The overall goal of this Program Project is to identify methods of reducing symptoms in multiple myeloma (MM) in order to deliver the best available therapy to the largest number of patients with this incurable disease. This Program Project focuses on the reduction of disease-related and treatment-related inflammation as a potential cause of many of these symptoms. In this project (Project 4), we propose clincial trials that will directly test whether modulation of inflammation will ease the symptomatic insult of therapy during inducton therapy and during stem cell treatment.
Specific Aim i tests the efficacy of either targeted (anti-TNF) or broad cytokine blockade to prevent treatment-induced neuropathy from thalidomide or bortezomib, an incapacitating toxicity of 2 of the most potent antimyeloma agents used as front-line therapy. We will also examine the effects of these therapies on other treatment-related symptoms.
Specific Aim 2 seeks to determine whether patients at the highest risk of developing severe transplantrelated symptoms (patients who are older, have comorbid conditions, or have amyloidosis) who receive a large dose of hematopoietic stem cells (HSCs) after high-dose melphalan will have less-severe symptoms than patients who receive a standard dose of HSCs.
This aim capitalizes on exciting new data that large numbers of HSCs dramatically decrease the most severe symptoms experienced by patients following AuSCT.
Specific Aim 3 tests the efficacy of IL-6 cytokine blockade in minimizing the most severe symptoms experienced by patients after high-dose melphalan with autologous stem cell support (AuSCT). In addition, the direct effect of each of these interventions on inflammation will be assessed by the measurement of specific inflammatory markers. These findings may directly benefit patients in terms of ameliorating symptom severity during treatment for MM and will further understanding of the mechanisms behind the development of symptoms. Reducing the symptom severity associated with AuSCT for at-risk patients will increase the number of patients who can undergo this strenuous but effective therapy. Finally, we expect to be able to use our results to validate, in humans, some potential pathogenetic mechanisms of treatment-induced neuropathy and post-AuSCT symptoms. Such findings will be extremely valuable in extending the relatively young science of symptom research. Successful completion of these 3 aims will allow us to determine the efficacy of a variety of strategies to reduce treatment-induced symptoms and will suggest avenues to decrease symptoms related to other diseases where aggressive therapies are employed.
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|Colvin, L A; Dougherty, P M (2015) Peripheral neuropathic pain: signs, symptoms, mechanisms, and causes: are they linked? Br J Anaesth 114:361-3|
|Robinson, C R; Dougherty, P M (2015) Spinal astrocyte gap junction and glutamate transporter expression contributes to a rat model of bortezomib-induced peripheral neuropathy. Neuroscience 285:1-10|
|Shi, Qiuling; Wang, Xin Shelley; Li, Guojun et al. (2015) Racial/ethnic disparities in inflammatory gene single-nucleotide polymorphisms as predictors of a high risk for symptom burden in patients with multiple myeloma 1 year after diagnosis. Cancer 121:1138-46|
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|Wang, Xin Shelley; Shi, Qiuling; Williams, Loretta A et al. (2015) Longitudinal analysis of patient-reported symptoms post-autologous stem cell transplant and their relationship to inflammation in patients with multiple myeloma. Leuk Lymphoma 56:1335-41|
|Robinson, Caleb R; Zhang, Hongmei; Dougherty, Patrick M (2014) Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy. Brain Res 1574:6-13|
|Zhang, Haijun; Dougherty, Patrick M (2014) Enhanced excitability of primary sensory neurons and altered gene expression of neuronal ion channels in dorsal root ganglion in paclitaxel-induced peripheral neuropathy. Anesthesiology 120:1463-75|
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