Introduction to therapies in multiple myeloma.

T HIS ISSUE of Seminars in Hematology reviews the state of the art of myeloma therapeutics. Three decades of cooperative clinical trials research, authoritatively reviewed by Crowley et al for the Southwest Oncology Group, remind the reader of the snail’s pace of progress in myeloma therapy until the concept of dose response was tested in earnest, first for glucocorticoids and subsequently for melphalan. Although highdose dexamethasone pulsing was an integral part of the vincristine, doxorubicin, and dexamethasone (VAD) regimen’ that accelerated onset and increased magnitude of tumor cytoreduction, survival was prolonged only marginally compared with melphalan-prednisone.” However, higher doses of prednisone given during maintenance therapy extended event-free and overall survival, thus establishing a definite role for glucocorticoids in maintaining remission.9 The pioneering work of the late Tim McElwain established a clear-cut dose-response effect for melphalan which, due to its toxicity for hematopoietic stem cells, was associated with prolonged neutropenia and hence a high death rate due to septicemia.” Autologous bone marrow autografts*, and especially chemotherapyor growth factor-mobilized peripheral blood cells’0 shortened the duration of bone marrow aplasia to a few days (especially when conducted early in the course of disease).i6 Thus high-dose melphalan therapy could be applied safely in the elderlyzJ4 and in patients presenting with renal failure.3 Single-institution studies (Sirohi et al for the Royal Marsden group, Fassas and Tricot for the Arkansas group), registry data (Bjorkstrand for the European Blood and Marrow Transplant Registry), and randomized trial results (Attal and Harrousseau for the Intergroupe Francais du Myelome) all have corroborated the clinical benefit of melphalan-based high-dose therapy. Repeated cycles (“tandem transplant”) can raise the rate of true complete remission into the 50% range and extend its duration sufficiently so as to be compatible, at least operationally, with cure.6 In the past, toxicity of allogeneic transplants in myeloma, with treatment-related mortalities in the 50% range, prevented routine application to the usually elderly and often frail patient popu1ation.s However, the recent demonstration of a powerful graftversus-myeloma effect has prompted clinical trials of nonmyeloablative conditioning regimens, lowering the transplant-related mortality to 10% to 20% and facilitating transplants in patients older than 60 years. Importantly, mini-allotransplants represent the only currently active modality for the prognostically grave entity of chromosome 13 deletion myeloma.’ The serendipitous discovery of thalidomide’s activity in myeloma i5 has sparked tremendous interest in this orphan drug and this orphan disease among basic and clinical researchers as well as the pharmaceutical industry. Anderson’s contribution on “Targeted Therapies” provides the reader with an exciting account of how the “Darwin” myeloma might be tricked into surrender, not only through direct attack but also by undermining its environment. As a disease of the B-cell immune system associated with profound Band T-cell immunoparesis, Ruffini and Kwak critically review the basic and clinical studies currently in progress on antibody-mediated immunotherapy, idiotypeand dendritic cellbased vaccination, as well as adoptive T-cell therapy. Russell and Dunbar give an account of the multiplicity of gene therapy approaches to inactivate myeloma cells directly or indirectly by either provoking a specific immune response or interfering with regulatory growth loops. Callander and Roodman aptly capture the intricate interaction between myeloma cells and the bone marrow microenvironment and how this interplay results in the most vexing