The Immunomodulatory Action of Thalidomide in Patients with Multiple Myeloma Involves a Clonal Expansion of Late-Differentiated Cytotoxic Effector Cells.

Although thalidomide has been reported to increase T cell activity and NK cell cytotoxicity in the blood of patients with multiple myeloma (MM) it is not known whether thalidomide stimulates tumour-specific T cells or causes a general lymphocytosis. We investigated the immunodulatory effects of thalidomide by studying peripheral blood samples from 64 patients in the Australian ALLG MM6 trial, a multicentre randomised phase III study of low-dose thalidomide, prednisolone and Zometa versus prednisolone and Zometa used as post-autologous stem cell transplant (ASCT) maintenance therapy in patients with MM. We have previously demonstrated that TCR Vβ clonal expansions are present in approximately 50% of patients with MM and that their presence correlates with a good prognosis. Sequencing has confirmed that these cells are a clonal expansion of CD3+CD8+CD57+CD28−CD27− late-differentiated cytotoxic effector cells. Flow cytometric analysis of TCR Vβ expansions (24 families) was performed on blood samples from 64 patients enrolled in the MM6 trial both prior to and 12 months post transplant. Prior to transplant, 59% of the 64 patients had TCR Vβ expansions. After thalidomide, T cell expansions were found in a further 8/34 patients compared with 3/30 in the control, no thalidomide group. In the thalidomide group, 70% of the patients had an expansion of more than one T cell clone compared with 32% in the control group (chi²=28.8; p<0.01). In the thalidomide treated patients there was a total of 32 new clones compared with 22 in the patients who did not receive thalidomide. There was a trend for an increase in NK and NKT cells following thalidomide. Further patients will be studied and the prognostic significance will be evaluated but these preliminary studies provide further evidence that thalidomide has an immunomodulatory action in patients with MM and that this is due, at least in part, to a clonal expansion of late-differentiated cytotoxic effector cells.