New insights into the knowledge of graft-versus-myeloma

Application of chemo(radio)therapy at doses requiring hematopoietic stem cell support has been challenging in multiple myeloma (MM). Extensive clinical trials conducted over the last decade and involving many thousands of patients have shown the ability of high-dose therapy to overcome, at least in part, chemoresistance, thereby increasing the complete remission (CR) rate up to the 40% to 50% range and providing a survival prolongation of 12 to 15 months in comparison with conventional chemotherapy.¹ 

Compared with autologous transplantation, allogeneic stem cell transplantation in patients with MM has been reported to effect more frequent molecular remissions, approaching 50%,^2,3  and more durable duration of disease control. Based on these observations, the existence of an allogeneic immune response against residual myeloma cells in vivo (graft-versus-myeloma [GVM]) has been postulated. Direct evidence for a GVM effect came from clinical studies of donor lymphocyte infusion(s) (DLI) in patients relapsing after a T-cell–depleted allogeneic transplantation. In several of these studies, response (both complete and partial) to DLI occurred in 35% to 50% of patients and was more frequently, albeit not always, associated with the development of acute and chronic graft-versus-host disease (GVHD). Disappointingly, most CRs were not durable and the probability of these patients remaining alive and free of disease at more than one year after DLI was less than 20%. Efforts to increase the efficacy of GVM and to separate the benefits of the immune response from the toxicity of GVHD should be made in an attempt to improve the outcome of patients receiving allogeneic stem cell transplantation.

In this issue, Bellucci and colleagues (page 656) provide new insights into the knowledge of the immunologic mechanisms and target antigens of the GVM response. To address these issues, the authors screened a cDNA expression library with serum samples from 4 patients who underwent T-cell–depleted allogeneic bone marrow transplantation (BMT) for relapsed MM and attained CR following the subsequent prophylactic infusion of CD8⁺ T-cell–depleted donor lymphocytes. Library screening with early and late post-DLI serum from these patients resulted in the identification of a panel of 13 antigens representing a diverse set of cellular proteins. High-titer antibody response against these proteins was detected in all 4 patients who responded to DLI, but was absent in their serum taken before BMT or DLI. However, no or minimal reactivity was detected in serum from healthy individuals, from MM patients who failed to respond to DLI, from patients who did not receive DLI after BMT, or from patients with either acute or chronic GVHD. Testing of serum samples from DLI responders showed that antibody response to the antigens was closely associated with the time of best antitumor response, suggesting that these proteins were potential targets of the immune response. Of these antigens, 5 were detected in more than 1 patient in CR following DLI. Using Northern blot analysis and oligonucleotide microarrays, the authors found that the corresponding genes were expressed in MM primary cells and in myeloma cell lines at higher levels than in plasma cells from healthy individuals or from patients with monoclonal gammopathy of undetermined significance.

The advent of DLI and the documented effect of the allogeneic immune response against residual tumor cells in vivo have brought about a shift in the field of allogeneic stem cell transplantation for the treatment of hematologic malignancies. Nonmyeloablative conditioning regimens that reduce the early complications and mortality of transplantation while retaining an immune response sufficient to induce remissions are increasingly used and increase the number of candidates for allogeneic transplantation. In MM, preliminary reports are promising, particularly if allogeneic transplantation is applied front-line, following an autologous transplantation to reduce the tumor burden.⁴  Such treatments are frequently combined with DLI. Immunogenic antigens that are highly expressed in primary myeloma cells, such as those characterized by Bellucci et al and reported in this issue, might be appropriate targets for potential immunotherapies aimed to enhance the antimyeloma activity in the near future.