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PubMed2006

Advances in oral therapy for multiple myeloma.

Conventional intravenous chemotherapy regimens are toxic, cumbersome, and negatively affect patients' quality of life, with oral treatment preferable to most patients with cancer. Multiple myeloma is the second most common haematological malignant disease, but cannot be cured with conventional and high-dose chemotherapy. New oral treatments that target myeloma cells or bone marrow are being developed that are highly effective yet have low toxic effects, such as the immunomodulatory drugs thalidomide and lenalidomide. Several treatments in early development have shown antimyeloma activity, including: CHIR-258, which inhibits fibroblast growth factor receptor 3; NVP-ADW742, which inhibits insulin-like growth factor receptor 1; and PTK787, which inhibits vascular endothelial growth factor. Additional drugs aimed at switching off silenced genes include histone deacetylase inhibitors. The availability of these various oral treatments is hoped to improve regimens that, if used sequentially or in combination, offer the potential of making multiple myeloma a chronic disease, thereby extending patients' lifespans and improving quality of life.

Administration, Oral↗

PubMed2006

Proteasome inhibitor bortezomib for the treatment of multiple myeloma.

Bortezomib (formerly PS-341) has been the first proteasome inhibitor to enter clinical trials in cancer patients. Based on results of preclinical studies showing that this novel agent directly inhibits the proliferation of myeloma cells, induces their apoptosis and abrogates paracrine tumor growth through alteration of myeloma-stromal cell interactions and nuclear factor-kappaB-dependent cytokine secretion, several large phase II and III studies of bortezomib were initiated in patients with advanced relapsed and/or refractory multiple myeloma (MM). Favorable results of these studies led to accelerated approval for use of bortezomib in MM patients who have progressed after at least their second therapy and, more recently, to expanded approval for second-line use in patients on whom one prior therapy has failed. In the meantime, combination studies of bortezomib with various agents, including dexamethasone, DNA-damaging drugs, thalidomide and lenalidomide, have been designed and are currently ongoing in patients with both relapsed/refractory and newly diagnosed disease. Bortezomib offers great promise to overcome resistance to conventional chemotherapy and may be the 'backbone' for the development of more effective treatment strategies to improve patient outcome in MM.

Antineoplastic Agents↗

PubMed2006

Treatment of relapsed chronic lymphocytic leukemia: old and new therapies.

There are several initial therapies available for chronic lymphocytic leukemia (CLL) that offer extended disease-free or treatment-free survival time. However, once patients relapse, particularly after fludarabine-based therapy, treatment choices have remained limited. Newer therapies have now become available, including alemtuzumab, fludarabine-based combinations, rituximab, methylprednisolone, alternative nucleoside analogs, flavopirodol, lenalidomide, signal transduction inhibitors/small molecules, and new monoclonal antibodies. We discuss selection of therapy for the relapsed patient using risk stratification and the role of clinical research in continuing to pursue therapeutic advances against CLL.

Antineoplastic Agents↗

PubMed2026

Metagenomic Deep Sequencing Identifies Gene Mutations Associated with Chemotherapeutic Resistance in Vitreoretinal Lymphoma.

PURPOSE: To identify gene mutations associated with chemotherapeutic resistance in patients with vitreoretinal lymphoma (VRL) using metagenomic deep sequencing (MDS) of intraocular specimens. METHODS: Patients with VRL confirmed by cytopathology and immunohistochemistry, flow cytometry, and/or polymerase chain reaction for MYD88, were included. Intraocular specimens underwent MDS of the host genome. Gene mutations were identified and cross-referenced with the Catalogue of Somatic Mutations in Cancer database to determine associations with chemotherapeutic resistance. RESULTS: Forty-nine patients with VRL underwent MDS, with six specimens from four patients revealing eight gene mutations associated with chemotherapeutic resistance. Four specimens from three patients harbored mutations associated with methotrexate resistance, the mainstay of VRL treatment. In one patient, serial sampling from the initial vitrectomy and two subsequent recurrences revealed distinct resistance-associated mutations at each time point. Despite multi-agent therapy including rituximab, consolidation regimens, and lenalidomide, this patient ultimately succumbed to the disease, whereas the other three patients remained in long-term remission. CONCLUSIONS: Our findings demonstrated that specific gene mutations associated with chemotherapeutic resistance may be harbored by VRL. The detection of different resistance mutations at sequential time points in one patient may reflect clonal selection, treatment pressure, or variable detection sensitivity. The ability to easily sample ocular fluid and detect different mutations associated with tumor recurrence or persistence may provide insights into tumor pathogenesis and could inform prognosis and influence treatment decisions. These findings establish a foundation for developing targeted PCR assays for identified resistance genes, which could transform clinical practice in VRL.

