Pathogenesis of monoclonal gammopathy of undetermined significance and progression to multiple myeloma

Abstract

Monoclonal gammopathy of undetermined significance (MGUS), including immunoglobulin light chain only MGUS, is an age-dependent premalignant tumor that is present in about 4% of Caucasian individuals over the age of 50 years. It is comprised of two different kinds of tumors: about 15% lymphoid or lymphoplasmacytoid MGUS and the remainder plasma cell MGUS. Plasma cell MGUS is stable but can sporadically progress to multiple myeloma (MM) at an average rate of about 1% per year. Most, if not all, MM tumors are preceded by plasma cell MGUS, which shares four partially overlapping oncogenic features with MM. It presently is not possible to unequivocally distinguish an MGUS tumor cell from an MM tumor cell. However, two models based on clinical laboratory tests indicate that it is possible to stratify MGUS tumors into groups that have average rates of progression as low as 0.26% per year and as high as 12% per year.

Figure 1

Molecular pathogenesis of MGUS and multiple myeloma. Four early and partially overlapping events are shared by MGUS and MM tumors, but it is not clear what other events are necessary for the transition (TR1) to a pre-malignant MGUS tumor. Some events (e.g. karyotypic abnormalities) probably can occur at any stage of pathogenesis, whereas other events (e.g., p53 inactivation) might occur mainly at late stages of tumor progression. Two events (deletion chr13 and activating K-RAS mutations) may be associated with the transition (TR2) from MGUS to MM for some tumors, whereas a third event (increased MYC expression and sometimes MYC locus rearrangements) may be more universally involved in this transition. Note that MYC(Ig) rearrangements can also occur as a late progression event. See text for additional details.