.S cells was detected by flow cytometry with Annexin V-FITC/PI double staining. Real-time quantitative PCR was used to determine CRBN gene expression level. Western blot was used to detect the effect of pomalidomide on the protein expression of CRBN in MM1.S cells. RESULTS: Pomalidomide has an inhibitory effect on MM1.S cells with time-and dose-dependent manners. Pomalidomide induced apoptosis in MM1.S cells. When the concentration of pomalidomide was 0, 40 and 80 μmol/L, the expression of CRBN gene after the treatment of MM1.S cells for 72 hours was 1.487±0.340, 0.211±0.054 and 0.055±0.005, by using actin as internal refereme. Pomalidomide significantly reduced CRBN protein expression in MM1.S cells. CONCLUSION Pomalidomide can inhibit the proliferation of MM1.S cells and promote its apoptosis. A certain concentration of pomalidomide can reduce the expression of CRBN gene and down-regulate its protein expression in MM1.S cells.
Adaptor Proteins, Signal Transducing ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Multiple Myeloma ; Thalidomide ; analogs & derivatives

OBJECTIVETo observe the cytotoxity of CD138-CAR-T cells on human multiple myeloma cell RPMI8226 and U266 cells and explore the impact of pomalidomide on the cytotoxity of CD138-CAR-T on RPMI8226 and U266 cells.

METHODSThe cytotoxity of CD138-CAR-T and CD138-CAR-T combined pomalidomide on RPMI8226 and U266 was detected by CFSE/7AAD. The effctor cells were co-cultured with target cells at 5:1 for 18 h, and then the supernatant were collected and used for ELISA assays.

RESULTSAfter 18 h co-culture, the cytotoxity of CD138-CAR-T on RPMI8226 and U266 was significantiy higher than control (P<0.01). There was no significant change on the cytotoxity of pomalidoide combined with CD138-CAR-T on RPMI8226 and U266. The results showed that co-cultured system contribted to a markedly increased production of IFN-γ, after adding pomalidomide to the co-cultured system. It can significantly enhance the production of IFN-γ, compared with CD138-CAR-T alone.

CONCLUSIONCD138-CAR-T had significantly cytotoxity on U266 and RPMI8226. Pomalidomide could promote CD138-CAR-T cells IFN-γ production.

Cell Line, Tumor ; Coculture Techniques ; Enzyme-Linked Immunosorbent Assay ; Humans ; Multiple Myeloma ; Recoverin ; T-Lymphocytes ; Thalidomide ; analogs & derivatives

Multiple myeloma (MM) is an uncurable disease. Chemotherapy with standard dose or autologous stem cell transplantation (auto-HSCT) after chemotherapy with high dose is able to induce remission, but relapse still exists. For this reason the ultimate goal of MM treatment is to improve relapse free survival (RFS) and progression free survival (PFS) efficiently. Recently, maintenance therapy made substantial progress in improving progression-free survival and overall survival (OS) of patients with multiple myeloma, especially thalidomide, lenalidomide and bortezomib used in clinic. Here, the latest advances of clinical researches on maintenance therapy of MM are summarized briefly in this review.
Boronic Acids ; Bortezomib ; Disease-Free Survival ; Hematopoietic Stem Cell Transplantation ; Humans ; Multiple Myeloma ; Pyrazines ; Thalidomide ; analogs & derivatives

Lenalidomide, a novel immunomodulatory agent, is a kind of thalidomide derivatives, which shows a good efficacy and safety for hematological system diseases. This review is aimed to evaluate the efficacy and safety of lenalidomide in treatment of patients with multiple myeloma, chronic lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, classical Hodgkin's lymphoma and POEMS syndrome at their replased or refractory state. At the same time, this review focuses on the newest clinical research and the latest application progress of lenalidomide for relapsed or refractory hematological system diseases.
Antineoplastic Combined Chemotherapy Protocols ; Humans ; Lenalidomide ; Leukemia, Lymphocytic, Chronic, B-Cell ; Lymphoma, Non-Hodgkin ; Multiple Myeloma ; Thalidomide ; analogs & derivatives ; pharmacology

