Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies

Abstract

Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias, with a propensity to progress to symptomatic MM. In recent years there have been improvements in risk stratification models (involving molecular markers) of both disorders, which have led to better understanding of the biology and probability of progression of MGUS and SMM. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS and SMM represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. In this review we discuss the current standard of care of patients with MGUS and SMM, the use of risk models, including flow cytometry and free-light chain analyses, for predicting risk of progression. Emerging evidence from molecular studies on MGUS and SMM, involving cytogenetics, gene-expression profiling, and microRNA as well as molecular imaging is described. Finally, future directions for improving individualized management of MGUS and SMM patients, as well as the potential for developing early treatment strategies designed to delay and prevent development of MM are discussed.

Figure 1

Biological events related to progression to multiple myeloma. The biologic transition from normal plasma cells to multiple myeloma precursor disease (monoclonal gammopathy of undetermined significance [MGUS] and smoldering myeloma) to multiple myeloma consists of many overlapping oncogenic events. These events do not all occur in each affected individual, for example, hyperdiploidy is present in approximately 50% of precursor and multiple myeloma tumors. In this illustration, solid lines approximate the period during which the oncogenic event is likely to occur; dashed lines indicate less certainty in the timing. Once an oncogenic event occurs, it almost always persists. The 2 major types of early events include IgH translocations [most commonly: t(4;14), t(14;16), t(6;14), t(11;14), and t(14;20)] and hyperdiploidy, although most tumor cells have only one of these two events. Either of these can coexist with deletion of chromosome 13, although this abnormality most commonly (> 80% to 90% of patients) occurs with the t(4;14), t(14;16), and t(14;20) IgH translocations.^, A unifying early event in most, perhaps all, precursor and multiple myeloma tumors is the dysregulation of a cyclin D gene. Secondary translocations, sometimes involving an Ig locus, can occur at any stage of myelomagenesis. Activating mutations of NRAS and KRAS are each present in about 15% of multiple myeloma tumors; NRAS mutations are present in MGUS tumors and KRAS mutations are absent from MGUS tumors. Constitutive activation of the nuclear factor κB (NFκB) pathway is mediated by mutations in some tumors during progression. Other events, such as Rb gene inactivation or deletion of p53 or p18 genes, are mostly seen at the level of advanced intramedullary or extramedullary multiple myeloma.^, Through the stage of intramedullary multiple myeloma, the tumor cells are strongly dependent on the bone marrow microenvironment. The reciprocal interaction of the bone marrow microenvironment and the tumor cells results in changes in the bone marrow microenvironment, which are responsible for the lytic lesions that are characteristic of multiple myeloma. Extramedullary tumor cells have developed features that make them independent of the bone marrow microenvironment. (Reprinted with permission.)