Daratumumab in Combination with Lenalidomide Plus Dexamethasone Induces Clonality Increase and T-Cell Expansion: Results from a Phase 3 Randomized Study (POLLUX)

Introduction: Daratumumab (DARA) is a human monoclonal IgG1κ CD38-targeting antibody that functions through several mechanisms of action (MOA), including CDC, ADCC, ADCP and induction of apoptosis. An additional, novel role of immune modulation and increased adaptive immune response was revealed from translational studies of DARA (16 mg/kg) in single-agent, phase 1/2 studies (SIRIUS [MMY2002] and GEN501; Krejcik J et al, Blood 2016;128:384-94). To further explore the ability of DARA to promote adaptive T-cell responses, we profiled T-cell repertoires (TCR) to evaluate T-cell clonality, expansion, and diversity from samples collected in POLLUX (MMY3003), a phase 3, randomized, open-label, multicenter study for patients with relapsed/refractory MM, in which DARA was tested in combination with lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone alone (DRd vs. Rd; Dimopoulos MA et al, N Engl J Med 2016; in press).

Methods: T-cell receptor beta (TCRβ) sequencing for repertoire profiling was conducted on whole blood samples collected at baseline and eight weeks after DARA treatment (cycle 3 [C3]) from subjects on both arms using the ImmunoSEQ assay (Adaptive Biotechnologies. Seattle, WA, USA). 133 subjects in DRd and 124 subjects in Rd treatment groups were included in this analysis and represented a balanced subgroup of the POLLUX clinical trial subjects. T-cell metric changes were compared between arms with ANOVA, including the treatment arm and visit interaction term. Within treatment-arm changes were evaluated with a Wilcoxon signed-rank test comparing baseline to on-treatment values per patient.

Results: Consistent with the randomized treatment groups, no baseline differences were observed in T-cell repertoire metrics between the treatment arms, including T-cell clonality, diversity (or richness), and T-cell fraction. Similar to prior findings from DARA monotherapy studies, significantly larger increase of TCRβ clonality was observed in the DRd arm (median of 0.166 at baseline to 0.263 at C3). Interestingly, there was no increase in TCRβ clonality in the Rd arm (median of 0.175 at baseline to 0.175 at C3). The change in TCRβ clonality between C1 and C3 was significantly different between DRd and Rd (p=3.26E-10), demonstrating that the addition of DARA to Rd induces a specific clonal expansion of T cells. Estimated richness (diversity), on the other hand, slightly decreased with DRd treatment but not with Rd treatment (median of 503,951 at baseline to 427,096 at C3 [p= 1.01E-04] vs 572,182 to 532,806 [p= 3.58-01]). Among patients in both treatment groups, a bigger increase in T-cell fraction was observed in DRd vs Rd (median of 0.231 at baseline to 0.278 at C3 [p= 2.62E-3] vs 0.228 to 0.249 [p= 1.91E-01]). Although there were no significant differences in baseline characteristics in T-cell clonality, richness, and T-cell fraction, quartile analysis demonstrated that high baseline TCR richness predicted for better PFS with DRd but not for Rd.

Conclusion: DARA in combination with lenalidomide plus dexamethasone specifically induced robust increases in T-cell clonality, which was not observed within the control lenalidomide plus dexamethasone arm. Interestingly, baseline TCR richness was associated with improved PFS in DRd subjects. This observation is similar to results with immune checkpoint inhibitors (Postow MA et al, J Immunother Cancer 2015;3:23), and together with the significant increase in T-cell clonality, provides further evidence for the immunomodulatory activity of DARA, even in combination therapy. These data support DARA's immune-modulatory MOA and provide additional insights into DARA's effect on the TCR in combination with standard of care treatment.

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