Tx mielom

aFrom www.bloodjournal.org by on May 10, 2008. For personal use only.

2004 103: 20-32 Prepublished online Sep 11, 2003; doi:10.1182/blood-2003-04-1045

Treatment of multiple myeloma
Bart Barlogie, John Shaughnessy, Guido Tricot, Joth Jacobson, Maurizio Zangari, Elias Anaissie, Ron Walker and John Crowley

Updated information and services can be found at:http://bloodjournal.hematologylibrary.org/cgi/content/full/103/1/20 Articles on similar topics may be found in the following Blood collections: Transplantation (1270 articles) Immunotherapy (575 articles) Review Articles (222 articles) Immunobiology (3464 articles) Neoplasia (3993 articles) Information about reproducing this article in parts or in its entirety may be found online at:http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/misc/rights.dtl#reprints Information about subscriptions and ASH membership may be found online at: http://bloodjournal.hematologylibrary.org/subscriptions/index.dtl

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published semimonthly by the American Societyof Hematology, 1900 M St, NW, Suite 200, Washington DC 20036. Copyright 2007 by The American Society of Hematology; all rights reserved.

From www.bloodjournal.org by on May 10, 2008. For personal use only.

Review article

Treatment of multiple myeloma
Bart Barlogie, John Shaughnessy, Guido Tricot, Joth Jacobson, Maurizio Zangari, Elias Anaissie, Ron Walker, and John Crowley

Autologousperipheral blood stem cell (PBSC)–supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents,such as thalidomide and CC-5013 (Revimid; Celgene,

Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment’s interaction with myeloma cells. Among the prognostic factors evaluated,cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prog-

nosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecularand biologic mechanisms of treatment failure in the high-risk subgroup. (Blood. 2004;103: 20-32)
© 2004 by The American Society of Hematology

Introduction
Since the last reviews on this topic,1,2 further insight has been gained into the biology and genetics of multiple myeloma.3,4 Therapeutic options have increased,5,6 and patient outcomes have improved.7,8 Regarding the fundamental biologyof myeloma, the presence of somatic hypermutations of immunoglobulin variable region genes is consistent with an immortalizing event during plasma cell generation in germinal centers of lymph nodes.4 The self-renewal capacity of CD38 , CD45 , and CD19 plasma cells in the severe combined immunodeficiency-human (SCID-hu) mouse, an animal model of myeloma growth, suggests that these apparentlyterminally differentiated B cells retain self-renewal capacity.9 Genomic instability, a hallmark of multiple myeloma, is already present at the stage of monoclonal gammopathy of undetermined significance (MGUS),10-12 but it is not clear whether MGUS represents a prerequisite precursor stage for all cases of myeloma. At the gene expression level, MGUS cannot be distinguished from myeloma, although plasma...