Multiple myeloma (MM) is an incurable but treatable cancer. Patients with MM patients suffer from multiple symptoms caused by their disease and by aggressive treatment, such as autologous transplantation (AuSCT) and novel agents used for induction or maintenance therapy. Symptoms create a """"""""symptom burden"""""""" that cause distress and that can compromise patient's function and cause treatment delays. There is increasing evidence that many of these symptoms may be caused by the deregulation of inflammatory cytokines and their precursors. Built on a large body of literature relating """"""""sickness behavior"""""""" in animals (including pain, sleep disorder, reduced appetite, and decreased activity), we have developed the hypothesis that many cancer-related symptoms might be improved by modulating inflammatory pathways. We and others have shown that circulating inflammatory cytokines (such as interleukin (IL)-6 and TNF) are strongly linked to symptom severity. For example, we have shown that increased IL-6 is related to the severity of a cluster of symptoms during AuSCT in patients with MM. What is not known is whether suppression of these cytokines might reduce or prevent the prevalence and severity of treatment-related symptoms. The objectives of this project are: (i) To use hierarchical dynamic modeling to examine the hypothesis that increases in the levels of inflammatory cytokines and NF-KB drive increases in symptom development in patients with MM that are related to status of disease as well as during cancer therapy (Specific Aims i, 2, 3);(2) We also will use anticytokine agents (cytokine IL-6 antibody CNTO 328) and an NF-KB inhibitor (curcumin) in phase 2 placebo-controlled randomized clinical trials, to test the hypothesis that reduction of specific inflammatory cytokine levels and/or NF-KB activation will reduce symptom expression. This provides an experimental test of the role of specific inflammatory cytokines (IL-i, IL-6, and TNF-a) and their precursors (NF-KB) in symptom development (Specific Aims 2,3). Taken together, these Aims should provide a strong test of our central hypothesis that a causal relationship exists between inflammatory cytokines and symptom production in patients with MM. Our long-term objectives are to characterize the basic mechanisms underlying symptom burden (with particular focus on cytokines and immune mediators), and to provide a rationale for mechanism-driven symptom management. Having the ability to reduce symptom burden or even prevent these consequences from therapy would be of potential benefit to thousands of cancer patients by improving the tolerability of treatment and the quality of their survivorship. PERFORMANCE SITE(S) (organization, city, state) The University of Texas M. D. Anderson Cancer Center Houston, Texas Page 157
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