Exercise in Patients With Multiple Myeloma

Background Physical exercise for haematological patients is a relevant complementary treatment, including in patients with multiple myeloma (MM) (Jones 2013). In hematological cancer, exercise is feasible, safe and beneficial in numerous aspects (aerobic capacity, muscle strength, quality of life (QOL), fatigue, psychosocial wellbeing, treatment-related symptoms and body composition, before, during and after stem cell transplantation (Persoon 2013; Haren 2013). Still the evidence for the value of exercise in hematological diseases is sparse, in general and to specific diagnoses (Jones 2013; Fong 2014; Liu 2009). Patients with MM may differ from other hematological diseases, by poorer functional status due to skeletal related pain, affected QOL and immune function, but also in return to work and in risk of disability pension, and furthermore physical performance and the time of being physical active is diminished throughout the treatment course and patients do not meet physical activity guidelines (Coleman 2004; Jones 2004; Craike 2013). Hence, there is a need to examine the effect of exercise to be able to give evidence based recommendations on exercise in MM patients.

In Denmark, 320 patients are diagnosed with MM annually. The median age at diagnosis is 68-71 years, and the incidence is increasing with age. The prevalence increases due to the aging population and improved survival because of improvement in medical treatment (Kyle 2007; Sihori 2006 \& 2004; Alexander 2007; Kumar 2008 \& 2014). Typically, the patient presents with bone pain, anaemia, renal failure, recurrent infections, or for some patients it is detected by chance through screening of blood or urine. Bone pain is caused by osteolytic destructions which also may lead to pathological fractures.

When diagnosed, most patients (80%) will have symptomatic disease and will need start treatment. The medical treatment for MM has two aims. Firstly, anti-myeloma systemic therapy aims at reducing tumor burden and to prolong disease free survival, and overall survival, and secondly, supportive care aims at preventing serious morbidity from disease complications. Younger patients (<65-70 year) are treated with high dose chemotherapy with stem cell support (HDT). Elderly patients receive less intensive, yet still effective treatments that include novel agents (bortezomib, thalidomide). Painful bone lytic lesions may be treated with radiation therapy. Patients receive i.v. bisphosphonates to reduce the risk of progressive bone disease and fractures (Rosen 2003; Morgan 2011).

Patients with MM (receiving HDT) perceive different symptoms (sleep and mood disturbances, diminished functional performance, pain, shortness of breath, distress, sadness and difficulty paying attention. Symptoms are interrelated and a vicious circle may be present (Coleman 2011; Anderson 2007).

Literature review: Exercise in patients with MM Only 3 RCT studies (Coleman 2003 \& 2008 \& 2012) and 1 single arm pilot study (Groeneveldt 2013) regarding the effect of exercise in patients with MM have been identified. Coleman investigated patients undergoing tandem autologous peripheral blood stem cell transplantation with no risk of fracture, while Groeneveldt investigated MM survivors. All the exercise programs were individualized and home-based, although one study also included weekly supervised training the first three months and monthly the following 3 months. The exercise programs, all compromising stretching, aerobic training and strength resistance training, had a duration of 6 months, and 3 of them started during induction and HDT. The controls were advised to walk 20 minutes 3 times a week.

The single arm pilot study in MM survivors showed significant positive changes in QOL, fatigue and muscle strength, but not in aerobic fitness. Positive, although not significant, changes were seen regarding anxiety/depression. In the studies of Coleman et al. there was a trend towards less decline in aerobic capacity/physical performance in the exercise group compared to the control group. Lean body weight (per month) were significantly increased among those exercising compared to controls. Over the 6 months period strength and lean body weight increased and they perceived less fatigue, better mood and more night time sleep than the controls. Trends of physiologic benefits regarding stem cell collection and transfusions during transplantation were shown.

One Coleman study showed statistical significant changes during the treatment course; decline in physical performance, increase in perceived fatigue, and negative effect on the night sleep, both in the exercise group or the control group. There was no statistical or clinical significant differences in any of the investigated outcomes between the exercise group and the control group at all test times prior to chemotherapy, 10-12 weeks later and 15-16 weeks after stem cell collection. The lack of significant results can be due to poor compliance (based on self-reported activity summary with no results reported in the paper), no structured supervision throughout the exercise intervention and perhaps inadequate intensity in relation to an effect in aerobic capacity. Moreover, the Arkansas anti-myeloma Total Therapy Program is a highly intensive chemotherapy that is not comparable with the induction regimens that are used in Denmark. This highly intensive treatment may very well counteract the benefits of physical training. However, it is noteworthy, that the exercise group had a better physical performance than the control group, although not significant. Importantly, the exercise programs were feasible, acceptable and safe. The performed studies have different shortcomings, such as small study populations, lack of control group, lack of supervised training, no description of whether the assessor was blinded, and inadequate description of the intervention.

