Mechanisms of Symptoms of Multiple Myeloma and Its Therapy

描述（由申请人提供）：癌症患者有多种症状，如疼痛、疲劳、睡眠障碍、食欲差等，这些症状会造成严重的痛苦，影响功能和康复，并可能导致治疗延误或过早终止治疗。这些症状是由癌症和治疗引起的。当癌症无法治愈时，如多发性骨髓瘤（MM），积极治疗的副作用和最佳功能之间的平衡变得至关重要。越来越多的证据表明，这些症状中的一些可能聚集在一起，并具有共同的生理机制，形成一种“症状负担”，这是肿瘤负担的主观对应物。动物“疾病行为”模型的最新演变与接受治疗的癌症患者报告的症状惊人相似(Cleeland et al., 2003; Lee et al., 2004；

DESCRIPTION (provided by applicant): Patients with cancer have multiple symptoms, such as pain, fatigue, sleep disturbance, and poor appetite that cause significant distress, impair function and rehabilitation, and may cause treatment delays or premature treatment termination. These symptoms are caused by both the cancer and its therapy. When the cancer is incurable, as is multiple myeloma (MM), the balance between the side effects of aggressive treatment and optimal function becomes critical. There is growing evidence that some of these symptoms may cluster together and share common physiologic mechanisms, creating a "symptom burden" that is the subjective counterpart of tumor burden. The recent evolution of the animal "sickness behavior" model which is strikingly similar to symptoms reported by cancer patients undergoing treatment (Cleeland et al., 2003; Lee et al., 2004, Dantzer & Kelley, 2007), presents an exciting opportunity I) to test for possible physiologic mechanisms of symptom production, and 2) to examine new strategies to reduce or prevent cancer-related symptoms. The overall hypothesis to be tested in this program project is that increases in specific proinflammatory cytokines, especially IL-I, IL-6 and TNF-a, and activation of their precursor, NF-kb, are associated with the emergence of individual symptoms or clusters of treatment-related symptoms, and that modulation of these inflammatory pathways will reduce both the prevalence and severity of symptoms. Preliminary data presented for this program are supportive of this hypothesis. A project of this nature necessitates a broadly based integrated and multidisciplinary Program Project that includes expertise in longitudinal symptom assessment, immunology, quantative motor and sensory assessment, and animal models of symptoms and disease where mechanisms of symptom expression can be examined. A special requirement is for the development of statistical models that can account for the relationship of symptom and biological variables over time. Components of the individual projects will follow MM patients from diagnosis through induction therapy, transplantation, and maintenance therapy. MM presents an ideal disease to test these hypotheses, since proinflammatory cytokines play a major role in the development of the disease, aggressive treatments exacerbate production of proinflammatory cytokines and, in recent years, there has been an increase in knowledge about and availability of agents for inflammatory blockade that make mechanistic symptom control a real possibility in the trajectory of this disease. Our long-term objective is to create a foundation for a mechanism-driven symptom control strategy for managing disease and treatment-related symptoms. Having the ability to reduce symptom burden or even prevent these consequences from therapy would be of potential benefit to thousands of cancer patients and survivors by improving the tolerability of treatment and reducing posttreatment residual symptoms.