Physical activity and exercise motivation of multiple myeloma patients: a prospective cross-sectional study

Abstract

Background

Multiple myeloma (MM) is the second most common hematological malignancy with its prevalence increasing. Patients with symptomatic MM can show numerous comorbidities, affecting their quality of life (QoL). Physical activity (PA) may improve QoL but is not a standardized intervention of comprehensive cancer centers (CCCs). Since data on the PA of patients with MM are scarce, we aimed to prospectively assess fitness levels and patients’ motivation to join PA-interventions at our CCC.

Methods

We generated an exercise questionnaire to interview consecutive patients MM. We prospectively collected data on (a) past and current PA, defined by the World Health Organization (WHO) recommendations, (b) knowledge on exercise effects, (c) exercise motivation, and (d) willingness to participate in PA-interventions. Demographics, comorbidities, response, progression-free survival (PFS), and overall survival (OS) were assessed in 211 symptomatic patients MM.

Results

While our patients were elderly and most showed bone involvement, their PA was similar to healthy individuals. Aerobic PA (≥ 60 minutes/week) was performed by 65%, and 25% exercised ≥ 150 minutes/week. WHO PA recommendations were fulfilled by 17% of patients. No sport activities or complete physical inactivity were observed in 35% and 16%, respectively. Notably, 38% were motivated to join MM-specific sport interventions. Self-reported knowledge of PA-induced benefits for patients cancer was high (82%), but only 27% knew which exercises were safe to perform.

Conclusion

This study provides an overview of the PA of patients MM. Our results suggest that the PA of patients MM might not be much lower than in the age-matched general population.

multiple myeloma, exercise, world health organization, motivation

Implications for practice

Physical activity (PA) has been shown to improve patients’ QoL and MM-related comorbidities. Our study demonstrated that aerobic PA was performed by 65% of patients MM, with 25% exercising ≥ 150 minutes/week, WHO-PA-recommendations being fulfilled by 17%, whereas physical inactivity was similar in patients and healthy individuals (35% vs 29%, respectively). While 38% of patients were interested in participating in a sports intervention, only 27% had knowledge about safe and feasible exercises. Appropriate recommendations would motivate 77% of patients to be more physically active. Individualized exercise recommendations should be provided by interdisciplinary teams and would further improve the PA of patients with MM.

Introduction

Multiple myeloma (MM) is the second most common malignant hematologic disease. Bone involvement is one of the most common symptoms of MM (the acronym CRAB describes the most common clinical signs: hypercalcemia, renal impairment, anemia, and bone disease). Therefore, substantial morbidity, physical impairment, compression fractures, pain, and reduced physical activity (PA) may occur. Patients with MM are usually diagnosed at a median age of 70 years and with a delay of at least 6 months between the onset of the first symptoms and the correct diagnosis.^1,2 MM is usually considered an incurable disease; however, long-lasting remissions have been observed. In rare cases, even cure can be achieved.^3,4 The prognosis of the disease has significantly improved due to numerous treatment options, including novel immunotherapies, such as bispecific antibodies or chimeric antigen receptor T- (CAR-T) cells.^5,6 Due to these improvements, patients with MM can survive for a median of 8-10 years.⁷ As a result of this and demographic changes, the prevalence of MM is increasing.⁸ Prolonged overall survival (OS) with longer and more intensive treatment (often lifelong antimyeloma drug exposure) can be observed. This leads to more treatment-emerging adverse events (AE), which can affect patients’ quality of life (QoL).^9-12

Anemia-related symptoms occur more frequently in patients with MM than in other cancer patients.¹³ Furthermore, myeloma cells increase the activity of osteoclasts, which leads to the breakdown of bone substance and induces osteopenia and osteolysis. This causes skeletal instability at the beginning of the disease, during treatment and at relapse.¹⁴ The combination of these two key symptoms—bone lesions and anemia—can limit patients’ ability to undergo PA. However, successful anti-MM-treatment can improve skeletal stability, anemia, and patients’ QoL.^11,13-15 Thereby, the ability to perform PA can be restored.

