Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance.

Introduction: Multiple Myeloma (MM) is a plasma cell disease that affects more men than women. Although there is an obvious imbalance in incidence, knowledge on differences in biology and outcome between the sexes is surprisingly rare. Methods: We performed a unicentric retrospective analysis of patients with MM treated at a tertiary cancer center between 2003 and 2018. Results: We present sex-disaggregated analysis of the characteristics and outcome of MM in a cohort of 655 patients (median age at diagnosis 62 years; 363 men with a median age at diagnosis 62 years and 292 women with a median age at diagnosis 63 years, p=0.086). Most patients (n=561, 86%) received myeloma-specific treatment. Median overall survival was 76 months (95% CI 63 – 89) (72 months in men [95% CI 54 – 90] and 83 months in women [95% CI 66 – 100], p=ns). Apart from a higher incidence of moderate and severe anaemia in women (p<0.001) there were no statistically significant differences in the biology of the underlying MM. Similarly, in the group of patients who received high-dose therapy with autologous stem cell transplantation (ASCT, n=313), no statistically significant differences apart from more frequent anaemia in women were detected regarding the biology of the disease. However, there was a trend towards a higher plasma cell infiltration of the bone marrow and towards more frequent high-risk features in women. In contrast, relevant comorbidities were significantly more common in men (for example coronary heart disease in 13% of men vs. 2% of women, p<0.001). Toxicities after ASCT were not significantly different between the sexes with the exception of severe mucositis, which occurred in 22% of men vs. 40% of women (p=0.001). Conclusion: In conclusion, this first sex-disaggregated analysis of MM patients in Germany supports previous findings that survival is comparable amongst sexes, but women experience more toxicity of high-dose therapy. The higher incidence of clinically relevant anaemia in women warrants further investigation to exclude underlying treatable causes.