Immunomodulation by durvalumab and pomalidomide in patients with relapsed/refractory multiple myeloma

Abstract

This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell activation and function in patients with relapsed/refractory (RR) multiple myeloma (MM). Immunologic changes in peripheral blood and bone marrow of patients treated with durvalumab as monotherapy or in combination with pomalidomide with/without dexamethasone were characterized by assessing subsets of immune cells and gene signatures to understand the immunomodulatory effect of the treatment. Soluble PD-L1 levels were elevated at screening in patients with RRMM but did not correlate with response to durvalumab combination therapy. Immune cell subsets were increased in peripheral blood during treatment with durvalumab and pomalidomide, and combination therapy induced significant gene expression changes in the MM tumor microenvironment versus durvalumab alone. Estimation of cell populations based on RNA sequencing data revealed increased monocytes, neutrophils, and natural killer cells with the combination therapy, but not with durvalumab alone. Additionally, multiplex immunofluorescence of bone marrow demonstrated that immune populations were different in responders versus nonresponders to durvalumab plus pomalidomide with dexamethasone therapy. Overall, durvalumab effectively blocked soluble PD-L1; however, durvalumab monotherapy was not associated with immunologic changes, which were observed with combination therapy.

Cellular immunity in the era of modern multiple myeloma therapy

“…Indeed, a larger increase in pomalidomide‐induced T‐cell abundance is associated with a better prognosis 29‐31 . Additionally, Treg abundance is increased after monotherapy and combination therapy 29,33 . Meanwhile, a decrease occurs in the abundance of naïve CD4 + or CD8 + T cells 31‐33 …”

“…Moreover, CD4 + and CD8 + T cells produce more lineage‐related cytokines, including IFN‐γ, TNF‐α, TIM‐3, CXCR3, IL‐2 and IL‐4, whereas NK cells produce TNF‐α and IFN‐γ and CD8 + T and NK cells produce granzyme B and perforin. In B cells, pomalidomide downregulates the expression of CD19, CD79B and BLK 29,33,117 . Meanwhile, the proportions of FOXP3 + Tregs, BTLA + T cells and TIM‐3 + NK cells are increased by pomalidomide therapy 29 .…”

“…However, single‐agent treatment with monoclonal antibodies against PD‐L1 or PD‐1 has proven unsatisfactory, 137‐139 with weak effects on T and NK cell proliferation. By contrast, a more significant increase in activated CD8 + and CD4 + T cells occurs after combinatorial durvalumab and pomalidomide therapy 33 . Meanwhile, pembrolizumab alone weakly stimulates CD8 + expansion, 41 and three clinical trials involving pembrolizumab have been halted by FDA due to an imbalance in the proportion of death between groups 138,140‐142 …”

“…[31][32][33] Pomalidomide not only alters the number and proportion of immune cells but also their function. For example, NK-cell abundance 29,30,33 and activation increase, as evidenced by upregulation of CD16, CD56 and NKG2D. 29 Moreover, CD4 + and CD8 + T cells produce more lineage-related cytokines, including IFN-γ, TNF-α, TIM-3, CXCR3, IL-2 and IL-4, whereas NK cells produce TNF-α and IFN-γ and CD8 + T and NK cells produce granzyme B and perforin.…”

“…[29][30][31] Additionally, Treg abundance is increased after monotherapy and combination therapy. 29,33 Meanwhile, a decrease occurs in the abundance of naïve CD4 + or CD8 + T cells. [31][32][33] Pomalidomide not only alters the number and proportion of immune cells but also their function.…”