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The patients with end-stage renal disease (ESRD) associated with hematologic malignancy are unique as they are not eligible for kidney transplantation because of the malignancy and for bone marrow transplantation because of renal failure. In contrast to the ESRD patients without malignancy, induction of durable full or mixed chimerism is necessary to induce a graft versus tumor (GvT) effect. With durable chimerism, there is also a risk of GVHD. To achieve potent GvT responses and induce tolerance for the renal allograft, ten patients (median age: 50 years [range: 34-57 years]) with multiple myeloma and ESRD have undergone an HLA-matched combined kidney and bone marrow transplantation (CKBMT) with lead follow-up time of more than 19 years. The initial preparative regimen for HLA matched transplants consisted of high-dose cyclophosphamide (60mg/kg on days -6 and -5), equine antithymocyte globulin (Atgam 15-20 mg/kg on days -1, +1, +3 and +5) and pretransplant thymic irradiation (7Gy on day -1).Cyclosporine was tapered and discontinued as early as day 73 post-transplant. All ten patients achieved mixed chimerism. Two patients developed acute GVHD and three chronic GVHD after their initial transplant. Five of ten patients are alive, two with no evidence of myeloma from 7.2 to 19.2 years post-transplant. Three patients have normal or near-normal renal function without immunosuppression (IS). Two patients with normal renal function off IS were returned to IS because of chronic GVHD. The patient survival of our approach with HLA-matched CKBMT for refractory myeloma has been 100% at 3 years, which is superior to the reported survival of myeloma patients with dialysis dependent ESRD without CKBMT (25% at 3 years). The regimen for HLA matched CKBMT has been revised to a TBI-based conditioning which has consisted of TBI 2-4Gy on day -1, Atgam (20mg/kg on days -3, -1, +3 and +5) and post-transplant CNI. Two patients (one with myeloma and one with systemic AL amyloidosis and myelodysplastic syndrome) have been treated with this regimen. Both developed persistent full donor chimerism (one after a second transplant from the same donor for hematopoietic graft rejection) and are currently doing well without immunosuppression. This approach has recently been extended to HLA haplo-identical CKBMT using post-BMT cyclophosphamide for GVHD prophylaxis. The conditioning regimen consisted of pre- transplant conditioning with Thymoglobulin (replaced with fludarabine after the second patient), low-dose cyclophosphamide, and 2 Gy of TBI. GVHD prophylaxis was post-transplant high-dose cyclophosphamide (50 mg/kg/day on days +3 and +4) followed by tacrolimus and mycophenolate mofetil (MMF) starting on day +5. Five haplo-identical CKBMT have performed and two of them have been off immunosuppression. We conclude that CKBMT can provide both treatment for hematologic malignancy and renal allograft tolerance.