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Epigenetic Modulation in Hematologic Malignancies: Challenges and Progress

Constantine S. Mitsiades and Kenneth C. Anderson

Genetic alterations, including gene mutations, and chromosomal amplifications, deletions, inversions, and translocations, are hallmarks of the molecular biology of cancer. These events lead to oncogene activation, formation of chimeric oncoproteins, and/or inactivation of tumor suppressor genes. Such genetic changes contribute to the neoplastic transformation of cells, as well as the eventual acquisition by malignant cells of a more aggressive biologic and clinical behavior. However, in recent years, it has become apparent that these genetic events are not the sole determinants of the biologic behavior of tumor cells. Indeed, it is becoming increasingly apparent that tumor cells with a given genotype exhibit a differential phenotype depending on the microenvironment in which they reside. Furthermore, extensive data have shown that derivative daughter cells of neoplastic, as well as normal cells, inherit changes in the patterns of gene expression that are not associated with changes in the primary DNA sequence but are instead related to changes in chromatin structure and its accessibility for transcriptional activity. These heritable gene expression changes that are not associated with changes in the primary nucleotide sequence are referred to as epigenetic changes. This review provides an overview of the regulation of the “epigenome” in neoplastic cells, with particular emphasis on DNA methylation and histone acetylation as therapeutic targets for hematologic malignancies.

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Complications of Multiple Myeloma Therapy, Part 1: Risk Reduction and Management of Peripheral Neuropathy and Asthenia

Paul G. Richardson, Jacob P. Laubach, Robert L. Schlossman, Constantine Mitsiades, and Kenneth Anderson

Peripheral neuropathy (PN) and asthenia (fatigue) occur as both disease- and treatment-related complications in patients with multiple myeloma (MM). Risk factors for treatment-related PN, which has an estimated incidence of 37% to 83% among patients with MM, include therapy duration, dose intensity, cumulative dose, and the presence of preexisting neuropathy. Asthenia is the most common adverse effect of treatment, occurring in approximately 76% to 96% of patients receiving therapy. The severity of PN and asthenia can range from mild to potentially debilitating. These conditions can be dose limiting; they may interfere with optimizing duration of therapy and may also substantially affect patient quality of life. Regular screening and monitoring, combined with patient education and effective management strategies, can reduce the risk of these treatment-related complications, as well as their consequences.

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The Emerging Role of Novel Therapies for the Treatment of Relapsed Myeloma

Paul G. Richardson, Teru Hideshima, Constantine Mitsiades, and Kenneth C. Anderson

Despite advances in the first-line treatment of multiple myeloma, almost all patients eventually relapse, become chemoresistant, and die of the disease. Improved understanding of potential myeloma targets and molecular mechanisms of drug resistance, along with the development and clinical investigation of targeted antitumor agents, have led to new strategies for the treatment of relapsed myeloma. The proteasome inhibitor bortezomib, the immunomodulatory agent thalidomide, and the thalidomide derivative lenalidomide, are all recently approved treatment options for myeloma. Single-agent bortezomib has been shown to provide significantly greater efficacy than high-dose dexamethasone, and bortezomib has also been investigated in combination with other agents commonly used to treat myeloma, including thalidomide and lenalidomide, with high overall and complete response rates. The safety profile of bortezomib has been well characterized, and side effects have been shown to be generally predictable and manageable, including in high-risk and elderly patients and those with renal impairment. Thalidomide has been extensively studied alone and in combination in patients with relapsed myeloma, demonstrating substantial efficacy, and is therefore widely used in this setting. The toxicity profile is dose- and duration-linked, with lower doses appearing to be better tolerated. Lenalidomide plus dexamethasone has been shown to have significantly greater activity than dexamethasone alone in the relapsed setting, with impressive duration of disease control. Other combinations are also under investigation, with promising early results. Some aspects of the toxicity profile appear significantly reduced relative to thalidomide, although myelosuppression is increased. Other novel therapies at earlier stages of development are being studied and may provide further options in the treatment of relapsed myeloma. This review focuses on results from key phase II and III trials of bortezomib, thalidomide, and lenalidomide alone or in combination, and their emerging role in improving outcomes.

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Novel Therapies in the Treatment of Multiple Myeloma

Jacob P. Laubach, Constantine S. Mitsiades, Anuj Mahindra, Robert L. Schlossman, Teru Hideshima, Dharminder Chauhan, Nicole A. Carreau, Irene M. Ghobrial, Noopur Raje, Nikhil C. Munshi, Kenneth C. Anderson, and Paul G. Richardson

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by aberrant expansion of plasma cells within bone marrow and extramedullary sites. In 2009, 20,580 new cases of MM and 10,580 deaths from the disease occurred in the United States. Treatment traditionally consists of systemic chemotherapy, with adjunctive use of radiation or surgery in selected cases associated with extramedullary disease. The therapeutic landscape in MM has changed markedly in the past decade with the introduction of the novel immunomodulatory agents thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib. Although MM remains an incurable malignancy, new approaches to therapy incorporating these agents have produced significantly higher response rates and improved intervals of both progression-free and overall survival in the context of randomized, controlled trials. In aggregate, the use of novel therapies in MM has been associated with substantial improvements in patient outcome.

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Management of Relapsed and Relapsed/Refractory Multiple Myeloma

Jacob P. Laubach, Constantine S. Mitsiades, Anuj Mahindra, Marlise R. Luskin, Jacalyn Rosenblatt, Irene M. Ghobrial, Robert L. Schlossman, David Avigan, Noopur Raje, Nikhil C. Munshi, Kenneth C. Anderson, and Paul G. Richardson

Despite significant progress in the treatment of multiple myeloma (MM) over the past decade, this disease remains incurable and almost all patients ultimately experience relapse and become refractory to treatment over time. However, the outlook for patients with relapsed MM has improved markedly with the use of the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Moreover, the development of new drug classes based on preclinical rationale and the introduction of next-generation agents is likely to further expand treatment options and improve outcomes for relapsed MM.