In summary, exercise is found to be safe and feasible in patients with MM during induction and HDT, and after discharge. There is a gap in the literature concerning elderly patients with MM and in general in patients treated with less intensive regimens than HDT.

The effect of exercise on physical function needs further examination, especially because the broad group of patients with MM also compromises elderly patients, making exercise even more relevant as a complementary treatment early in the disease course in order to maintain physical function. Because of the nature of the disease involving the bones, it is believed that exercise may be beneficial for maintaining MM patients´ both regarding physical function and bone loss, as in the older population (Chin 2008) and in patients with osteoporosis (Hagen 2011; Howe 2011) or as found in the encouraging results regarding bone health among cancer survivors (Winters-Stone 2010). The literature suggests that combined training is beneficial in order to maintain or increase BMD and lean body mass among patients with prostate cancer or breast cancer (Bolam 2012; Cormie 2014), among post menopausal women (Martyn-St James 2008 \& 2009; Palombaro 2006) and among elderly (Gómez-Cabello 2012). Change in bone markers as an effect of exercise have also been investigated, although in different exercise protocols. The results from healthy women and men are promising. Bone formation markers are significantly increased, without significant changes in bone resorption markers (Shibata 2003; Karabulut 2011). OQL, in a disease specific perspective, needs attention since exercise can improve QOL (Persoon 2013; Haren 2013; Mishra 2012 \& 2012), and since bone pain is a major problem in patients with MM, it is relevant to investigate pain as a separate outcome. It has been demonstrated, that breast cancer survivors meeting physical activity guidelines are significant less likely to report above-average pain than breast cancer survivors not meeting physical activity guidelines, and those who always have been physically active report less pain than inactive women (Forsythe 2013). Griffith (2009) have found, that cancer patients report a lower pain level, if they become more physically active (adjusted for age, cancer diagnosis, pretest pain, pretest physical activity/physical functioning), but Forsythe (2013) have demonstrated unchanged pain level despite increase in physical activity. These results make it even more important to investigate pain in the investigators set up. Physical functioning will have impact on the level of physical activity, which has importance in a long term perspective, but to the investigators knowledge the level of physical activity has not been investigated in patients with MM neither in a prospective design nor with objective measurements.

Recruitment All patients with newly diagnosed MM at Roskilde Hospital and Odense University Hospital will be screened for eligibility on the basis of inclusion and exclusion criteria, at their first appointment with the physician (hematologist) at time of diagnosis.

If eligible, the physician will both briefly inform the patient about the project, and give the written participation information. Before the next consultation (typically after 2-3 days), the investigator will call the patient with further information and address any questions the patient may have regarding the project before written informed consent is obtained.If not eligible or the patient does not want to participate, the patient will be registered only by the reason for exclusion.

Design After inclusion the patients will be randomized 1:1 into an intervention group or control group. The participants will be block randomized and stratified to treatment (planned HDT versus (vs.) non-intensive treatment), performance status (PFS 0-1 vs. PFS≥2) (Oken 1982), and study site (Roskilde vs. Odense). The intervention will start at day 8 (in the 2nd week) after start of treatment unless safety reasons make it necessary to postpone start of exercise. The measurements at all time points will be conducted by experienced, educated investigators (physiotherapists). Measurements will preferably be conducted by the same physiotherapist at each site.

Power calculation The number of patients to be included has been determined by a power calculation, with a significance level, α = 0.05 and 80% power, β = 0.20 and a minimum clinical difference of mean(SD) 7 kg(13.1) in the knee extensor strength (Groeneveldt 2013), which is the primary outcome (corresponding to an increase of approximately 23 %). The number of patients needed, can be estimated to 44 patients in each group (intervention and control).

Statistical analysis It will be tested whether data follow a normal distribution.The following description is based on the assumption that data is normally distributed. For continuous data in an interval scale, mean(sd) will be used and for data in an ordinal scale, median(range) and quartiles will be used to describe data. Differences within group between test times and between groups at all test times will be examined by t-test. The significance level is set to p<0,05. The analysis will be conducted in accordance with ITT.

To test the investigators hypothesis on the primary outcome (knee extensor strength), t-test will be used and the standard error of the mean difference will be calculated. A mean difference of 7 kg is considered clinical significant, and if this is obtained H0 can be rejected.

To investigate associations between physical function and physical activity, QOL, pain, lean body mass, BMD, and bone markers, scatter plots will be used. If linear correlations exist, the correlations coefficients will be calculated. The correlation will be tested with Fisher´s z transformation and 95%CI will be formed.