Apoptosis ; drug effects ; Cell Line, Tumor ; Drug Synergism ; Flavanones ; administration & dosage ; pharmacology ; Humans ; Multiple Myeloma ; pathology ; Thalidomide ; administration & dosage ; analogs & derivatives ; pharmacology

OBJECTIVETo explore the clinical efficacy and safety of lenalidomide plus low dose dexamethasone for treating patients with multiple myeloma (MM).

METHODSA total of 19 MM patients were enrolled to receive the therapeutic schedule of lenalidomide plus dexamethasone in our hospital from May 2013 to June 2015. Lenalidomide 25 mg was taken orally daily for 21 days and resting for 7 days, and dexamethasone 10 mg was taken orally daily on the day 1-4, 7-10 and 13-16. The regimens were Rd (lenalidomide and dexamethasone, n = 12), and RCd (lenalidomide, ifosfamide and dexamethasone, n = 7).

RESULTSAmong 19 patients received 1 cycle of treatment 3 patients achieved complete remission (CR), 3 patients achieved very good partial remission (VGPR), 10 patients achieved partial remission (PR) and 3 patients in stable disease (SD) with an overall response rate (ORR = CR + VGPR + PR) of 84%; their ORR rate was 89% after 2 cycles of treatment. In the early stage of treatment, the renal function was improved in 4 out of 5 patients with renal dysfunction. And the common adverse reactions were hematologic toxicity in 4 patients, 1 degree rash in 5 patients, and gastrointestinal side effects in 4 patients.

CONCLUSIONThe lenalidomide plus dexamethasone regimen has a good anti-multiple myeloma effect, which can control the disease rapidly and overcome the multidrug resistance in MM, improving the poor prognosis with renal dysfunction, and showing high remission rate in the patients exposed to bortezomib with low toxicity.

Antineoplastic Combined Chemotherapy Protocols ; Dexamethasone ; administration & dosage ; therapeutic use ; Humans ; Ifosfamide ; therapeutic use ; Multiple Myeloma ; drug therapy ; Remission Induction ; Thalidomide ; administration & dosage ; analogs & derivatives ; therapeutic use

BACKGROUNDLenalidomide has emerged as an important treatment for patients with multiple myeloma (MM). However, its role in the management of MM is still controversial and requires further clarification. The aim of this study was to evaluate efficacy and safety of lenalidomide for MM using a meta-analysis.

METHODSWe searched the electronic databases including: PubMed, EMBASE and the Cochrane Center Register of Controlled Trials. Seven randomized clinical trials were identified, which included a total of 2357 patients with MM who received lenalidomide-containing, noncontaining lenalidomide regimens or placebo as induction therapy or maintenance therapy. The outcomes included overall response (OR) rate, complete response (CR) rate, 3-year progression-free survival (PFS) rate, 3-year overall survival (OS) rate, and different types of treatment-related adverse events. We calculated the risk ratios (RRs) as well as their 95% confidence intervals of these outcomes and pooled the results using RevMan 5.2 software.

RESULTSFor patients with previously untreated MM, OR rate and CR rate was significantly higher in lenalidomide-containing group than the control group. For relapsed or refractory MM patients, lenalidomide-containing regimens significantly improved the OR rate, CR rate, 3-year PFS rate and 3-year OS rate. With regard to MM patients after autologous stem cell transplantation, lenalidomide maintenance therapy significantly improved 3-year PFS rate but did not result in improved 3-year OS rate. In terms of toxicities, lenalidomide therapy has a higher rate of Grade 3-4 grade cytopenias, infection, deep-vein thrombosis, and diarrhea. Furthermore, the incidence of second primary malignancies was significantly higher in the lenalidomide group.

