Graft-versus-myeloma after withdrawal of immunosuppression following allogeneic peripheral stem cell transplantation

Abstract

Summary:There is growing evidence for a graft-versus-myeloma effect following allogeneic stem cell transplantation. We add to this evidence by reporting complete remission achieved by withdrawal of immunosuppression in a patient with multiple myeloma progressing after HLAidentical sibling peripheral stem cell transplantation. De novo chronic graft-versus-host disease coincided with the anti-myeloma effect and responded to treatment. The patient remains in complete remission 3 years after transplant. Keywords: multiple myeloma; graft-versus-myeloma; graft-versus-leukemia; allogeneic stem cell transplantationThe graft-versus-leukemia effect (GVL) is important in eradicating residual leukemia after allogeneic stem cell transplantation (SCT). Clinical evidence for GVL is found in higher relapse rates after autologous or syngeneic transplants as compared to allogeneic transplants, and in higher relapse rates in patients without graft-versus-host disease (GVHD) or in recipients of T cell-depleted transplants. 1 Induction of GVL has become an important option for treatment of relapse after allogeneic SCT. 2-4 GVL can be induced by infusion of donor lymphocytes (DLI) and occasionally by rapid tapering of immunosuppression. These immunological interventions, supported occasionally by administration of cytokines (IFN-␣, IL-2) result in significant proportions of complete remissions. 2-5 GVL susceptibility differs among leukemias. Stronger GVL is observed in CML and weaker effects in patients with ALL. 3 High relapse rates of multiple myeloma (MM) after autologous SCT suggest that myeloablative conditioning regimens are incapable of eradicating the disease. Lower relapse rates after allogeneic SCT may be due to additional immunological reactivity of the allograft analogous to the well characterized GVL effect. 6 A graft-versus-myeloma (GVM) effect, is further demonstrated by response to DLI to treat relapsed myeloma after allogeneic SCT 7-13 and this has recently been reviewed. 8 However, data on GVM after withdrawal of immunosuppression are limited. We add to the ongoing discussion by documenting an impressive response to withdrawal of immunosuppression in a patient with multiple myeloma progressing after HLA-identical sibling transplantation. Case reportA 37-year-old female was diagnosed with multiple myeloma IgG lambda, stage IIIA in January 1996. Diagnosis was based on presence of a major gammopathy of 45.7 g/l (normal values for ␥-globulins: 6.2-14.4 g/l), bone marrow infiltration with Ͼ30% atypical plasma cells, multiple osteolytic lesions (skull, humerus, pelvis, shoulder girdle), and trace positive Bence-Jones proteinuria. Hemoglobin was 12.5 g/dl, calcium, creatinine and ␤-2-microglobulin were within normal range. She was treated with three cycles of VAD (vincristine, adriamycin, dexamethasone) with minimal response: 14,15 ␥-globulins decreased to 36.4 g/l, Bence-Jones proteinuria became negative, plasma cell infiltration of more than 30% persisted.On 28 August 1996, she underwent allogeneic peripheral blood stem ...

High rate of remission and low rate of disease recurrence in patients with multiple myeloma allografted with PBSC from their HLA-identical sibling donors

“…The key role of allogeneic T cells is strengthened by the results of donor lymphocyte infusions after failure of T-cell depleted allografts: in most cases, the response came along with GVHD emergence. 29,[36][37][38][39] In the present study, we attempted to analyze the influence of the following factors on TRM, OS, and EFS: age (o49 vs X49 years), sex, Ig-class, stage, time to transplant, previous autograft, status at transplantation, number of CD34+ and CD3+ cells infused, aGVHD, and cGVHD. A significantly negative influence on TRM was found only for aGVHD (P ¼ 0.0068), which also negatively influenced OS (P ¼ 0.0047).…”

Allogeneic stem cell transplantation for multiple myeloma: is there a future?

“…52 There is a report of complete remission in a patient after immunosuppression withdrawal in patient progressing after allo-SCT. 9 Other new promising immune therapies include anti-PD1 agents, vaccines and CAR T-cell approaches in MM and monoclonal Abs against CD38. 8,[53][54][55][56] Abbreviations: Auto-HCT = autogeneic hematopoietic cell transplantation; CIBMTR = Center for International Blood and Marrow Transplant Research; m = months; NRM = non-relapse mortality; NS = not stated; OS = overall survival; RIC = reduced-intensity conditioning; RR = relapse rate; yrs = years.…”

“…Currently, there is clear evidence of cures in MM with allogeneic transplant (allogeneic hematopoietic cell transplantation (allo-SCT)) as documented by older myeloablative preparative regimens, immunosuppressive agent withdrawal and/or donor lymphocyte infusions (DLIs). 9,10 However, the role of allo-SCT remains controversial owing to reports of varying benefit and the associated high transplant-related mortality (TRM). 11,12 Despite these concerns, interest persists in striving for a curative therapy for an incurable malignancy.…”

The allogeneic dilemma

“…While attempts to reduce GVHD have frequently been associated with a higher incidence of relapse, small retrospective studies were in favor of a graftversus-myeloma effect associated with GVHD. 12,13 Proof of the graft-versus-myeloma effect was obtained by the occurrence of remissions following donor lymphocyte infusions in patients relapsing after allogeneic SCT. [14][15][16] Again, the likelihood of a graft-versus-myeloma effect was higher in patients with GVHD.…”