We recently showed that the outcome of
multiple myeloma (MM) patients treated in the REPEAT study (evaluation of
lenalidomide combined with low-dose
cyclophosphamide and
prednisone (REP) in
lenalidomide-refractory MM) was markedly better than what has been described with
cyclophosphamide-
prednisone alone. The outcome with REP was not associated with plasma cell Cereblon expression levels, suggesting that the effect of REP treatment may involve mechanisms independent of plasma cell Cereblon-mediated direct anti-
tumor activity. We therefore hypothesized that immunomodulatory effects contribute to the anti-MM activity of REP treatment, rather than plasma cell Cereblon-mediated effects. Consequently, we now characterized the effect of REP treatment on immune cell subsets in peripheral blood samples collected on day 1 and 14 of cycle 1, as well as on day 1 of cycle 2. We observed a significant mid-cycle decrease in the Cereblon substrate
proteins Ikaros and Aiolos in diverse lymphocyte subsets, which was paralleled by an increase in T-cell activation. These effects were restored to baseline at day one of the second cycle, one week after
lenalidomide interruption. In vitro,
lenalidomide enhanced peripheral blood mononuclear cell-mediated killing of both
lenalidomide-sensitive and
lenalidomide-resistant MM cells in a co-culture system. These results indicate that the Cereblon-mediated immunomodulatory properties of
lenalidomide are maintained in
lenalidomide-refractory MM patients and may contribute to immune-mediated killing of MM cells. Therefore, combining
lenalidomide with other drugs can have potent effects through
immunomodulation, even in patients considered to be
lenalidomide-refractory.