The Acidic Microenvironment: Is It a Phenotype of All Cancers? A Focus on Multiple Myeloma and Some Analogies with Diabetes Mellitus

Simple Summary Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clone of plasma cells in the bone marrow. Currently, both the disease progression and its therapy are too often followed by a series of complications and the standard treatment for MM is aimed at improving the quality of life and to prolong progression-free survival (PFS), and overall survival (OS) of patients. This review looks at MM therapies from a different sight. It starts from a clear scientific background, suggesting that many malignant tumors have some common phenotype that isolates the tumor from the rest of the body. Between these phenotypes, extracellular acidity exerts a key role and data collected in the last two decades support the use of anti-acidic drugs in the treatment of cancers, including MM. Lastly, as many cancers, MM has some similarities with type II diabetes mellitus (DM) in the mechanism leading to the extracellular acidity, supporting the use of both a wide panel of proton transporters inhibitors and probably also of some anti-DM drugs in the treatment of both MM and DM. Abstract Multiple myeloma (MM) is a hematological malignancy with a poor prognosis while with a long and progressive outcome. To date, the therapeutic options are restricted to few drugs, including thalidomide or its derivates and autologous transplantation including stem-cell transplantation. More recently, the use of both proteasome inhibitors and monoclonal antibodies have been included in MM therapy, but the clinical results are still under evaluation. Unfortunately, death rates (within the 5-year overall survival rates) are still very high (45%), with no relevant improvement over the past 10 years. Here, we discuss data supporting a new therapeutic approach against MM, based on a common phenotype of tumor malignancies, which is the acidic microenvironment. Extracellular acidity drastically reduces the efficacy of both anti-tumor drugs and the immune reaction against tumors. Pre-clinical data have shown that anti-acidic drugs, such as proton pump inhibitors (PPIs), have a potent cytotoxic effect against human MM cells, thus supporting their use in the treatment of this malignancy. Here, we discuss also similarities between MM and type II diabetes mellitus (DM) with high risk of developing MM, suggesting that both anti-diabetic drugs and a hypocaloric diet may help in curing MM patients.