Analysis of immunodeficiency in multiple myeloma: Observations and hypothesis

Abstract

Patients with multiple myeloma suffer from often profound immunodeficiency that seriously compromises both longevity and quality of life. The cellular basis for the immunodeficiency is unknown and the mechanism(s) giving rise to and possibly maintaining it is also unknown. In this review, evidence defining cellular defects in the nonmalignant B and T peripheral blood lymphocyte pool is summarized and discussed in terms of possible mechanisms that could give rise to the abberrant immune phenotype characteristic of many patients. The abnormalities we have defined include a deficiency of mature B lymphocytes, presence of often large numbers of pre-B cells in the blood, arrested differentiation of B cells into immunoglobulin (lg)-secreting cells, and abnormal progenitorlike T cells in blood. The specificity repertoire of the remaining B lymphocyte population is heavily skewed toward recognition of idiotypic and shared epitopes on the variable region of Ig, perhaps reflecting immune reaction with the monoclonal myeloma Ig. This may begin as a response to tumor antigen that gradually progresses to autoimmunity. A second subset of B cells present at abnormally high frequency in myeloma patients is that of antigen-experienced memory B cells, which probably encountered antigen prior to the events leading to frank myeloma. In this instance, the high frequency reflects a decrease in aggregate numbers of B cells, although it seems likely that expansion of memory clones also occurs. This is exemplified by the set of memory B cells specific for tetanus toxoid, which are present at normal number but highly enriched frequency in myeloma PBL. Both the antitumor B cells (anti-idiotype, and anti-Ig) and the memory cells specific for environmental pathogens appear to be arrested in their differentiation to Ig-secretors as evidenced by the lack of serum antibody in patients. The above observations are interpreted in terms of the hypothesis that immunoregulatory events triggered by the monoclonal myeloma Ig establish and maintain the immunodeficiency. We speculate that autoimmune suppressor T cells specific for conserved determinants of Ig prevent pre-B cell differentiation to slg + B cells, and B cell terminal differentiation to Ig-secretors. If correct, this analysis could lead to therapeutic approaches for the reversal of the immunodeficiency and perhaps some degree of control over the malignant growth.