Favorable Progression-Free Survival Associated with Immune Bio-Markers Modulated By Pomalidomide in Relapsed/Refractory Multiple Myeloma: An Analysis of Phase III Study

We have previously shown that immune cells, including regulatory T cells, Th17 cells, myeloid-derived suppressor cells and NK cells are abnormal in multiple myeloma (MM). It is well demonstrated that immune-modulatory drugs like pomalidomide (POM) have shown impact on various immune sub-populations in pre-clinical studies. Relapsed/refractory (RR) MM (N=540) patients were randomized to be bortezomib and dexamethasone (Vd) with or without pomalidomide POM (Vd) in a large Phase III CC4047-MM007 (OPTIMISMM, NCT01734928) study, allowing for critical investigation into the impact of POM on immune cell-subset. We have analyzed 197 RRMM patients utilizing 366 peripheral blood samples collected at screening, day 8 of cycle 1 and day 8 of cycle 3 using 98 immune biomarker-panel with multi-color flow to identify changes with POM exposure in various sub-populations of B, T, & NK cells. The primary objective was to investigate association of PFS with the modulation of predictive and prognostic immune bio-markers by POM. The analyzed patient-treatment cohorts had identical characteristics as the total patient population and was balanced for the 2-treatment arms, overall patient characteristics and response. Among B-Cell-subpopulations, we observed significant up-regulation of B1b cells (CD19+CD43+) and down-regulation of regulatory B cells (Bregs, CD19+CD5+CD43-) by the PVd arm as compared with the Vd arm. A significant increase in MZB cells were observed in both arms. Patients with a higher proportion of either CD19+ B cells or Bregs at screening showed significantly favorable PFS (logrank p value < 0.05) in the PVd arm as compared with the VD arm, which indicates that these markers are predictive of PFS for PVd treatment. Moreover, patients with a higher proportion of either [naïve B cells (CD19+CD27-IgD+)] or [CD95+ B cells that display germinal center differentiation features (CD19+ CD185+) at cycle 1 day 8] showed significantly favorable PFS in PVd arm (logrank p value < 0.05); however, they were not prognostic with the Vd arm alone. This indicates that the early impact of Pom on these cell types may provide a prognostic bio-marker outcome following PVd therapy in B cell-compartment at cycle 1. Among T-Cell subpopulations, we observed that patients with higher proportion of CD4+ T cells at screening showed significantly favorable PFS in PVd arm, indicating a predictive marker. We observed significantly favorable PFS in PVd arm in both patients with a higher number