Targeting the Microenvironment for Treating Multiple Myeloma

Multiple myeloma (MM) is a malignant, incurable disease characterized by the expansion of monoclonal terminally differentiated plasma cells in the bone marrow. MM is consistently preceded by an asymptomatic monoclonal gammopathy of undetermined significance, and in the absence of myeloma defining events followed by a stage termed smoldering multiple myeloma (SMM), which finally progresses to active myeloma if signs of organ damage are present. The reciprocal interaction between tumor cells and the tumor microenvironment plays a crucial role in the development of MM and the establishment of a tumor-promoting stroma facilitates tumor growth and myeloma progression. Since myeloma cells depend on signals from the bone marrow microenvironment (BMME) for their survival, therapeutic interventions targeting the BMME are a novel and successful strategy for myeloma care. Here, we describe the complex interplay between myeloma cells and the cellular components of the BMME that is essential for MM development and progression. Finally, we present BMME modifying treatment options such as anti-CD38 based therapies, immunomodulatory drugs (IMiDs), CAR T-cell therapies, bispecific antibodies, and antibody-drug conjugates which have significantly improved the long-term outcome of myeloma patients, and thus represent novel therapeutic standards.