Exercise in Patients With Multiple Myeloma
Exercise in Patients With Multiple Myeloma
The overall aim is to examine whether early initiated, individualized exercise training in
 patients newly diagnosed with multiple myeloma, irrespective of age and current performance
 status, will be beneficial for the patients´physical function, level of physical activity and
 quality of life, pain and bone disease.

 The investigators will examine the effect of supervised in-hospital exercise training
 sessions combined with home-based exercise training, initiated at time of diagnosis. The
 outcomes of interest are physical function, level of physical activity, QOL, pain and bone
 disease.

 Furthermore, to describe the disease in patients with newly diagnosed MM in relation to
 physical function, level of physical activity, QOL, pain and bone condition at time of
 diagnosis.

 The investigators hypotheses are:

 -  Individualized exercise starting at time of diagnosis will have positive effects on
 physical function, physical activity, QOL and pain.

 -  Individualized exercise starting at time of diagnosis will have positive effects on bone
 disease (bone markers), bone mineral density (BMD) and lean body mass.

 -  A higher level of physical function is associated with a higher level of physical
 activity, less pain, better QOL, and higher BMD and lean body mass.
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.
Inclusion Criteria:

 -  Newly diagnosed with Multiple Myeloma requiring treatment.

 -  The patient must be able to speak and understand Danish and be able to give his/her
 informed consent.

 Exclusion Criteria:

 -  Patients with spinal cord compression

 -  Unstable vertebral fracture (SINS score >12) (52)

 -  Untreated cardiac failure and untreated cardiac arrythmia

 -  Severe chronic cardiac failure (NYHA 3-4)

 -  Other severe comorbidity that will not allow physical training, e.g. neurological or
 uncompensated liver failure and psychological or psychiatric disorder that will not
 allow compliance in physical training.