Epigenetics is defined as changes in genetic function without alteration of the underlying
genetic code.[1] Dysregulation of normal epigenetic control in plasma cells is being increasingly
described with effects on disease pathogenesis, drug resistance, and plasma cell (PC)
plasticity. Of all epigenetic processes, DNA methylation represents a realistic target
due to a significant role in pathogenesis and easy availability of hypomethylating
agents in routine practice.
The best described epigenetic modification in Multiple Myeloma (MM) included promoter
region methylation of tumor suppressor genes. It is now clear that the overall methylation
pattern in myeloma, as with several other malignancies, is that of global DNA hypomethylation
and promotor region hypermethylation of tumor suppressor genes, leading to genomic
instability and disease progression. In MM, the pattern of DNA methylation varies
depending on the stage at which MM cell lines are studied. In an elegant analysis,
PCs from patients with MGUS, Smouldering Multiple Myeloma, and MM are shown to demonstrate
a serial increase in differentially methylated loci (DMLs) with disease progression.[2] These modifications also have a potential prognostic role. For instance, as described
by Choudhary et al,[3] Patterns of aberrant methylation can provide prognostic information in patients
with newly diagnosed myeloma.
This mechanism has been exploited for evaluation of hypomethylating agents (HMAs)
as potentially active agents in MM. As far back in 2008, azacytidine was shown to
be active against MM cell lines in vitro by causing de methylation of p16, theoretically
restoring its tumor suppressor function. Interestingly, exposure to azacytidine also
inhibited interleukin (IL)-6 production which plays a key role in end-organ damage
mediated by plasma cells. Both these processes led to apoptosis of MM cells in vitro,
indicating potential clinical utility.[4] Azacytidine has also been shown to have synergistic activity with several chemotherapeutic
agents used in MM. For instance, bortezomib and doxorubicin have been shown to sensitize
PCs in MM to the effects of azacytidine by synergistic induction of double strand
DNA breaks.[5]
A recent phase-1 clinical study in 2020 evaluated the utility of azacytidine in combination
with lenalidomide for patients with relapsed/refractory myeloma with median of five
lines of therapy. It was noted that azacytidine restored the sensitivity of plasma
cells to lenalidomide by reactivation of pathways controlling plasma cell differentiation.
This translated into an overall response rate of 22% and progression-free survival
(PFS) of 3.1 months.[6] Similar findings were noted by Kallf et al,[7] With oral azacytidine enabling a median PFS of 2.6 months in patients with lenalidomide
refractory myeloma.
Identification of this novel mechanism of disease pathogenesis provides a potentially
new target in MM. This pathway is especially attractive, as HMAs have been in clinical
use for over a decade for acute myeloid leukemia with excellent data on toxicity and
clinical use. Although several questions concerning clinical implications of plasma
cell DNA methylation remain unanswered, development of further clinical data can potentially
provide us a new, inexpensive treatment option for patients with MM.
