Authors: Wee Joo Chng, MD; Lee Gong Lau, MD; Noorainun Yusof, MD; Benjamin M. F. Mow, MD

Abstract

Background: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. Methods: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. Results: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. Conclusions: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients.

Introduction

Multiple myeloma (MM) is a malignancy arising from postgerminal mature B cells characterized by an excess of monotypic plasma cells in the bone marrow secreting monoclonal immunoglobulins in the serum and/or urine, with a concomitant decrease in normal immunoglobulins and lytic bone lesions.[1] In the United States, the estimated incidence of MM in 2005 is 16,000, and it accounts for 10% of hematologic malignancies and 1% of all malignancies.[2] Despite therapeutic advances, the disease is essentially incurable. The current standard of treatment with high-dose therapy followed by autologous stem cell transplant3,4 prolongs survival to a median of 4 to 5 years compared to 3 years with conventional chemotherapy.[5, 6] Attempts at improving autografting with a tandem procedure has improved outcome,[7, 8]but despite a small subgroup of patients surviving more than 8 years, there is currently no plateau in the overall survival curves. Allogeneic stem cell transplant offers a potential for cure due to the well-documented graft-vs-myeloma effect[9] but is associated with a high transplant-related mortality.[10] Recent efforts to reduce the transplant-related mortality with nonmyeloablative conditioning have shown encouraging results, but longer follow-up is needed to determine the role of this treatment modality.[11—13] New insights into the biology of MM have provided a framework in the development of drugs that target not only specific intracellular pathways but also the myeloma-bone marrow interaction. These agents have shown promising results in clinical trials and are reviewed in this paper.