Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple myeloma (MM) is one of the key hematologic malignancies in which the impact of dose intensity has been demonstrated. Consequently, in 2005, MM was the most common disease for which autologous stem cell transplantation (ASCT) was indicated both in Europe and in the U.S. However, ASCT is not curative, and most patients relapse within a median of 3 years. Novel agents such as thalidomide (Thalidomid), bortezomib (Velcade), or lenalidomide (Revlimid) have been introduced to improve high-dose therapy, and promising results have been reported. Conversely, results from myeloablative allogeneic stem cell transplantation remain disappointing due to high transplantation-related mortality, justifying the exploration of strategies such as reduced-intensity conditioning, which have been shown to be feasible but for which proof of efficacy requires continued study.
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PMID:Stem cell transplantation in multiple myeloma. 1802 45

Multiple myeloma (MM) is one of the diseases in which the impact of dose intensity has been demonstrated. Consequently, in 2005 MM was the first disease for which autologous stem-cell transplantation (ASCT) was indicated in Europe and the US. However, ASCT is not curative, and most patients relapse in a median of 3 years. The introduction of novel agents such as thalidomide, bortezomib (Velcade) or lenalidomide (Revlimid) was logical to try to improve the high-dose strategy, and promising results have been reported. This article will focus on the current results of ASCT and will discuss the main research area to try to improve this strategy.
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PMID:Role of autologous stem-cell transplantation in multiple myeloma. 1807 Jul 17

Lenalidomide (also known as Revlimid((R)), CC-5013) is an immunomodulatory derivative of thalidomide and has more potent anti-tumor and anti-inflammatory effects than thalidomide. The molecular mechanisms of anti-tumor activity of lenalidomide have been extensively studied in multiple myeloma (MM) both preclinical models and in clinical trials. Lenalidomide: directly triggers growth arrest and/or apoptosis of drug resistant MM cells; inhibits binding of MM cells to bone marrow (BM) extracellular matrix proteins and stromal cells; modulates cytokine secretion and inhibits angiogenesis in the BM milieu; and augments host anti-tumor immunity. Lenalidomide achieved responses in patients with relapsed refractory MM. Moreover, lenalidomide with dexamethasone (Dex) demonstrates more potent anti-MM activities than Dex both in vitro and in randomized phase III clinical trials. Specifically, the combination improved overall and extent of response, as well as prolonged time to progression and overall survival, resulting in FDA approval of lenalidomide with Dex for therapy MM relapsing after prior therapy.
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PMID:A review of lenalidomide in combination with dexamethasone for the treatment of multiple myeloma. 1872 2

Lenalidomide (Revlimid) is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk Myelodysplastic Syndromes (MDS) associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy. Previous reports suggest that lenalidomide is anti-angiogenic and this property appears to be related to efficacy in patients with MDS. We have investigated the effect of lenalidomide on the formation of microvessels in a novel in vitro angiogenesis assay utilizing human umbilical arterial rings and in a capillary-like cord formation assay using cultured primary endothelial cells. We found that lenalidomide consistently inhibits both sprout formation by arterial rings and cord formation by endothelial cells in a dose-dependent manner. We also found an inhibitory effect of lenalidomide on the associations between cadherin 5, beta-catenin and CD31, adherens junction proteins whose interaction is critical for endothelial cell cord formation. Furthermore, lenalidomide inhibited VEGF-induced PI3K-Akt pathway signaling, which is known to regulate adherens junction formation. We also found a strong inhibitory effect of lenalidomide on hypoxia-induced endothelial cell formation of cords and HIF-1 alpha expression, the main mediator of hypoxia-mediated effects and a key driver of angiogenesis and metastasis. Anti-metastatic activity of lenalidomide in vivo was confirmed in the B16-F10 mouse melanoma model by a >40% reduction in melanoma lung colony counts versus untreated mice. Our results suggest that inhibitory effects on microvessel formation, in particular adherens junction formation and inhibition of hypoxia-induced processes support a potential anti-angiogenic and anti-metastatic mechanism for this clinically active drug.
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PMID:The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. 1880 33

Lenalidomide (Revlimid; CC-5013) and pomalidomide (CC-4047) are IMiDs proprietary drugs having immunomodulatory properties that have both shown activity in cancer clinical trials; lenalidomide is approved in the United States for a subset of MDS patients and for treatment of patients with multiple myeloma when used in combination with dexamethasone. These drugs exhibit a range of interesting clinical properties, including anti-angiogenic, anti-proliferative, and pro-erythropoietic activities although exact cellular target(s) remain unclear. Also, anti-inflammatory effects on LPS-stimulated monocytes (TNF-alpha is decreased) and costimulatory effects on anti-CD3 stimulated T cells, (enhanced T cell proliferation and proinflammatory cytokine production) are observed. These drugs also cause augmentation of NK-cell cytotoxic activity against tumour-cell targets. Having shown that pomalidomide confers T cell-dependent adjuvant-like protection in a preclinical whole tumour-cell vaccine-model, we now show that lenalidomide and pomalidomide strongly inhibit T-regulatory cell proliferation and suppressor-function. Both drugs inhibit IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25high CD4+ T regulatory cells from PBMCs by upto 50%. Furthermore, suppressor function of pre-treated T regulatory cells against autologous responder-cells is abolished or markedly inhibited without drug related cytotoxicity. Also, Balb/C mice exhibit 25% reduction of lymph-node T regulatory cells after pomalidomide treatment. Inhibition of T regulatory cell function was not due to changes in TGF-beta or IL-10 production but was associated with decreased T regulatory cell FOXP3 expression. In conclusion, our data provide one explanation for adjuvant properties of lenalidomide and pomalidomide and suggest that they may help overcome an important barrier to tumour-specific immunity in cancer patients.
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PMID:The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. 1900 91