Some studies have shown definite benefits of PA regarding various MM-related comorbidities, such as the general well-being, pain, fatigue, tolerance of cancer treatment, hospitalization rates, response to treatment and others.^16-22 However, contradictory results were also reported.²³ Even though prior studies performed by Coleman et al. could not show fatigue significantly diminishing in patients with MM, they were able to demonstrate safety and feasibility of their exercise intervention.²⁴ Larsen et al. confirmed safety and feasibility of exercise interventions in MM.²⁵ However, more recent studies of various cancer entities, including MM, showed beneficial effects of PA on fatigue.^16,17 In 2013, a qualitative study was published by Craike et al. that demonstrated benefits of moderate exercise in patients with MM, who received intensive treatment, and an autologous stem cell transplantation (ASCT).¹⁸ This is in line with earlier studies by Dimeo et al. over 20 years ago, who demonstrated benefits of performing guided exercise programs in ASCT-undergoing patients with cancer.^18-21,26

Unfortunately, patients with fragile bone status are often excluded from randomized clinical trials (RCTs) aiming to investigate exercise interventions, due to their fracture risk.²⁷ In a recent publication, Kitzman et al. performed an exercise intervention in frail cardiac patients and showed that exercise interventions were feasible.²⁸ The authors argued that older patients who were hospitalized for acute decompensated heart failure had high rates of physical frailty, poor QoL, delayed recovery and frequent rehospitalizations. Since interventions to address physical frailty in this population are not established, they conducted an RCT in 349 patients hospitalized for acute decompensated heart failure. A transitional, tailored, progressive rehabilitation intervention that included physical-function domains (strength, balance, mobility, endurance) was initiated during, or soon after hospitalization for heart failure and was continued after discharge for 36 outpatient sessions. Of 175 patients assigned to the rehabilitation intervention and 174 to usual care, both groups were frail at baseline, but the intervention with multiple physical-function domains resulted in greater improvement in physical function in the exercise group. So far, there are no such data for patients with MM, but the data of Kitzman et al. provide a framework and suggest that conducting studies with exercise interventions could likewise be beneficial for patients with MM.

Methods

Data source and study design

To prospectively assess PA-related information in consecutive patients with MM attending our outpatient clinics at the Comprehensive Cancer Center Freiburg (CCCF), we generated, tested, and adapted an exercise questionnaire in close collaboration with our Institute for Exercise and Occupational Medicine (P.D.; Figure 1). It gathered information about PA before and at the time of the initial diagnosis (ID) of MM. We assessed the exercising hours per week, workout intensity and muscle strengthening activity in order to evaluate, whether patients fulfilled the World Health Organization (WHO) PA recommendations for cancer patients.²⁹ Additionally, the questionnaire assessed data on patients’ knowledge on potential benefits of exercising for cancer patients, knowledge of feasible and useful exercises, and whether this knowledge motivated them to exercise. It also assessed patients’ subjective fitness levels and their willingness to join a MM-specific sport intervention program or RCT. Moreover, patient characteristics, comorbidities, therapy response, PFS and OS were assessed, using our electronic documentation systems, as described.^15,30-32 Of 232 patients participating and being assessed in our survey, 21 had to be excluded due to not fulfilling the diagnosis criteria of MM (mostly having precursor-forms of MM), leaving 211 patients for the entire assessment. To minimize inter-observer variability, the survey was conducted in face-to-face conversations, consistently led by the same interviewer (J.R.). Questions were read and explained to each patient, and the entire assessment process took 15 minutes/patient.

Figure 1.

Physical activity questionnaire for patients with multiple myeloma.

Definitions and tools

WHO PA recommendations for cancer patients were scored as fulfilled, when ≥ 150 minutes of moderate-intensity aerobic PA/week or ≥ 75 minutes of high-intensity aerobic PA/week and muscle-strengthening activities ≥ 2 days/week were performed.²⁹ Activities that strengthen the large muscle groups and activities that focus on functional training and balance, but include strength elements, were counted as muscle strengthening exercises: ie, participation in a yoga group, if several times a week or combined with another strengthening activity. To differentiate between moderate and high intensity PA and to not over-estimate moderate-intensity activity, patients were asked, whether they were completely exhausted during exercising and had to rate their exercise intensity on the BORG-RPE-scale (ranging from 6 to 20, Supplementary Material 1). Ratings of at least 11 were valued as moderate-intensity PA, since intensity of 11-13 is recommended in training for lesser trained individuals.^33,34 The subjective self-assessment of physical fitness was based on German school grades. For better visualization, 2 grades were combined into one group, namely “1 + 2” as “excellent or good,” “3 + 4” as “satisfactory or sufficient” and “5 + 6” as “poor or insufficient.”

Statistical analysis

The study size was determined after an extensive literature search, where median patient numbers of prior analyses had been 80. We assumed that ~200 surveyed patients would allow valid group comparisons. For example, a two group χ² test with a 5% 2-sided significance level will have 80% power to detect the difference between a group 1 proportion, π₁, of 0.4 and a group 2 proportion, π₂ of 0.6 (odds ratio of 2.25) when the sample sizes are 122 and 80, respectively (a total sample size of 202).

