Multiple Myeloma: Molecular Pathogenesis and Disease Evolution

Abstract

Background: Multiple myeloma is the second most common hematologic malignancy, which to date remains incurable despite advances in treatment strategies including the use of novel substances such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies.

Summary: The bone marrow-based disease is preceded by the 2 sequential premalignant conditions: monoclonal gammo-pathy of undetermined significance and smoldering myeloma. Plasma cell leukemia and extramedullary disease occur, when malignant clones lose their dependency on the bone marrow. Key genetic features of these plasma cell dyscrasias include chromosomal aberrations such as translocations and hyperdiploidy, which occur during error-prone physiologic processes in B-cell development. Next-generation sequencing studies have identified mutations in major oncogenic pathways and tumor suppressors, which contribute to the pathogenesis of multiple myeloma and have revealed insights into the clonal evolution of the disease, particularly along different lines of therapy. More recently, the importance of epigenetic alterations and the role of the bone marrow microenvironment, including immune and osteogenic cells, have become evident. Key Messages: We herein review the current knowledge of the pathogenesis of multiple myeloma, which is crucial for the development of novel targeted therapeutic strategies. These can contribute to the endeavor to make multiple myeloma a curable disease.

Keywords: Genetics; Multiple myeloma; Pathogenesis; Plasma cells.

Fig. 1

Key features of multiple myeloma pathogenesis. Errors during physiologic B-cell development can result in primary genetic events such as hyperdiploidy and translocations. Further secondary events, such as mutations in oncogenic pathways, loss of tumor suppressor function through mutation or deletion, epigenetic alterations, and changes in the bone marrow microenvironment, cause the transition to symptomatic myeloma. End-stage disease is characterized by cells circulating in the blood stream/infiltrating other organs. MGUS, monoclonal gammopathy of undetermined significance; SMM, smoldering multiple myeloma; MM, multiple myeloma; EMD, extramedullary disease; PCL, plasma cell leukemia. Illustration adapted from [47].

Fig. 2

Branched clonal evolution patterns in plasma cell disorders. Clonal evolution of MM follows a branched pattern from an original propagating cell to symptomatic disease. Several clones may be present at each stage. Treatment can reset the clonal heterogeneity, and different clones can lead to relapse. MGUS, monoclonal gammopathy of undetermined significance; SMM, smoldering multiple myeloma; MM, multiple myeloma; EMD, extramedullary disease; PCL, plasma cell leukemia. Illustration adapted from [20].