Tenfold increased incidence of spontaneous multiple myeloma in long-term immunosuppressed aging C57BL/KaLwRij mice.

Persons undergoing maintenance immunosuppressive treatment (MIST) were shown to be at increased risk for the development of early malignancies, often of cells of the immune system. Very little is known about the late effects of MIST. Some clinical studies indicated an age-related increase in the incidence of plasma-cell disorders, in particular in that of multiple myeloma (MM). In the present study the influence of MIST on the development of monoclonal B-cell proliferative disorders, monoclonal gammopathies (MG), was studied in an animal model, the C57BL/KaLwRij mouse. This strain is known for its susceptibility to develop with aging MG similar to those in humans. Two widely used treatment protocols (azathioprine/prednisolone and Cyclosporin A/prednisolone) were tested in young and adult mice. Both regiments were shown to increase 10-fold the incidence of spontaneous multiple myeloma. Unexpectedly, the same high incidence of MM and in addition the development of a life-shortening lymphoblastic lymphoma were found in a high frequency in the control group that received Cremophor EL only, i.e., the solvent of Cyclosporin A. Repeated experiments with another lot of Cremophor showed a 6-fold increased frequency of NM but no lymphoblastic lymphoma. With respect to the life-span and the incidence of hemopoietic neoplasms the least harmful drugs for MIST appeared to be azathioprine/prednisolone. The results of the experiments in this C57BL/KaLwRij mouse model give a warning for increased incidence of MM in susceptible aging individuals and address a question whether Cremophor EL is a safe solvent for Cyclosporin A.