The survey was conducted in patients who attended the outpatient clinic at the Freiburg University Medical Center (UKF). This excluded inpatients, but allowed to assess PA especially in outpatients with long survival times. Statistical analysis was performed with SAS 9.4 (SAS Institute, Inc., Cary, NC), and with Excel and SPSS using counting functions and histograms. Patients were descriptively characterized (Table 1) and results of the questionnaire exemplified in Figures 2 and 3. In addition, patient characteristics were compared in those who did or did not fulfill WHO criteria (Table 2). Group comparisons were performed with Wilcoxon’s 2-sample test for continuous measures and with Chi-square tests for categorical variables. A P-value of < .05 was considered as statistically significant.

Table 1.

Patient characteristics (n = 211).

Variables	Median (range)/n (%)
Median age at interview [years; (range)] Median age at initial diagnosis of MM [years; (range)]	68 (38-88) 64 (27-86)
Gender: male/female	112 (53)/99 (47)
KPS: 100%/80-90%/≤70%	20 (10)/142 (67)/49 (23)
R-MCI: fit: 0-3/intermediate: 4-6/frail: 7-9 0/1/2/3/4/5/6/7/8/9	64 (30)/119 (57)/28 (13) 4 (2)/7 (3)/20 (10)/33 (16)/52 (25)/41 (19)/26 (12)/17 (8)/9 (4)/2 (1)
Median BMI (range)	25 (15.3-48)
Type of MM: IgG/IgA/IgM and others/LC/asecretory/biclonal LC type: kappa/lambda/asecretory/biclonal	115 (54)/33 (16)/4 (2)/54 (26)/3 (1)/2 (1) 148 (70)/58 (28)/3 (1)/2 (1)
CRAB-criteria at initial diagnosis: 0/1/2/3/4	9 (4)/73 (35)/77 (37)/32 (15)/20 (9)
ISS: I/II/III R-ISS: I/II/III Durie & Salmon: I/II/III A/B	93 (44)/54 (26)/64 (30) 52 (24)/109 (52)/50 (24) 27 (13)/25 (12)/159 (75) 174 (82)/37 (18)
Cytogenetics: favorable/unfavorable*	113 (54)/98 (46)
Osteolytic lesions: 0-2/3 or more	42 (20)/169 (80)
Lung disease: No/Yes	155 (73)/56 (27)
Employed/working at time of survey: No/yes, light physical labor/yes, hard physical labor	142 (67)/59 (28)/10 (5)
Therapy: active anti-MM therapy/no therapy Line of therapy: 0/1st/2nd/3rd/4th or more	155 (73)/56 (27) 12 (6)/111 (53)/40 (19)/14 (7)/34 (16)
Stem cell transplantation (SCT) performed: No/only auto/auto + allo/only allo SCT	69 (33)/133 (63)/6 (3)/3 (1)
Best response: CR/vgPR/PR/SD/PD Remission status at survey: SD or better/PD	51 (24)/82 (39)/56 (27)/8 (4)/14 (7) 168 (80)/43 (20)

Definitions: Numbers rounded for 100%

^*Unfavorable cytogenetics defined as: t(4,14), t(14,16), t(14,20), del(17p), hypodiploidy, c-myc, chromosome 1 aberrations.

Abbreviations: allo: allogeneic; auto: autologous; CR: complete remission; CRAB: calcium elevation, renal insufficiency, anemia, bone lesions; ISS: International Staging System; BMI: Body Mass Index; KPS: Karnofsky performance status; LC: light chain; MM: multiple myeloma; n: number of patients; PD: progressive disease; PR: partial remission; R-ISS: Revised International Staging System; R-MCI: Revised Myeloma Comorbidity Index; SD: stable disease; vgPR: very good partial remission.

Table 2.

Entire patient cohort and those with vs without WHO recommendations being fulfilled: substantial group differences.

