Iberdomide (CC-220) Has Synergistic Anti-Tumor and Immunostimulatory Activity Against Multiple Myeloma in Combination with Both Bortezomib and Dexamethasone, or in Combination with Daratumumab in Vitro

Despite significant progress in the treatment of multiple myeloma (MM), the disease remains incurable. Multiple targeted and biologics-based therapies, including immunomodulatory agent IMiD^® compounds (lenalidomide and pomalidomide), proteasome inhibitors (bortezomib and carfilzomib), and monoclonal antibodies (daratumumab and elotuzumab) have shown impressive activity in treating advanced MM. Moreover, triplet regimens combining these agents have consistently proven to be more efficacious than doublets in heavily pretreated patients with limited additional toxic effects. Iberdomide (CC-220) is a novel compound being investigated in a phase I/II study (clinicaltrials.gov NCT02773030) for treatment of lenalidomide- and pomalidomide-relapsed/refractory MM (RRMM) in combination with dexamethasone. Preclinical studies of iberdomide have shown that it more potently binds to cereblon than other cereblon-binding compounds, is more efficient at degrading Aiolos and Ikaros, and has enhanced immunomodulatory activity, inducing greater interleukin-2 secretion and granzyme-b degranulation in immune cells (Matyskiela et al and Bjorklund et al, submitted abstract). Clinical studies of bortezomib and daratumumab in combination with other cereblon-binding agents have demonstrated high tolerability with notable efficacy in the RRMM setting; however, these combinations with iberdomide have not been investigated. Here we show in MM cell lines that iberdomide induces deep Aiolos and Ikaros degradation in the presence of bortezomib at clinically relevant concentrations as determined in healthy volunteers. Furthermore, iberdomide treatment in combination with bortezomib produced synergistic antiproliferative activity and deeper induction of apoptosis than combinations of other clinically approved cereblon-binding compounds with bortezomib across multiple cell lines. In addition, adding dexamethasone resulted in further synergistic antiproliferative activity. In combination with daratumumab, iberdomide also had synergistic anti-MM activity in Complement-Dependent Cytotoxicity (CDC) assays. In co-culture systems using myeloma and immune cells, iberdomide significantly increased the antibody-dependent cellular cytotoxic activity of daratumumab. While iberdomide treatment of MM cell lines resulted in increased CD38 surface expression, combinations were more effective when peripheral blood mononuclear cells (PBMCs) were pretreated, suggesting that iberdomide immunomodulatory activity is a significant contributor to the synergy observed. Interestingly, pretreatment of PBMCs with daratumumab resulted in reduced efficacy of the combination. We observed that the treatment of PBMCs with daratumumab resulted in killing of natural killer (NK) cells in the PBMC culture. In contrast, treatment of PBMCs with iberdomide resulted in proliferation of NK cells, possibly helping to rescue the antagonistic effect of daratumumab on NK cell-mediated antibody‐dependent cellular cytotoxicity. Taken together, these preclinical data support further investigation of iberdomide in combination with both bortezomib/dexamethasone and daratumumab in the clinic.