Date of Graduation
8-2014
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Patrick M. Dougherty
Committee Member
James M. Reuben
Committee Member
Edgar T. Walters
Committee Member
M. Neal Waxham
Committee Member
Jack C. Waymire
Abstract
MULTIPLE MYELOMA AND ITS TREATMENT ALTER PERIPHERAL NERVOUS SYSTEM STRUCTURE AND FUNCTION
Alyssa Katarina Kosturakis, BA
Supervisory Professor: Patrick M. Dougherty, PhD
Peripheral neuropathy is among the most deleterious side effects of frontline chemotherapeutics used to treat prevalent cancers. Chemotherapy-induced peripheral neuropathy (CIPN) refers to the collection of symptoms (e.g. pain, paresthesias and dysesthesias) that develop in distal, glabrous (non-hairy) skin of 20 to 100% of patients treated with chemotherapy. Peripheral neuropathy negatively impacts quality of life in cancer patients and survivors, is refractory to treatment, and is the impetus for dose-reduction and/or cessation of chemotherapy, thereby limiting treatment. Proteasome inhibitor, bortezomib (Velcade®) is an effective treatment of multiple myeloma (MM), but often provokes the development of small fiber, sensory, distal neuropathy in patients. MM is caused by malignancy of plasma cells, which indirectly compromises multiple organ systems. Therefore, the contribution of underlying disease versus chemotherapeutic treatment on the development of sensory deficits in MM patients remains unclear.
This study determined the incidence of subclinical neuropathy in multiple myeloma patients prior to receiving chemotherapy. MM patients underwent quantitative sensory testing (QST), which is a non-invasive battery of tests that provides information about the function of discrete sensory fiber types. Patients exhibited a high incidence (>80%) of one or more subclinical QST deficits, including mechanical stimulation, fine tactile discrimination, and warmth detection thresholds, compared to healthy volunteers. QST also demonstrated enhanced cold pain, sensorimotor deficits, and higher overall neuropathy scores in MM patients. The peripheral innervation of the skin was visualized with non-invasive confocal microscopy and revealed a reduction in the density of touch receptors (Meissner’s corpuscles) that negatively correlated with performance on the Bumps detection task. Therefore, MM patients commonly present with sensory and sensorimotor deficits prior to undergoing treatment, and these deficits appear to be due to disease-related decreases in peripheral innervation density.
This study subsequently evaluated the efficacy of minocycline in the prevention of treatment-emergent bortezomib-induced peripheral neuropathy in a double-blind, placebo-controlled, randomized phase I clinical trial by assessing QST and patient reports. The placebo group did not show changes in sensory thresholds after bortezomib treatment, making it difficult to assess the impact of minocycline on sensory deficits. The minocycline group reported lower rates of tingling that approached statistical significance (P=0.11). Although statistical significance was not reached in patient reports of symptoms, several limitations inherent in the study design and data collection likely impacted the result. Therefore, the use of minocycline to prevent chemotherapy-induced peripheral neuropathy warrants further investigation in a follow-up trial.
Keywords
multiple myeloma, bortezomib, chemotherapy-induced peripheral neuropathy, quantitative sensory testing, Meissner's corpuscle, minocycline