Immunobiology and Immunotherapy of Multiple Myeloma

Abstract

Multiple myeloma (MM) is a common B-cell malignancy characterized by clonal expansion of transformed plasma cells in the bone marrow. 1 Natural history of MM is characterized by disease progression, and the development of anemia, lytic bone disease, and infections. However, although clonal expansion of transformed plasma cells is an essential prerequisite for the development of MM, the most common clinical outcome of such expansions in vivo in humans is not MM, but the development of monoclonal gammopathy of undetermined significance (MGUS). MGUS has been estimated to occur in up to 1–3% of the elderly population, and is commonly viewed as a preneoplastic state. However, most patients with MGUS will generally remain stable throughout their life, and only a small proportion (estimated at about 1% per year) will develop MM. 2 Another clinically distinct subset is patients with asymptomatic MM, who also have a relatively indolent course, but much higher risk for transformation to symptomatic MM. 3 Recent application of interphase cytogenetics and genomic technologies has yielded the surprising finding that many of the cytogenetic and genomic changes in tumor cells initially identified in MM can now also be detected in the tumor cells in MGUS. 4 , 5 In many instances, genetic lesions such as deletion of chromosome 13 that seem to impart an adverse outcome in MM do not do so in MGUS. These findings therefore suggest the possibility that clinical outcome in MM depends not only on the properties of the tumor cells themselves but also on changes in the host tumor microenvironment and their interactions with the tumor cells. An important component of this microenvironment is the cells of the immune system. 6 Therefore, improved understanding of the immune microenvironment in MM might provide newer approaches for therapy and prevention of this disease. Below, I will first briefly discuss some of the general principles underlying the mechanisms of immune control and escape of tumors, and then describe the current studies about the status of immune cells in MM and MGUS. Understanding the status of the host immune response is an essential first step for optimal development of therapeutic approaches targeting the immune system in MM. Chapter 11