Chemotherapeutic resistance-associated mutations↗

PubMed2006

Clinical implications of chromosomal abnormalities in multiple myeloma.

The adverse prognostic role of cytogenetic abnormalities has recently been established in plasma cell dyscrasias. Modern techniques such as fluorescence in situ hybridization and comparative genomic hybridization have revealed a higher incidence of cytogenetic abnormalities in patients with multiple myeloma (MM) compared to conventional cytogenetics. Hypodiploidy and chromosome 13 abnormalities are found in more than 50% of myeloma patients, representing well known factors with adverse prognosis. Rearrangements involving the switch regions of immunoglobulin heavy chain (IgH) gene at 14q32 with various partner genes represent the most common structural abnormalities, having an incidence of 70% in MM. Structural abnormalities of chromosomes 17 and 8 involving the p53 and c-myc genes are considered to be less frequent events, but carry a poor prognosis. New therapeutic approaches such as non-myeloablative allotransplantation and modern therapeutic agents (thalidomide, lenalidomide, and bortezomib) and their combinations give promise for an improved therapeutic management of patients with MM. The detection of t(4;14), t(14;16), deletion of chromosome 13 on metaphase analysis, or deletion of p53 by FISH will define high-risk prognostic groups that are not generally controlled with high-dose melphalan and autologous stem cell transplantation (ASCT), and should therefore be treated with more investigational therapies. Alternatively, eligible patients who do not have these poor risk factors are more likely to benefit from a high-dose, melphalan-based, regimen followed by ASCT.

Chromosome Aberrations↗

PubMed2005

Progress in hematopoietic stem cell transplantation in multiple myeloma.

PURPOSE OF REVIEW: An attempt is made to value the place of autologous and allogeneic hematopoietic stem cell transplantation in the treatment of multiple myeloma. Recent progress with each treatment modality has significantly changed the outcome for myeloma patients. RECENT FINDINGS: The gold standard for conditioning treatment before autologous transplantation is melphalan 200 mg/m, and the use of peripheral blood stem cells is superior to that of bone marrow. Tandem autologous transplantation is superior to single autologous transplantation, at least for patients who do not respond with complete remission to the first transplant. Allogeneic transplantation using standard high-dose myeloablative conditioning reduces the relapse rate in comparison with autologous transplantation; however, treatment-related mortality is significantly higher. Progress in allogeneic transplantation has been significant, and transplant-related mortality has been reduced. The recent use of nonmyeloablative reduced-intensity conditioning has significantly decreased transplant-related mortality; however, the relapse rate is higher than with standard conditioning, and therefore no significant improvement in overall survival has as yet been seen. Relapse following allogeneic transplantation can be counteracted by donor lymphocyte infusions, but the survival results are so far inconclusive. SUMMARY: Autologous transplantation is still the first choice for most myeloma patients, but it does not seem to be curative. 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.

Hematopoietic Stem Cell Transplantation↗

PubMed2006

New insights into the pathogenesis and drug treatment of myelofibrosis.

PURPOSE OF REVIEW: Myelofibrosis with myeloid metaplasia was first described in 1879, classified as a myeloproliferative disorder in 1951, and characterized as a clonal stem cell disorder in 1978. Despite the passing of time, the molecular basis of the disease has remained elusive although substantial progress has been made regarding the pathogenesis of the associated bone marrow stromal reaction. Advances have also been meager in terms of treatment for disease complications, including anemia, splenomegaly, and leukemic transformation. RECENT FINDINGS: At the molecular level, a JAK2 tyrosine kinase mutation (JAK2) has recently been described in a spectrum of myeloproliferative disorders including myelofibrosis with myeloid metaplasia with the reported mutational frequency ranging from 35% to 57% with 9-29% homozygosity. To date, the presence of JAK2 in myelofibrosis with myeloid metaplasia has not been shown to have prognostic relevance. Other recent observations of potential pathogenetic relevance in this disease include the description of a highly specific chromosomal translocation {der(6)t(1;6)(q23;p21)}, the demonstration of an epigenetic downregulation of the retinoic acid receptor-beta2 expression in CD34 cells, and the direct implication of transforming growth factor-beta1 in thrombopoietin-driven experimental myelofibrosis in mice. From a therapeutic standpoint, benefit to a subset of patients has been demonstrated for both allogeneic stem cell transplantation and novel drugs, including thalidomide and lenalidomide. SUMMARY: Recent advances in the pathogenesis of myelofibrosis with myeloid metaplasia are expected to facilitate the development of molecularly targeted therapy. In the mean time, current management strategies include observation, participation in experimental drug therapy, and allogeneic stem cell transplantation for low-risk, intermediate-risk, and high-risk disease, respectively.