Parameters	All patients (n = 211)	WHO-recommendations fulfilled since ID of MM (n = 35, 17%)	WHO-recommendations not fulfilled since ID of MM (n = 176, 83%)	P-value
WHO-recommendations fulfilled before ID [n (%)]: yes/no	99 (47)/112 (53)	29 (83)/6 (17)	70 (40)/106 (60)	<.0001
Subjective fitness at survey [n (%)]: very good or good/intermediate/poor	27 (13)/112 (53)/72 (34)	9 (26)/22 (63)/4 (11)	18 (10)/90 (51)/68 (39)	.0019
R-MCI risk groups at survey [n (%)]: Fit/intermediate fit/frail patients	64 (31)/119 (56)/28 (13)	15 (43)/19 (54)/1 (3)	49 (28)/100 (57)/27 (15)	.0598
R-MCI at survey (single scores)	4 (0-9)	4 (1-7)	4 (0-9)	.0175
[median (range)]: [Mean]:	4.4	3.8	4.5
CRAB-criteria at ID [n (%)]: 0/1/2/3/4	9 (4)/73 (35)/77 (36)/32 (15)/20 (10)	0 (0)/11 (31)/13 (37)/7 (20)/4 (11)	9 (5)/62 (35)/64 (36)/25 (14)/16 (9)	.6038
ISS [n (%)]: I/II/III at ID R-ISS [n (%)]: I/II/III at ID	93 (44)/54 (26)/64 (30) 52 (25)/109 (51)/50 (24)	19 (54)/8 (23)/8 (23) 10 (29)/19 (54)/6 (17)	74 (42)/46 (26)/56 (32) 42 (24)/90 (51)/44 (25)	.3891 .5830
Median BMI at survey (kg/m2) (range)	25 (15 - 48)	25 (16 - 36)	25 (15 - 48)	.3139
Gender: male/female [n (%)]	112 (53)/99 (47)	23 (66)/12 (34)	89 (51)/87 (49)	.1458
Under treatment at survey [n (%)]: Yes/No	155 (73)/56 (27)	20 (57)/15 (43)	135 (77)/41 (23)	.0169
Stem cell transplant at survey [n (%)]: Yes/No	142 (67)/69 (33)	33 (94)/2 (6)	109 (62)/67 (38)	.0004

Abbreviations: WHO: World Health Organization, ID: initial diagnosis, R-MCI: revised myeloma comorbidity index, CRAB: hypercalcemia, renal impairment, anemia, bone disease, R-ISS: revised international staging system, BMI: Body Mass Index.

Figure 2.

Physical activity of 211 patients with multiple myeloma since initial diagnosis. (A) PA of patients with MM since ID in hours per week, color coded for WHO PA recommendations. (B) Muscle strengthening activity performed by patients with MM since ID. (C) Percentage of patients in the cohort fulfilling both WHO recommended criteria for PA since ID MM. Abbreviations: PA: physical activity, MM: multiple myeloma, ID: initial diagnosis, WHO: World Health Organization.

Figure 3.

Subjective fitness levels, knowledge of physical activity benefits and exercises, and progression-free survival and overall survival of 211 patients with multiple myeloma. (A) Subjective fitness levels before ID of MM. (B) Subjective fitness levels of patients with MM at the time of survey. (C) Percentage of 211 patients with MM having knowledge on PA’s potential beneficial effects compared to the percentage of 211 patients with MM knowing which exercises are safe and valuable to perform. Abbreviations: ID: initial diagnosis, PA: physical activity, MM: multiple myeloma.

PA in our patients was also compared to that of healthy controls obtained from a literature search in Pubmed using the search terms “WHO recomm* [TI] AND physical activity (Tables 3 and 4). OS was defined as the time from start of induction to death from any cause and PFS as the time from start of induction to cancer recurrence or death from any cause. Data for patients alive at the time of the final analysis were censored at the last follow-up. Probabilities of PFS and OS were estimated using Kaplan-Meier method. The analysis was carried out according to the guidelines of the Declaration of Helsinki and Good Clinical Practice. All patients gave their written informed consent for institutional-initiated research studies and analyses of clinical outcome studies conforming to the institutional review board guidelines (ethics committee Freiburg, 20-1351).

Table 3.

Fulfillment of WHO PA recommendations of patients with MM in this analysis compared to prior surveys in various countries using healthy participants.

