Donor lymphocyte infusions for multiple myeloma: clinical results and novel perspectives

Abstract

Summary:Donor lymphocyte infusions (DLIs) provide effective therapy for patients with various hematological malignancies who have relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). In patients with multiple myeloma (MM), DLIs can induce response rates of 40-52%. DLIs were employed as treatment for MM relapse or as prophylaxis for relapse in MM patients undergoing allo-HSCT. The clinically most relevant treatment-related morbidity with DLIs is the occurrence of graft-versus-host disease (GVHD). Secondly, graft failure and the immune escape of extramedullary plasmocytoma have been reported. The fact that previous clinical reports have documented graft-versus-myeloma (GVM) activity without GVHD suggests that at least two distinct immunocompetent cell populations mediating GVHD and/or GVM may exist. Further characterization of the effector cells such as T cells and/or NK cells and their targets may help to clarify the immune response that mediates the GVM effect. This review considers the results of clinical approaches with DLI for MM, with emphasis on strategies to prevent GVHD while preserving the GVM effect. Furthermore, currently investigated molecular antigenic targets for the GVM effect such as MM-specific idiotypic determinant of immunglobulin variable regions, several PRAME epitopes and antigenic structures encoded by cancer germline-specific genes as candidates for immunotherapy trials are discussed. Several studies have demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) can provide effective therapy for patients with MM, improve long-term survival and even cure the patient. 1-5 Although high-dose chemotherapy and total body irradiation prior transplantation effectively reduce the plasma-cell burden, donorderived immunocompetent cells have been shown to play an important role in the curative effects of allogeneic HSCT. 4-8 DLI alone have been demonstrated to induce response rates in 40-67% of patients with MM. [9][10][11][12][13][14][15][16][17][18][19][20] Experience was collected with DLI as prophylaxis 9-12 for myeloma relapse or as relapse treatment 13-20 after allo-HSCT.Although a graft-versus-myeloma (GVM) effect has been documented in several case reports and small populations, 13-18 the results must be interpreted with respect to additional chemotherapy preceding DLI administration 19 or interferon (IFN)-a 15,19 for immunological modulation. IFN-a might enhance the GVM effect by increasing the expression of cell-surface molecules necessary for the interaction of effector cells with the neoplastic plama cell 21,22 or by a direct antimyeloma effect. Although some patients seem to respond only to DLI when IFN-a is added, no randomized trial has been performed to evaluate the benefit from the cytokine in addition to DLIs. 23 Furthermore, corticosteroids, the most common employed treatment for graft-versus-host disease (GVHD) occurring after DLI, have antimyeloma activity and thus may contribute to a response.The response rates in the two larger studies (25...

Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation

“…In addition, several of the relapses presented at unusual extramedullary sites, a phenomenon described before in conjunction with DLI. [35][36][37][38][39] Together, these observations are compatible with the notion that immune intervention may have influenced the timing and presentation of leukemia recurrence. Strong indications for the presence of immunological pressure on leukemic AML cells by the emergence of HLA loss variants have been recently reported.…”

Bortezomib and donor lymphocyte infusion in multiple myeloma relapsed after allo-SCT does not result in durable remissions

“…Response rates of 30-50% in relapsed MM patients have been reported. 1,2 Several studies have shown that the novel agents in the treatment of MM bortezomib, thalidomide and lenalidomide, besides their anti-myeloma effect, also have immune-modulating effects that may enhance the graft-versus-myeloma reaction. 3,4 In this retrospective analysis, we evaluated the anti-myeloma effect of bortezomib in combination with DLI in 30 patients with MM relapsed after allo-SCT from two Dutch transplant centres (Nijmegen n ¼ 15 and Utrecht n ¼ 15).…”

In pursuit of the allo-immune response in multiple myeloma: where do we go from here?

“…In the Vancouver series 5 of 14 patients receiving DLI responded. 21 Zeiser et al 48 reviewed the published myeloma DLI data in 2004. Overall 40-52% responded, with 25% having a CR.…”