Anemia↗

PubMed2007

Current and emerging views and treatments of systemic immunoglobulin light-chain (Al) amyloidosis.

Amyloidosis is a disease in which abnormal proteins form toxic intermediates and fibrillar tissue-deposits that compromise key viscera and lead to early death. In order to treat amyloidosis, the type of abnormal protein must be identified. The most common type is monoclonal immunoglobulin light chain or AL amyloidosis. One-third to one-half of patients with systemic AL amyloidosis has renal involvement in the form of glomerular, vascular and interstitial deposits of amyloid causing progressive proteinuria. Less than 5% of AL patients present with renal failure requiring dialysis; patients with renal involvement usually present with fatigue, peripheral edema, proteinuria and hypoalbuminemia. The aim of therapy in systemic AL amyloidosis is to reduce the amyloid-forming monoclonal light chains, measured with the serum free light chain assay, by suppressing the underlying plasma cell dyscrasia, while using supportive measures to sustain organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor light chain is eliminated. The most effective treatment for systemic AL is risk-adapted melphalan with peripheral blood stem cell transplant; oral melphalan and dexamethasone is the most effective therapy for patients who are not stem cell transplant candidates although it carries a risk of myelodysplasia and leukemia. Novel therapies currently under study include thalidomide, bortezomib and lenalidomide. With therapy, a majority of patients can achieve long-term durable remissions with stabilization or recovery of organ function. The use of novel antibody-based approaches for imaging amyloid and possibly for accelerating removal of deposits is under active investigation.

Amyloid↗

PubMed2006

Clinical issues in the management of patients with myelodysplasia.

The management of patients with myelodysplasia (MDS) can be quite complex and varies according to both the clinical manifestations in individual patients as well as complicating medical conditions. Allogeneic stem cell transplantation is the only curative treatment, but because of the older age of the patient population must be applied selectively, particularly in those with lower risk MDS as well as in patients whose clinical course is more frankly "preleukemic." Issues pertinent to the use of 5-azacytidine, decitabine and lenalidomide in patients with both higher and lower International Prognostic Staging System (IPSS) stage disease are discussed.

Age Factors↗

PubMed2006

Initial therapy of multiple myeloma patients who are not candidates for stem cell transplantation.

Multiple myeloma patients deemed to not be candidates for high-dose therapy followed by stem cell rescue who nonetheless need chemotherapy have traditionally received an oral regimen combining melphalan and prednisone. With the advent of novel agents, however, such as immunomodulatory drugs and proteasome inhibitors that are active in the relapsed/refractory setting, there has been an impetus to incorporate these new options into front-line therapy. Several phase II studies have recently revealed that addition of either thalidomide, lenalidomide, or bortezomib to melphalan and prednisone increased the overall and complete response rates, albeit at the cost of some increased toxicity. Randomized phase III studies of melphalan and prednisone with thalidomide have already shown that, compared to melphalan and prednisone alone, the three-drug regimen prolonged time to progression and overall survival in this population, thereby defining a new standard of care. Moreover, our increasing knowledge of the molecular role that cytogenetic abnormalities play in the biology of multiple myeloma and our growing chemotherapeutic armamentarium are beginning to allow us to rationally select therapies based on these characteristics of each patient's disease. Such a risk- and molecular-adapted strategy to the therapy of multiple myeloma promises to revolutionize and personalize our care of these patients and bring us closer to a cure for this disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Thrombotic complications of myeloma therapy.

