Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 -5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents -small molecules as well as therapeutic antibodies -that hold promise to further improve outcome in MM.
Keywordsbone marrow microenvironment; combination therapy; multiple myeloma
BackgroundMultiple myeloma (MM) is a clonal plasma cell malignancy with a highly heterogeneous genetic background, characterized by bone marrow (BM) plasmocytosis, production of monoclonal proteins, osteolytic bone lesions, renal disease, anemia, hypercalcemia, and immunodeficiency. Its development is a complex multistep process involving both early and late genetic changes in the tumor cell, as well as selective supportive conditions in the BM microenvironment. Specifically, MM cells disrupt homeostasis of stromal cell-stromal cell and stromal cell-extracellular matrix interactions and liquid factors (cytokines and growth factors). Tumor cells thereby induce direct as well as indirect signaling sequelae in the BM, which in turn supports MM cell proliferation, survival, migration, and drug resistance. MM bone disease, which occurs in 80% of MM patients, reflects an imbalance of osteoblast and
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript osteoclast activity and is characterized by severe bone pain (25%), pathologic nonvertebral (12%) and vertebral (30%) fractures, and hypercalcemia (13%). These skeletal-related events (SRE) not only have a negative impact on patients' quality of life, but also reduce their survival [1].Although MM was first described in the mid 1850s, successful treatment was begun using a combination of melphalan and prednisone in the late 1960s and achieved a median survival of 3 -4 years. Treatment regimens were further improved with the introduction of high-dose therapy with autologous stem cell transplantation (SCT). However, it was not until the late 1990s that a new era of MM treatment was initiated with the introduction of thalidomide (Thal), and later its ana...
