Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease.

BACKGROUND

Two patients with end-stage renal disease secondary to multiple myelomas were treated with combined kidney and bone marrow transplantation in an effort to achieve donor-specific allotolerance through the induction of mixed lymphohematopoietic chimerism.

METHODS

Two female patients (55 and 50 years of age) with end-stage renal disease secondary to kappa light-chain multiple myelomas received a nonmyeloablative conditioning regimen that consisted of 60 mg/kg cyclophosphamide intravenously (IV) on days -5 and -4; 15 mg/kg equine anti-thymocyte globulin (ATGAM) IV on days -1, +1, and +3; and thymic irradiation (700 cGy) on day -1. On day 0, the recipients underwent kidney transplantation, followed by IV infusion of donor bone marrow (2.7x10(8) and 3.8x10(8) /kg nucleated cells, respectively) obtained from a human leukocyte antigen (HLA)-matched sibling. Cyclosporine A was administered IV at a dose of 5 mg/kg on day -1, then continued orally at 8 to 12 mg/kg per day until days +73 and +77, respectively, after which no further immunosuppression was given. Donor leukocyte infusions (1x10(7) /kg CD3+ T cells) were administered in an attempt to enhance the graft-versus-myeloma effect (days +66 and +112 in the first patient and day +78 in the second patient). Hematopoietic chimerism was monitored weekly by microsatellite assays.

RESULTS

Multilineage lymphohematopoietic chimerism (5%-80% donor CD3+ or CD3- cells, or both) was first detected during the second posttransplant week and was maintained for approximately 12 weeks, after which there was a gradual decline to undetectable levels (<1% donor cells) after day 105 in the first patient and after day 123 in the second patient. In both recipients, the blood urea nitrogen and creatinine levels returned to normal within 3 days. No rejection episodes have occurred. Quantification of urinary kappa light chains revealed a decline from 28 mg/dL to undetectable levels (<2.5 mg/dL) within 29 days in the first case and from 99.8 mg/dL to <10 mg/dL within 50 days in the second case. Both patients continue with normal kidney function and sustained anti-tumor responses, while receiving no immunosuppression for nearly 4 years and 2 years, respectively.

CONCLUSIONS

This nonmyeloablative regimen followed by combined HLA-matched donor bone marrow and renal allotransplantation is the first example of an intentional and clinically applicable approach to inducing renal allograft tolerance and achieving potent and sustained antitumor effects in patients with multiple myeloma.