Sleep Measured by Polysomnography in Patients Receiving High-Dose Chemotherapy for Multiple Myeloma Prior to Stem Cell Transplantation

Sleep-wake disturbances are common among patients with cancer (Berger, 2009; Berger et al., 2005; Davidson, Maclean, Brundage, & Schulze, 2002; Sateia & Lang, 2008; Savard, Ivers, Villa, Caplette-Gingras, & Morin, 2011), and are multifactorial in origin (Vena, Parker, Cunningham, Clark, & McMillan, 2004). Among cancer populations, sleep has been studied extensively among patients with breast or lung cancer either subjectively or in combination with actigraphy (ACTG). Although convenient, ACTG assesses only motion or its absence as a proxy of wakefulness or sleep (Tyron, 1991). The sleep of patients with all types of cancer has been studied less extensively using polysomnography (PSG). PSG is considered the gold standard of objective sleep measurement because it assesses and records electroencephalographic sleep changes (Dement, 2011). The current study is the first to describe sleep using PSG in patients with multiple myeloma (MM). MM involves the development of abnormal plasma cells that collect in bone marrow and damage bone. Myeloma cells produce abnormal antibodies called plasma M proteins that accumulate in organs such as the kidneys, resulting in renal damage and failure. An estimated 21,000 new cases of MM, the most common type of plasma cell cancer, were diagnosed in the United States in 2012 (National Cancer Institute [NCI], 2012). MM usually develops in adults older than 65 years and is most common among African Americans and men (NCI, 2012). Disease-related risk factors that may impair sleep in patients with MM include bone pain and peripheral neuropathy, which are among the most common neurologic symptoms of plasma cell cancer (Mangan, 2005). Opiates, often used to manage bone pain, are associated with drowsiness (Rome, 2010), which may contribute to daytime activity and excessive daytime napping, decreasing the homeostatic sleep drive and disrupting circadian rhythms. Treatment-related risk factors that may impair sleep include pain related to oral mucositis and peripheral neuropathy (Palumbo et al., 2008). Oral mucositis is a common side effect of chemotherapy, particularly with intensive treatment (Niscola et al., 2006). Chemotherapy- induced peripheral neuropathy has been well-established in relation to several agents used for MM therapy (such as thalidomide and bortezomib) (Chaudhry, Combiath, Polydefkis, Ferguson, & Borrello, 2008; Delforge et al., 2010; El-Cheikh et al., 2008), and associated sensory symptoms usually are worse at night (Snowden et al., 2011). Other treatment-related side effects include insomnia associated with adjunct corticosteroids (Faiman, Bilotti, Mangan, & Rogers, 2008) and daytime sleepiness and fatigue associated with thalidomide (Celgene Corporation, 2006). Those factors place patients with MM at higher risk for insomnia, noted as a common problem for patients with cancer (Savard et al., 2011). Common complications with MM and its treatment may indirectly contribute to sleep disturbance. Anemia, renal failure, and peripheral neuropathy (Berenson, 2005) are related to iron deficiency, renal disease, and neuropathy, which are major risk factors for restless legs syndrome (RLS) and periodic limb movements (PLMs) (Allen & Earley, 2007; National Center on Sleep Disorders Research, n.d.). Anemia in MM is associated with inadequate erythropoietin production and responsiveness, decreased red blood cell lifespan, and incorrect release of iron from macrophages (normal to high iron stores with low serum iron) (Ludwig & Osterborg, 2010). Renal disease in MM is associated with the immunoglobulin products (M proteins) of monoclonal plasma cells in the bone marrow, which form kidney deposits typically progressing to renal tubular, glomerular, and vascular pathology and failure (Soloman, Weiss, & Herrera, 2010). Those disease-related factors may predispose patients with MM to develop secondary sleep disorders such as RLS and PLMs. Psychosocial factors, such as anxiety, are theorized to be experienced by patients with cancer from the time of diagnosis through completion of induction therapy (Sherman, Simonton, Latif, Plante, & Anaissie, 2009) and may impact sleep. Depression highly correlates with sleep disturbance even before chemotherapy (Phillips, Jim, Donovan, Pinder-Schenck, & Jacobsen, 2012). In addition, depression and anxiety have been associated strongly with sleep problems in older patients with cancer during and following treatment (Sharma et al., 2011). Coleman et al. (2010) reported disturbed sleep and mood in patients with MM. Unpublished findings from that study suggested that total mood disturbance negatively correlated with sleep efficiency, a measure of how long patients slept while in bed attempting to sleep. Sleep efficiency also is considered an objective reflection of subjective sleep quality, the perception of sleep as restorative for function (Van Cauter & Allostatic Working Group, 1997). Therefore, mood disturbance may contribute to the risk of sleep disturbance in patients with MM. Sleep disturbance in patients with MM may result in alteration of normal sleep types, stages, and variables in the daily sleep-wake pattern. Non–rapid eye movement (NREM) sleep is characterized by progression to deep sleep with decreased responsiveness to stimuli and retained muscle tone. Stages 1 and 2 of NREM sleep often are referred to as light sleep, and stages 3 and 4 as deep or slow-wave sleep. Rapid eye movement (REM) sleep is characterized by dreaming, varied responsiveness to stimuli, paralysis of voluntary muscles, increased vital signs and cerebral blood flow, and decreased temperature regulation. A typical night of sleep is composed of four to six 90–110 minute cycles of NREM and REM sleep. Total sleep time is predominantly composed of 75%–80% NREM sleep and 20%–25% REM sleep (Carskadon & Dement, 2005). The inability to attain adequate amounts of deep NREM or REM sleep may change the quality or restorative potential of sleep. Those changes also may be reflected through alterations in sleep variables such as sleep onset latency (time taken to fall asleep), wake time after sleep onset (time spent awake after initial onset of sleep), and sleep efficiency (amount of time spent asleep while attempting to sleep) in addition to the duration of total sleep time. Despite the many risks for sleep disturbance, limited knowledge of sleep problems experienced by patients with MM exists. Coleman et al. (2010) found that sleep for patients with MM was characterized by decreased nocturnal sleep time for age, frequent wake episodes, and a low percentage of time asleep while in bed. However, the objective sleep of patients with MM assessed with PSG has not been described. Therefore, the primary purpose of the current study was to describe the sleep of patients with MM using PSG, before and after a second cycle of high-dose chemotherapy patients received prior to stem cell transplantation.