Multiple myeloma (MM) is associated with significant immunodeficiency involving T, B, NK and NKT cells. Moreover, impact of immunomodulatory agents, such as lenalidomide and pomalidomide (Pom), has been demonstrated in pre-clinical studies, however their in vivo impact on immune function remains unclear.
The large MM007 study in relapsed/refractory MM (N = 540) randomizing patients to receive Pom (PVd) versus placebo (Vd) in combination with bortezomib and dexamethasone provided us a unique opportunity to investigate the impact of Pom on immune cell subsets.
We have analyzed 366 peripheral blood samples collected at screening, day 8 of cycle 1 and day 8 of cycle 3 from 197 RRMM patients entered on this study using a 38 antigen panel with multi-color flow to identify changes in sub-populations of B, T, NK and NKT cells. The primary purpose of the investigation was to identify changes induced by pomalidomide containing regimen, and then to identify changes in responders vs non-responders. The analyzed patient cohort was balanced for the 2-treatment arms, overall patient characteristics and response.
Importantly, amongst the B cell-subsets analyzed (B1a, B1b, IRA-B, B2, MZB, FB and Breg) the Pom-containing regimen induced significant increase in B1b and decrease in Bregs cells at 8 days cycle 1 and persisted after 2 cycles. These changes were observed in both proportion of cells as well as absolute numbers. A significant decrease in MZB and increase in FB cell subpopulations were observed in both arms after the treatment compared to baseline suggesting possible effects of bortezomib and dex combination. Investigation of four T cell sub-populations including memory cell sub-types based on the expression of CCR7 and CD45RA within CD4+ helper T cells and CD8+ CTL cells showed decline in effector memory cells with Pom regimen, while the observed decline in central memory cells with Vd was not observed with addition of Pom. Moreover, significant increase in activated T cell population was observed in patients responding (> PR) to the Pom containing regimen. This was not observed in patients receiving Vd therapy and in non-responders who had significant decrease in CD3+ T cells. Finally, we evaluated impact on NK and NKT cells, specifically on activation (p46 and NKG2D) and suppressive markers (KIRs including CD159a, p75, CD158a and b). Overall, Pom regimen had the most significant effects on NK/NKT cell population. Total percentage of NK cells were significantly elevated following Pom containing regimen as early as day 8 cycle 1 and persisted at cycle 3. Importantly at day 8, cycle 1, NKG2D was upregulated and CD159a downregulated in responders versus non-responders to Pom regimen, suggesting a potential early biomarker. Similar changes were not observed with Vd treatment. In both NK and NKT cells, the single positives (CD159a) KIR expression was significantly decreased in Pom containing regimen but not Vd. However, cells with double positives (CD159a and p75) were significantly decreased in both Vd and PVd arms. On the other hand, the double negatives for these two suppressive KIRs were significantly elevated in only PVd arm.
In summary, this large cohort study identifies specific upregulation of immune stimulating subsets (B, T & NK) vs. downregulation of regulatory subsets specifically following pomalidomide therapy. Early induction of changes suggest a rapid impact of Pom on immune function. Our result also identifies immune changes as possible biomarkers of clinical response following pomalidomide therapy.