The role of the bone marrow microenvironment in disease progression and drug resistance in multiple myeloma in the era of novel agents

Multiple myeloma (MM) the second most frequent hematological malignancy is typically preceded by asymptomatic precursor stages. Genetic alterations alone do not fully explain disease progression, as many are already present in pre-malignant stages, highlighting the critical role of the bone marrow microenvironment (BMME) in supporting malignant transformation, disease progression, and therapy resistance. BMME provide survival cues, mediate adhesion-dependent drug resistance, and orchestrate cytokine networks that protect MM cells from therapeutic stress. Despite the advances made in the past two decades, MM is, in most cases, still an incurable disease. The rising use of T cell redirecting therapy (CAR-T cells and bispecific antibodies) has increased awareness on the importance of the immune microenvironment. In this paper we will review the role of the different components of the BMME putting them in the context of novel therapy, with a special focus on T-cell redirecting therapies, with a glance at future perspectives and developments.