Circulating clonotypic B cells in the biology of multiple myeloma: Speculations on the origin of myeloma

The population of circulating B cells in myeloma patients includes an apparently large but variable subset with the IgH VDJ rearrangement diagnostic for the malignant clone of plasma cells in individual myeloma patients. Although the biological significance is at present unknown, it is likely that they include both malignant and non-malignant clonal relatives of the myeloma plasma cells. This article presents speculations on the significance of these cells in the origin of myeloma and the relationship between monoclonal gammopathy of undetermined significance (MGUS) and frank myeloma. MGUS appears to represent the establishment of clonal dominance probably by a chronically antigen-stimulated B cell clone. It seems likely that malignant transformation event(s) occurring in a clonal daughter cell give rise to myeloma. If correct, this implies that in a myeloma patient, non-malignant antigen-responsive B cells expressing the patient-specific IgH rearrangement coexist in the circulation and probably all lymphoid tissues, with their malignant antigen-independent relatives. However, the significance one attributes to the clonotypic B cells detected in the blood of myeloma patients depends in part on the view one takes of the progression from MGUS to myeloma. An alternative perspective is that MGUS represents a dormant state of malignancy held in check by controlled apoptosis, arrested cell cycling, and/or by immunoregulatory networks. Although lacking in experimental support, if this interpretation were correct, myeloma would occur when the regulatory mechanisms fail, allowing uncontrolled malignant cell renewal. This alternative view would imply that the majority of circulating clonotypic B cells might be malignant. Thus, an analysis of the biology of these clonotypic circulating B cells, with an emphasis on measures of malignancy, is likely to shed considerable light on the events underlying myeloma genesis, progression and spread.