Conference Correspondent

Phase 3 Study: Daratumumab in Combination with Lenalidomide plus Dexamethasone Induces Clonality Increase and T-Cell Expansion

Conference Correspondent 

The human monoclonal antibody daratumumab functions through several mechanisms of action, and translational studies of single-agent daratumumab have revealed an additional, novel role of immune modulation and increased adaptive immune response.

Chiu and coworkers evaluated T-cell clonality, expansion, and diversity from samples collected in POLLUX (MMY3003), which was a phase 3, randomized, open-label, multicenter study of patients with relapsed/refractory multiple myeloma. Patients were randomized to daratumumab in combination with lenalidomide plus dexamethasone (DRd) or lenalidomide plus dexamethasone alone (Rd). The analysis included 133 patients in the DRd group and 124 patients in the Rd group.

No baseline differences were observed in T-cell repertoire metrics between the treatment arms. Similar to prior findings from daratumumab monotherapy studies, the authors observed a significantly larger increase of T-cell receptor (TCR)-beta clonality in the DRd arm. There was no increase in TCR-beta clonality in the Rd arm.

As well, adding daratumumab to Rd induced a specific clonal expansion of T cells. Estimated richness (diversity), on the other hand, slightly decreased with DRd treatment, but not with Rd treatment.

In both treatment groups, a bigger increase in T-cell fraction was observed with DRd compared with Rd. High baseline TCR richness predicted for better progression-free survival (PFS) with DRd, but not for Rd.

The authors noted that the improved PFS in DRd patients with baseline TCR richness is similar to results obtained with immune checkpoint inhibitors. Together with the significant increase in T-cell clonality, this finding provides further evidence for the immunomodulatory activity of daratumumab, even in combination therapy. They concluded that the data support daratumumab’s immune modulatory mechanisms of action and provide additional insights into the drug’s effect on the TCR when administered in combination with Rd.

Chiu C, et al. ASH 2016. Abstract 4531.

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