Multiple myeloma remains an incurable cancer with standard and even high dose chemotherapy with autologous transplantation; however, allogeneic transplantation (allotx) with a similar conditioning regimen as autotransplantation, may be curative in 25-30 percent of patients. These data raise an important question of a possible graft versus myeloma effect? The infusion of allogeneic peripheral blood mononuclear cells appears to induce complete remissions in patients with CML relapsing after allotx. Preliminary data in myeloma indicates that infusion of donor derived lymphocytes in patients with relapsed myeloma after T-cell depleted allotx is successful in inducing sustained complete remissions. Based on these observations, we propose to test the hypothesis that a graft versus myeloma effect following allotx can be induced by the infusion of donor lymphocytes in refractory myeloma patients. Patients with relapsed or persistent myeloma, following T-cell depleted allotx, will be infused with thymidine kinase (TK) gene-transduced lymphocytes. TK-transduction of the cells allows us to monitor the fate of the infused lymphocytes and provides us with the ability to eliminate these cells specifically, by Ganciclovir infusion in the patient. We propose to infuse the transduced lymphocytes twice, with an attempt to remove lymphocytes by Ganciclovir after the first infusion. These patients will be evaluated for clinical efficacy of the lymphocyte infusions and the infused cells will be examined for the generation of anti-myeloma reactivity. This gives us an opportunity to study GVM with increased safety of TK transduction. Following aims will be pursued:
Specific aim 1 is to evaluate the clinical effect of transduced- lymphocyte infusion by investigating (1) antimyeloma effects of donor T-lymphocytes, (2) efficacy of ganciclovir to decrease or abrogate the clinical manifestations of severe acute and chronic GVHD, and (3) occurrence of bone marrow hypoplasia following transduced-lymphocyte infusions and the role of donor lymphocyte removal with ganciclovir on its prevention.
Specific aim 2 is to evaluate a graft versus myeloma effect by studying the phenotype of lymphocytes involved in the process, the role of various cytokines, specificity of the reaction and the relationship between graft versus host disease and graft versus myeloma effects.