Over the past 5 years, lenalidomide (Revlimid, Celgene Co., Summit, NJ, USA), a member of a class of drugs termed immunomodulatory drugs, has emerged as a significant weapon in the arsenal of cancer-therapeutics. It is a lead therapeutic in multiple myeloma and del-5q myelodysplastic syndromes and has also been trialed for acute leukaemia and chronic lymphocytic leukaemia, relapsed or refractory Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, prostate cancer, non-small cell lung cancer, malignant melanoma, renal cancer, advanced ovarian and peritoneal carcinoma. The most significant development for lenalidomide has been its FDA approval (US and Europe) for previously treated multiple myeloma in combination with dexamethasone. The following review describes key clinical and mechanistic breakthroughs that have made lenalidomide a leading cancer therapeutic.
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PMID:Lenalidomide: a novel anticancer drug with multiple modalities. 1923 86

Melphalan combined with prednisone (MP) has long been the historical treatment of reference for a large proportion of elderly myeloma (MM) patients ineligible for autologous stem cell transplantation, and is still the backbone of new regimens that include the new era of novel agents. Melphalan-prednisone-thalidomide (MPT) and melphalan-prednisone-bortezomib (Velcade((R)), MPV), proved superior to MP, currently appear to be the treatments of choice for this population. In the near future melphalan-prednisone-lenalidomide (Revlimid((R)), MPR) will also provide a third therapeutic option (MPT, MPV, and MPR), in elderly multiple myeloma, eventually. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. Dexamethasone-based regimen is another option and questions regarding the relative efficacy of melphalan-based versus low-dose dexamethasone-based regimens will require randomized phase III trials. More intensive approaches with new drug combinations or with the incorporation of polyethylene glycolated (PEGylated) liposomal doxorubicin will also require additional studies. Additionally, the important issue of maintenance treatment needs to be further investigated. These new and emerging therapies offer multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians.
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PMID:Front line treatment of elderly multiple myeloma in the era of novel agents. 1970 99

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 is distinct from bortezomib (Velcade) and, importantly, triggers apoptosis in multiple myeloma (MM) cells resistant to bortezomib. Here we demonstrate that combining NPI-0052 and lenalidomide (Revlimid) induces synergistic anti-MM activity in vitro using MM-cell lines or patient MM cells. NPI-0052 plus lenalidomide-induced apoptosis is associated with (1) activation of caspase-8, caspase-9, caspase-12, caspase-3, and poly(ADP) ribose polymerase; (2) activation of BH-3 protein BIM; (3) translocation of BIM to endoplasmic reticulum; (4) inhibition of migration of MM cells and angiogenesis; and (5) suppression of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities. Importantly, blockade of BIM using siRNA significantly abrogates NPI-0052 plus lenalidomide-induced apoptosis. Furthermore, studies using biochemical inhibitors of caspase-8 versus caspase-9 demonstrate that NPI-0052 plus lenalidomide-triggered apoptosis is primarily dependent on caspase-8 signaling. In animal tumor model studies, low-dose combination of NPI-0052 and lenalidomide is well tolerated, significantly inhibits tumor growth, and prolongs survival. Taken together, our study provides the preclinical rationale for clinical protocols evaluating lenalidomide together with NPI-0052 to improve patient outcome in MM.
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PMID:Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. 1996 74

High-dose melphalan (Alkeran) and autologous stem cell transplantation are commonly incorporated into the initial line of therapy for patients newly diagnosed with multiple myeloma. This option is usually offered to patients less than 70 years old who have no major comorbidities. Selected older patients and those with mild to moderate organ dysfunction may also be reasonable candidates. An important goal of induction therapy is to achieve remission; a complete response predicts longer survival after transplantation. The regimens for initial therapy that are based on level 1 evidence and consensus include bortezomib (Velcade)/dexamethasone, bortezomib/doxorubicin/dexamethasone, bortezomib/thalidomide (Thalomid)/dexamethasone, and lenalidomide (Revlimid)/low-dose dexamethasone. Recent studies have provided guidance for choosing among these regimens for patients with cytogenetic abnormalities, renal disease, and other negative prognostic indicators. There is evidence from phase III studies that use of thalidomide/dexamethasone and bortezomib-based induction regimens can translate into significantly better survival after transplantation compared with the older chemotherapy regimens.
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PMID:Tailoring initial treatment for newly diagnosed, transplantation-eligible multiple myeloma. 2051 65

No survival advantage of autologous stem cell transplantation (ASCT) has been documented for patients older than 65 years, and in the era of thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid), ASCT has a diminished role in the front-line treatment of older patients with myeloma. For these individuals and for those who cannot or choose not to undergo ASCT, the initial treatment regimens now recommended by both the National Comprehensive Cancer Network and the International Myeloma Working Group are melphalan (Alkeran)/prednisone/thalidomide (MPT), bortezomib/melphalan/prednisone (VMP), and lenalidomide/low-dose dexamethasone. Melphalan/prednisone should no longer be considered the reference treatment, although it may be appropriate for a small number of patients with serious comorbidity and/or poor performance status. Advantages of VMP over MPT include rapid response, high rates of complete response, patient compliance, and more extensive evidence of efficacy in patients with certain cytogenetic abnormalities. Lenalidomide/low-dose dexamethasone is particularly appropriate for patients with preexisting neurotoxicity and those who wish to postpone ASCT. Toxicity profiles differ among the newly established and emerging regimens, and oncology teams must take care to apply the appropriate risk management measures, including dose reduction where necessary.
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PMID:Best practices in the management of newly diagnosed multiple myeloma patients who will not undergo transplant. 2051 66


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