CONCLUSIONSThe lenalidomide-containing regimens as induction therapy clearly increased response rates and improved intervals of survival with acceptable toxicity rates for patients with MM. However, when physicians choose to use the lenalidomide as maintenance therapy, whether the benefits outweigh the risks should be taken into account.

Angiogenesis Inhibitors ; adverse effects ; therapeutic use ; Humans ; Multiple Myeloma ; drug therapy ; Randomized Controlled Trials as Topic ; Thalidomide ; adverse effects ; analogs & derivatives ; therapeutic use ; Treatment Outcome

Lenalidomide is an immunomodulatory, antiangiogenic drug that is a structural analog of thalidomide. Studies showed that lenalidomide may work through various mechanisms in hematologic malignancies. These mechanisms involved direct cytotoxicity as well as through indirect effects on tumor immunity etc. It is approved by the Food and Drug Administration for treatment of multiple myeloma and myelodysplastic syndromes, and proved to have a good efficacy. Recent studies demonstrate that oral lenalidomide alone produces durable responses with manageable adverse events in patients with non-Hodgkin's lymphoma, relapsed/refractory Hodgkin's lymphoma, chronic lymphocytic leukemia and older patients with acute myeloid leukemia etc, warranting further investigation of treatment for these patients. This review focuses the related studies and the latest progression about lenalidomide in hematological malignancies in order to provide some references and help to the use of lenalidomide for the treatment of hematological malignancies.
Angiogenesis Inhibitors ; therapeutic use ; Hematologic Neoplasms ; drug therapy ; Humans ; Multiple Myeloma ; drug therapy ; Myelodysplastic Syndromes ; drug therapy ; Thalidomide ; analogs & derivatives ; therapeutic use

BACKGROUNDGlioma is the most common primary brain tumor with poor prognosis. Temozolomide has been used with thalidomide to treat gliomas. We investigated the synergistic mechanism of these two drugs in vitro.

METHODSHuman malignant glioma cells U251-MG were cultured and assigned to four groups with different treatments for 3 days: temozolomide group (100 micromol/L), thalidomide group (100 microg/L), temozolomide (100 micromol/L) plus thalidomide group (100 microg/L) and control group. MTT assay was applied to evaluate the cell viability. Cell cycle was analyzed by flow cytometry. The ultra-structural features of autophagosomes were observed with electron microscope. Acridine orange and monodansylcadaverine were adopted to label autophagosomes and flow cytometry was applied for quantification of autophagosomes. The expression of autophagy-associated protein was detected by Western blotting.

RESULTSProliferation of tumor cell was obviously suppressed by temozolomide with thalidomide treatment than by either drug used alone (P = 0.000 for each day). The combination treatment induced cell cycle arrest at G0/G1 phase. Typical autophagic ultra-structural character was found after the combined treatment. Thalidomide promoted the autophagy induced by temozolomide. The autophagy-associated proteins-microtubule associated protein 1 light chain 3 (MAP1LC3) and Beclin1 were more significantly up-regulated by the combined treatment than temozolomide used alone (MAP1LC3, P = 0.000; Beclin1, P = 0.004). The expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN), which promoted autophagy by suppressing PI3K/Akt/mTOR signaling pathway, was elevated by thalidomide (thalidomide group: P = 0.000; combined group: P = 0.002).

CONCLUSIONSThalidomide enhances the cytotoxicity of temozolomide by promoting the autophagy induced by temozolomide. Contributing to the up-regulation of PTEN by thalidomide, the expression of autophagy associated protein-MAP1LC3 and Beclin1 was enhanced, which leads to a reinforced autophagy in the combined treatment of temozolomide and thalidomide in vitro.

Antineoplastic Agents, Alkylating ; pharmacology ; Autophagy ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dacarbazine ; analogs & derivatives ; pharmacology ; Glioma ; pathology ; Humans ; Thalidomide ; pharmacology