Patients with multiple myeloma are at relatively high baseline risk of developing thromboembolic events (TEE), usually deep vein thromboses. There are numerous contributing factors, among them certain treatment regimens that include thalidomide or related compounds such as lenalidomide combined with glucocorticoids and/or cytotoxic chemotherapy. The risk of developing TEE appears to be particularly high when these immunomodulatory agents are combined with anthracyclines as treatment of newly-diagnosed disease. Up-front combinations including thalidomide plus pulse dexamethasone and/or alkylating agents are associated with an intermediate risk, whereas the same regimens for relapsed/refractory myeloma seem to be associated with the lowest risk. Several different thromboprophylaxis strategies have been effective in lowering the risk of developing clots: daily aspirin (81-325 mg/day), full-intensity warfarin (INR 2-3), and prophylactic enoxaparin (40 mg SQ daily). Low, fixed-dose warfarin may also reduce the risk of TEE, but the data on this are disputable. None of these TEE prevention strategies have been prospectively compared head-to-head, so the choice often reflects physician and/or patient preferences. The available evidence upon which one might make such a decision is reviewed here.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl).

In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester-induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCmu. Importantly, it also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when enzastaurin is combined with bortezomib and moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, tumor growth, survival, and angiogenesis are abrogated by enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve outcome in patients with MM.

Administration, Oral↗

PubMed2005

Overview of drug therapy for multiple myeloma.

BACKGROUND: Multiple myeloma accounts for 10% of all haematologic malignancies worldwide. In Europe, over 10,000 new cases and nearly 8000 deaths were attributed to multiple myeloma in 2000. Unlike other malignancies, in which surgery and radiation are important treatment modalities, myeloma is exclusively treated with stem cell transplantation and drug therapy, requiring pharmacists to stay abreast of new developments. The melphalan-prednisolone and vincristine-doxorubicin-dexamethasone (VAD) regimens, which have been standard treatments for multiple myeloma over the past few decades, have yielded responses without real survival benefits. Transplantation utilizing high-dose chemotherapy has produced the only meaningful survival benefits for patients with multiple myeloma, but many patients are not candidates for this aggressive treatment option. More effective therapies for multiple myeloma are needed. OBJECTIVE: To address the mechanisms of action, safety, and efficacy of novel approaches to the treatment of myeloma involving bortezomib, thalidomide and its analogues, lenalidomide and CC-4047 (Actimid), and arsenic trioxide as single agents or in combination regimens. DATA SOURCES: Published preclinical and primary clinical trial results, as well as scientific or clinical meeting abstracts. The author determined the relevance and subsequent inclusion of the data. CONCLUSIONS: Bortezomib is approved in the US and Europe as single-agent therapy for the treatment of relapsed or refractory multiple myeloma. Thalidomide, its analogues, and arsenic trioxide have demonstrated activity and are under investigation in this disease. Further clinical trials of the efficacy and toxicity of these novel agents are ongoing and will further define optimal combinations and sequencing with conventional therapies.

Animals↗

PubMed2006

Investigational treatments for multiple myeloma.

Multiple myeloma remains a fatal neoplasm and new treatments are urgently needed. In recent years, advances in understanding the molecular pathophysiology of myeloma and the mechanisms of drug resistance led to the development of several novel agents. The drugs with the most available clinical data are thalidomide, bortezomib and lenalidomide. Impressive results obtained with these agents - both in relapsed disease and in newly diagnosed patients - have significantly improved the outcome of myeloma patients. Several other new targeted agents are presently under investigation. These include monoclonal antibodies, agents that target mammalian target of rapamycin, histone acetylation, heat-shock proteins, growth factor signalling cascades, oncogenes, signal transducer and activators of the transcription pathway, Akt pathway and MAPK pathway. Their mechanisms of action, the available knowledge on their efficacy, safety and possible future clinical application are reviewed.

Aged↗

PubMed2007

The role of decitabine in the treatment of myelodysplastic syndromes.

Supportive care with red cell and platelet transfusions and use of growth factors has long been the standard of care for patients with myelodysplastic syndromes (MDS) ineligible for stem cell transplantation. Although these measures improve quality of life, their impact on the natural history of the disease is questionable. Recently, three new agents have been approved for the treatment of MDS. These include: 5-azacytidine, lenalidomide and, more recently, 5-aza-2 -deoxycytidine (decitabine). Decitabine is a hypomethylating agent that is incorporated into DNA and forms irreversible covalent adducts with DNA-methyltransferases. At high concentrations, this leads to cell death. At low concentrations, decitabine is considered to exert its anticancer effects by inducing DNA hypomethylation. This results in reactivation of epigenetically repressed genes, such as tumour suppressor genes and, potentially, cell differentiation. In a randomized, Phase III trial of decitabine versus best supportive care in patients with MDS, the overall response rate with decitabine was 17%, including 9% complete remissions. Patients at high risk had a statistically significant prolongation of time to acute myelogenous leukemia transformation or death. This experience has been followed by a study of low-dose decitabine using a five-times daily 1-h infusion schedule, with significant efficacy in patients with MDS observed. Ongoing studies are evaluating the activity and safety of the combination of decitabine with several histone deacetylase inhibitors and other indications. This article summarizes the experience in with decitabine in MDS.

