Multiple myeloma remains an incurable B-cell malignancy whose victims survive a median of about 4 years. Over the past decade new therapies and supportive measures have provided incremental gains. No effective monoclonal antibody therapy exists for myeloma, but that is not for want of trying. Promising immunotherapeutic strategies involving CD38, CD20, and other antigens have been touted but did not succeed (Ellis et al, J Immunol. 1995;155:925-37; Maloney et al, Semin Hematol. 1999;36: 30-33; Treon et al, Semin Oncol. 1999;26: 97-106; Ozaki et al, Blood. 1999;93:3922-3930; Gemmel et al, Ann Hematol. 2002;81: 119-123). These therapies failed because the antigens were not pan-specific myeloma cell antigens and, less commonly, because the monoclonals cross-reacted with similar epitopes present on other cell types (eg, spinal neurons), causing unanticipated toxicities. New candidates continue to be put forward (Satoh et al, J Clin Lab Anal. 2002; 16:79-85). In this issue, Kumar and colleagues (page 1075) present flow-cytometric data regarding the CD52 antigen on clonal cells from patients with plasma cell disorders and suggest that clinical trials be developed to test the efficacy of alemtuzumab (Campath-1H), a humanized monoclonal antibody (MoAb) against CD52, in myeloma and primary systemic amyloidosis.
Alemtuzumab antibodies recognize an epitope that consists of the C-terminal peptide and part of the glycosylphosphatidylinositol lipid anchor that binds CD52 to the cell membrane (Hale et al, Blood. 1983;62: 873-882). CD52 is widely and densely expressed on human lymphocytes (T and B cells, monocytes, and some dendritic cells; Ratzinger et al, Blood. 2003;101:1422-1429) and in the male reproductive tract. Alemtuzumab is a human IgG1 that binds to all human IgG Fc receptors and activates both complement and antibody-dependent cellular cytotoxicity (ADCC). Over the past decade anti-CD52 immunotherapy has been used to prevent acute graft-versus-host disease and graft rejection in reduced intensity allogeneic bone marrow transplantation, and to treat chronic lymphocytic leukemia (CLL) and autoimmune diseases. In May 2001 alemtuzumab was approved by the FDA for the treatment of patients with CLL who have failed alkylating agents and fludarabine. Its use has been associated with significant immunosuppression and in the allograft setting with a risk of late infections (Kottaridis et al, Blood. 2000;96;2419-2425).
Why not myeloma? Is alemtuzumab the one? Maybe. But given the track record of prior immunotherapies, a modicum of skepticism is in order. One problem is that the fraction of plasma cells expressing CD52 is low and likely quite variable. Kumar and colleagues report that, of 23 myeloma patients tested, half had CD52 on their malignant plasma cells. They also report that a median of 23% of the malignant plasma cells expressed the antigen and that 7 myeloma cell lines either minimally displayed or did not express CD52. To what degree the CD52 antigen on plasma cells would allow complement activation is also unclear. The clinical trials obviously should be restricted to patients whose malignant plasma cells express a certain density of CD52. The ideal population might be CD52+ myeloma patients with persistent minimally responsive disease within 6 months of autologous hematopoietic cell transplantation, a time when ADCC may be enhanced. Risks of infectious complications and broad-spectrum prophylaxis would be important features of such a trial.
