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Novel Biologically Based Therapies for Multiple Myeloma

US Oncology Review, 2005;1(1):1-6 DOI: http://doi.org/10.17925/OHR.2005.00.00.1h

Abstract:

Introduction
Multiple myeloma (MM) is a malignant hematological disorder that until now has remained almost universally fatal. It represents approximately 1% of all malignancies and 13% of hematological malignancies in adults. The incidence of MM increases with age.The mean age of affected men is 62 years (75% <70 years old), and for women 61 years (79% <70 years old).The surveillance, epidemiology and end results (SEER) age-adjusted incidence between 1973 and 1999 was 5.6 cases per 100,000 for all races.1

The disease results from malignant plasma cells, which infiltrate the bone marrow.Although much is known about the nature of MM, the causes remain unknown. Genetic abnormalities are common and varied.2 The disease is predominantly localized to the bone marrow.The malignant plasma cells adhere to bone marrow stromal cells (BMSCs), resulting in the up- regulation of cytokines such as interleukin (IL)-1_,IL-6, insulin-like growth factor (IGF)-1, and vascular endothelial growth factor (VEGF).3 These cytokines are important for the regulation of plasma cell proliferation and migration, as well as for the development of drug resistance in myeloma. CD40 is present on MM plasma cells and BMSCs. CD40 ligand, present on T-cells, increases endogenous IL-6 secretion by MM cells and BMSCs through activation of nuclear factor-kappa B (NF-ggB),4 and increases expression of bcl-2, which increases drug resistance. Chemotherapy itself induces drug resistance by activation of NF-ggB5 and up- regulation of bcl-2 in MM cells.6

The clinical manifestations of MM result predominantly from marrow failure, immunosuppression, lytic lesions of the axial skeleton and long bones, and renal failure. Anemia occurs in the majority of myeloma patients, secondary to plasma cell infiltration and anemia of chronic disease.The overall median survival is three years. When patients are diagnosed with MM,chemotherapy is usually initiated to relieve symptoms and to prolong survival, but cures are rare. Therefore, with current standard treatment strategies the goals are prolongation of survival and improvement of symptoms. Recent years have seen a major change in the treatment of MM. By understanding the biology of malignant disease and defining important potential treatment targets, effective new drugs can be developed to improve patient outcome in MM.This article provides only a brief summary of some of the major recent developments in biologically based therapy for MM. As an increasing number of targets are being identified and mechanisms of resistance are elucidated, combinations of drugs will be developed to optimize new therapeutic combinations.

Conventional Chemotherapy
Untreated, the average survival of patients with MM is approximately six months.Although low doses of oral melphalan with prednisone has extended the median survival of MM from six months to three years, the response rates to melphalan and prednisone have been only 50% to 60%. Complete remissions are rare, and myeloma remains incurable with conventional chemotherapy. Overall survival has not been significantly improved with vincristine, adriamycin, and dexamethasone (VAD), or other forms of infusional chemotherapy, over melphalan and prednisone.7 The bone marrow toxicity of conven- tional chemotherapy is dose-limiting. Hematopoietic cell transplantation, or marrow transplantation, with either a patientýs own marrow (autologous) or a family member (allogeneic) has been explored extensively as a means to increase doses of conventional chemotherapy.

Allogeneic transplantation has been associated with a very high treatment-related mortality of up to 40%, and therefore has been performed infrequently. In contrast to allogeneic transplantation, autologous transplantation has been much safer, with a treatment- related mortality of <3%.Autologous transplantation is superior to conventional chemotherapy for the treatment of MM, and has been associated with a median survival to 55ý72 months.8 However, only 50% of patients aged 60 or under, and fewer than 20% of patients between 60 and 70, receive transplantation due to early death, co-morbidity, poor response to therapy, and failed peripheral blood stem cell harvests.9 For these patients, new therapies are urgently needed. For those who do receive marrow transplantation, improved patient outcome has been associated with increased remission rates and prolonged survival, but cures remain elusive.New strategies to control minimal residual disease after marrow transplantation are needed. Over the last decade, major advances in understanding the biology of MM have led to significant advances in treatment that are aimed at new cellular molecular targets. Novel therapies may improve response to marrow transplantation and may improve the overall survival of all MM patients with or without transplantation and, in contrast to transplan- tation, should be feasible for most patients.

Novel Biologically Based Therapies
Recently, there have been major new developments in novel biologically based therapies for MM. In particular, proteasome inhibitors, thalidomide and immuno- modulatory analogs of thalidomide, 2-methoxyestradiol, arsenic trioxide, monoclonal antibodies, and histone deacetylase inhibitors have entered into clinical trials for MM. Although these novel therapies were initially evaluated primarily in patients who relapse after transplantation, due to their efficacy and tolerability, some of these agents are now being evaluated in earlier stage patients, as initial therapy or treatment of first relapse, and in combination with other therapies. The examples presented in this review represent the beginning of a new age of translational research, when understanding the molecular biology of malignant disease can be translated into a favorable therapeutic outcome for patients.