Azacitidine↗

PubMed2004

Thalidomide-derived immunomodulatory drugs as therapeutic agents.

Thalidomide, a drug originally used to treat morning sickness, was removed from the market place in the early 1960s after it was found to cause serious congenital birth defects. However, thalidomide has recently been investigated in a new light following its activity in a number of chronic diseases. Moreover, like thalidomide itself, its second-generation immunomodulatory drug (IMiD) analogues have been shown to act as powerful anticancer agents and are clearly active in the treatment of patients with relapsed multiple myeloma. These new drugs, in particular the second-generation IMiDs, lenalidomide (CC-5013, REVLIMID; Celgene Corp., NJ, USA) and CC-4047 (ACTIMID; Celgene Corp.), offer improvements over thalidomide (a first-generation IMiD) in terms of efficacy and safety in human studies. The key to the therapeutic potential of IMiDs lies in the fact that the drugs have multiple mechanisms of action, which may produce both anti-inflammatory and antitumour effects. These effects are probably contextual, depending both on the cell type and the stimulus involved. Mechanisms associated with IMiD activity include TNF-alpha-inhibitory, T cell costimulatory and antiangiogenic activities. Studies of the mechanisms of action of these drugs are ongoing and will facilitate the continued development of this class of compound in a number of diseases.

Anti-Inflammatory Agents↗

PubMed2005

Strategies for biology- and molecular-based treatment of myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) constitute a group of clonal stem cell disorders characterized by cytopenia, ineffective hematopoiesis, bone marrow dysplasia, and a risk of progression to acute myeloid leukemia (AML). Disease mechanisms can be divided into two main groups; those underlying the increased apoptosis of bone marrow progenitors, and those associated with progressive blast proliferation, and transformation to acute myeloid leukemia. The recently published WHO classification includes one subtype with a specific cytogenetic lesion, the 5q- syndrome, but otherwise classification of MDS is based solely on clinical and morphological criteria. Subsequently, few therapeutic options have been directed towards specific biological or molecular mechanisms in MDS. Progenitor apoptosis in MDS may be initiated by extrinsic and intrinsic mechanisms. The extrinsic pathway includes T-cell mediated bone marrow failure, for which antithymocyte globulin treatment may be an effective, as well as negative effects caused by the marrow microenvironment. New therapeutic options targeting the microenvironment include thalidomide and its analogue, lenalidomide, which has proven extremely effective for patients with 5q- syndrome. The erythroid apoptosis of in particular sideroblastic anemia is mediated by mitochondrial release of cytochrome c, which may be inhibited by treatment with erythropoietin and granulocyte-colony-stimulating-factor. Important mechanisms for disease progression are DNA hypermethylation, histone deacetylation, and possibly RAS mutations. Two new DNA hypomethylating agents, azacytidine and decitabine, have shown efficacy in patients with high-risk MDS, and may prolong time to progression. In conclusion, recent advances in the pathogenetic understanding of MDS have led to significant therapeutic progress.

Apoptosis↗

PubMed2006

Thalidomide in multiple myeloma: past, present and future.

Thalidomide was introduced in the treatment of multiple myeloma in the late 1990s. Following the initial results, which demonstrated dramatic response rates in heavily pretreated patients, a number of Phase II studies have confirmed the efficacy of this agent in relapsed patients. However, a high incidence of side effects at the dosage initially recommended (400 mg/day) justified further studies with lower doses of thalidomide given alone or in combination with dexamethasone or chemotherapy. Thalidomide is currently considered as one of the most active agents in relapsed myeloma. Recent studies have demonstrated that thalidomide could also be used as part of frontline therapy. The combination of thalidomide plus dexamethasone as initial therapy appears to be slightly superior to dexamethasone alone or to vincristine-doxorubicine-dexamethasone, but with an increased risk of deep vein thrombosis. Maintenance with thalidomide after autologous transplantation appears to increase the complete remission rate and to prolong progression-free survival. The combination of thalidomide plus melphalan and prednisone is superior to the classical melphalan-prednisone regimen in elderly patients, and will become the standard of care. 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.

Angiogenesis Inhibitors↗