Identification of myeloma-specific antigens associated with the Graft-vs-Myeloma effect after donor lymphocyte infusion

The ability of donor lymphocyte infusions (DLI) to induce complete responses (CR) in patients with relapsed myeloma following allogeneic bone marrow transplantation (BMT) provides clear evidence of an effective graft vs myeloma (GVM) response. To identify target antigens of the GVM response, we screened a myeloma cDNA expression library with post-DLI serum from 4 patients with multiple myeloma (MM) who achieved CR after DLI and 1 patient who was in CR before DLI. We identified a panel of 13 gene products reactive with post-DLI serum but negative with pre-DLI and pre-BMT serum. Antibodies to these proteins were not detected in serum from 10 patients who underwent allogeneic BMT without DLI and 5 patients with acute graft versus host disease (GVHD). Minimal reactivity with these proteins was detected in serum from 20 normal donors and 20 patients with chronic GVHD. In contrast, 5 of these proteins were recognized by more than 1 myeloma DLI responder. Testing of serial serum samples showed an association between antibody response and time of best response after DLI. The expression of these genes was evaluated in primary myeloma cells as well as normal plasma cells. One of the B cell antigens identified in these studies was BCMA, a transmembrane receptor of the TNF superfamily that is selectively expressed by mature B cells. Post-DLI patient serum was able to induce complement-mediated lysis and antibody dependent cellular cytotoxicity (ADCC) of transfected cells and primary myeloma cells expressing BCMA. These studies demonstrate that the GVM response is associated with antibody responses to highly expressed myeloma-associated antigens.