Gene expression profiling illuminates myeloma biology

An abiding mystery in multiple myeloma (MM) has been the surprising heterogeneity in clinical outcome that characterizes this morphologically homogenous disease. For example, survival may be influenced by the immunoglobulin isotype expressed by MM cells. Similarly, some patients develop bone disease while others are spared. The genetic basis for both observations is obscure. Now, pioneering gene expression profiling studies are addressing such unexplained clinical truisms through the development of a comprehensive molecular portrait of the disease (Claudio et al, Blood. 2002;100:2175-2186; and references below).

A common theme of these early studies is the realization that MM can be classified into subgroups that associate with a normal physiologic counterpart of plasma-cell differentiation (Zhan et al, Blood. 2003;101: 1128-1140; Tarte et al. Blood. 2002;100: 1113-1122). In brief, some MM cells resemble late-stage B cells while others associate genetically with their normal, fully differentiated plasma cell counterparts. The proliferative nature of “B cell–like” MM seems evident from the expression profile and the clustering of such MMs with end-stage human MM cell lines (Zhan et al). Nevertheless, clinical evidence of poor outcome associated with a B cell–like profile is, as yet, lacking.

In this issue, Magrangeas and colleagues (page 4998) have taken such observations one step further. The gene expression profiles of 92 newly diagnosed patients are reported. Two clinically relevant observations result. First, expression profiles reveal a unique molecular signature that distinguishes IgA from IgG, or light-chain, disease. In a second clinically relevant finding, several genes discriminate between κ and λ MM. Remarkably, a strong association was noted between a κ subgroup expressing high levels of Mip-1α and active myeloma bone disease. Thus the transcriptional profiles of a plasma cell and its growth-arrested MM counterpart appear linked, relate to the stage of development of the cell, and reflect various differentiation processes, including isotype switching. By inference, these unique MM expression profiles linked to plasma-cell differentiation may explain previously noted clinical observations.

These studies are among the first to link molecular profile to clinical observation in this disease and support the hypothesis that a differentiated hierarchy of plasma cells exists in MM. Apparently the stage of growth arrest in MM correlates with and may, in part, explain clinical phenotype. Further studies of clinical outcome and its relationship to expression profiles are required to further this hypothesis.