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Kenneth C. Anderson

With the availability of a new proteasome inhibitor, carfilzomib, and a new immunomodulatory drug, pomalidomide, the treatment of multiple myeloma has become more effective. The updated NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma provide new recommendations for use of carfilzomib and pomalidomide. As new classes of drugs such as monoclonal antibodies become available, the treatment landscape will be rendered even brighter.

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Kenneth C. Anderson

The updated NCCN Guidelines for Multiple Myeloma feature several changes in the diagnosis and management of this disease. Criteria for treatment initiation have been broadened, new staging has been recommended, and new classes of agents and combinations are included as recommended treatment. Monoclonal antibodies are among the expanded therapeutic choices, along with a histone deacetylase inhibitor and third-generation proteosome inhibitor, and there is excitement about exploring new immune-based approaches.

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Kenneth C. Anderson

The past decade has been a time of rapid progress in multiple myeloma, but the future therapeutic landscape may be even more promising, as new agents are better tolerated and novel pathways are exploited. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) now include the proteasome inhibitor carfilzomib and immunomodulatory drug pomalidomide, which are more potent than previous generations of these drugs have been. These agents are extending progression free and overall survival of patients with relapsed refractory myeloma, as is maintenance therapy with lenalidomide after initial therapy of patients with newly diagnosed disease At the NCCN 18th Annual Conference, Dr. Kenneth C. Anderson from Dana-Farber Cancer Institute reviewed the data leading to the approval of these exciting agents, discussed the efficacy of current regimens, and described the future landscape and the exciting potential of new agents to further improve and extend the lives of patients with myeloma.

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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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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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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.

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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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Kenneth C. Anderson, Melissa Alsina, William Bensinger, J. Sybil Biermann, Asher Chanan-Khan, Adam D. Cohen, Steven Devine, Benjamin Djulbegovic, Cristina Gasparetto, Carol Ann Huff, Madan Jagasia, Bruno C. Medeiros, Ruby Meredith, Noopur Raje, Jeffrey Schriber, Seema Singhal, George Somlo, Keith Stockerl-Goldstein, Guido Tricot, Julie M. Vose, Donna Weber, Joachim Yahalom and Furhan Yunus

Multiple Myeloma Clinical Practice Guidelines in Oncology NCCN Categories of Evidence and Consensus Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus. Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus. Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement). Category 3: The recommendation is based on any level of evidence but reflects major disagreement. All recommendations are category 2A unless otherwise noted. Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Overview Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. The American Cancer Society estimates that 20,580 new cases of MM will occur in the United States in 2009, including 11,680 in men and 8900 in women, with an estimated 10,580 deaths.1 The mean age of affected individuals is 62 years for men (75% > 70 years) and 61 years for women (79% > 70 years). The treatment of MM has dramatically improved over the past decade. The 5-year survival rate reported in the Surveillance Epidemiology and End Results database has increased from 25% in 1975 to 34% in 2003 because of the availability of newer and more effective treatment options.2,3 MM is typically sensitive to various cytotoxic drugs, both as initial treatment...
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Kenneth C. Anderson, Melissa Alsina, Djordje Atanackovic, J. Sybil Biermann, Jason C. Chandler, Caitlin Costello, Benjamin Djulbegovic, Henry C. Fung, Cristina Gasparetto, Kelly Godby, Craig Hofmeister, Leona Holmberg, Sarah Holstein, Carol Ann Huff, Adetola Kassim, Amrita Y. Krishnan, Shaji K. Kumar, Michaela Liedtke, Matthew Lunning, Noopur Raje, Seema Singhal, Clayton Smith, George Somlo, Keith Stockerl-Goldstein, Steven P. Treon, Donna Weber, Joachim Yahalom, Dorothy A. Shead and Rashmi Kumar

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM.