Nontraditional cytotoxic therapies for relapsed/refractory multiple myeloma.
Multiple myeloma remains an incurable disease, with median survival rates of 4-6 years even with aggressive, high-dose chemotherapy, bone marrow transplantation, and intensive supportive care. Additionally, multiple myeloma is primarily a disease of the elderly, many of whom cannot tolerate aggressive chemotherapy. Thus, newer treatments with good safety profiles are needed to improve the quality of responses and, hopefully, to translate into prolonged progression and overall survival. The pathophysiology of multiple myeloma is complex, involving many pathways and interactions among cytokines, adhesion molecules, angiogenesis, and mechanisms of resistance, which, taken together, provide multiple targets for novel therapeutic modalities. Agents currently under investigation for treating multiple myeloma include thalidomide and its successors, PS-341, and arsenic trioxide. Thalidomide and immunomodulatory drugs both exhibit activity against multiple myeloma by affecting different levels of the immune system. PS-341 is a proteasome inhibitor that halts the cell cycle, resulting in apoptosis; it also inhibits a key transcription factor and may have antiangiogenic activity. Arsenic trioxide activates multicellular mechanisms to induce apoptosis, inhibit angiogenesis, and stimulate immune responses. Preclinical and early clinical data suggest that combination regimens should be pursued, given the different mechanisms of action of these compounds on the immune system and their non-overlapping toxicities at low dosages.
Hussein
Mohamad A
MA
Cleveland Clinic Myeloma Research Program, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio 44195, USA. husseim@ccf.org
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D015815:Cell Adhesion Molecules / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010087:Oxides / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D013792:Thalidomide / Q000627:therapeutic use*; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001152:Arsenicals; D001897:Boronic Acids; D015815:Cell Adhesion Molecules; D016207:Cytokines; D010087:Oxides; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D000077237:Arsenic Trioxide