Authors and year of publication	Number of patients with MM (country of analysis)	Number of healthy participants (country of analysis)	Average age (years; range or SD)	Gender status: male/female	WHO recommendation fulfilled [%]	Data source, how analysis and results were verified
Räder et al (2024)	211 (German)	—	68 (38-88)	53%/47%	17%	Survey
Luzak et al (2017)	—	475 (German)	58 (48-68)	47%/53%	14%	Accelerometer
Seidu et al (2012)	—	1542 (Ghana students)	Age 12-17 years: 708 Age 18 + years: 834	51%/49%	25% (males/females: 29%/22%)	Survey
Guthold et al (2018)	—	1 900 000 (global)	Standardized to the WHO standard population	Standardized to the WHO standard population	63% (high-income countries 2016, muscle strengthening was not considered)	Survey
Haider et al (2018)	—	24 590 (European subgroup)	73.8 (SD 6.7)	46%/54%	Austria: 26% (extrapolated)	Survey
Macek et al (2019)	—	4619 (European)	56.4 (45-65)	33%/67%	4% (45% “much activity”)	Survey
Anokye et al (2012)	—	14 142 (Great Britain)	49.3 (SD 18.6)	45%/55%	10% (self-declared)	Survey
∑	211	~2 000 000 healthy participants	68 in MM; 49-74 in healthy participants	Males: females fairly balanced in different analyses	WHO recommendations claimed to have been reached: 17% in MM 4%-63% in healthy participants = largely variable	Mostly surveys

WHO recommendations of recommended physical activity/week: ≥150 minutes.

Abbreviations: MM, multiple myeloma; PA, physical activity; WHO, world health organization; ∑, summary of results.

Table 4.

Comparison of aerobic PA in Haider et al and Räder et al.

	Haider et al (healthy German individuals) (%)	Räder et al (German patients with MM)
0 min/week (%)	29	35% (+ 6%)a
1-149 min/week (%)	23	40% (+ 17%)a
≥150 min/week (%)	48	25% (-23%)a

^aDifferences between Haider et al and Räder et al are given in brackets.

Abbreviation: MM: multiple myeloma.

Results

Patient characteristics

During the survey from March 1 2020 to December 31 2020, 232 patients consented to participate in the study. After excluding duplicates and patients who did not meet the inclusion criteria (Monoclonal gammopathy of undetermined significance; smoldering MM), 211 patients were included in the final analysis. In most characteristics, the cohort corresponded well with other referral centers (Table 1). The median age of patients with MM at time of the interview was 68 years; males (53%) and females (47%) were almost balanced, and most patients (67%) showed a Karnofsky performance status (KPS) of 80-90%. According to the revised myeloma comorbidity index (R-MCI), 30% of patients with MM were fit, 57% were intermediate-fit, and 13% were frail, which was in line with prior analyses.^30,31 The median body mass index (BMI) was 25 kg/m². Expectedly, most patients fulfilled either one (35%) or two (37%) CRAB criteria at ID, with bone involvement being the most commonly met criterion, followed by anemia, with renal dysfunction being the third most common and hypercalcemia the least common. Advanced (II + III) International Staging System (ISS) and revised (R)-ISS were observed in 56% and 76%, respectively. Three or more (≥3) osteolytic lesions were perceived in 80% of patients, while 20% had few (0-2) osteolytic lesions. Active anti-MM therapy at the time of the interview was performed in 73%, whereas 27% were in stable remission, without any need for anti-MM therapy. Lines of therapy at the time of the interview were first-line (1.LT) or second-line treatment (2.LT) in 53% and 19%, respectively. ASCT had been performed in 63% and any transplant in 67%. The remission status at our survey was stable disease (SD) or better in 80% and active or progressive disease (PD) in 20%, reflecting the fact that these patients were seen as outpatients at our CCCF.

Results of the questionnaire-based survey

Employment and PA

The question of employment proved to be important for the assessment of patients’ PA, as physically active work must be considered when evaluating PA. As 67% of our patients were retired, only 28% performed light work and even fewer heavy work (5%). Of interest, in the latter group, only 20% met WHO recommendations, although 60% of them strengthened their muscles several times a week.

PA levels

Sixteen percent of patients stated that they were entirely inactive since the ID of MM, defined as reporting no walks and no housekeeping activities. The main reasons given for inactivity were osteolyses (44%), too much effort (41%), lack of motivation (21%), fear of injury (12%), and high time expenditure (3%).

Thirty-five percent did not perform moderate or high intensity PA (≥ 11 on the BORG RPE scale; Figure 2A). Low and very low intensity PA (BORG RPE scale < 11) are not required to fulfill WHO recommendations. The evaluation of results therefore focused on moderate and high-intensity PA (BORG RPE ≥ 11).

Sixty-five percent of patients performed at least 1 hour/week of moderate or high-intensity PA (Figure 2A). The most relevant sport restrictions given in these active patients were osteolyses (21%), too much of exertion (29%), and fear of injury (2%). Interestingly, 37% of physically active patients said they sensed no sport restrictions at all, and 25% of our patients were as physically active as the WHO recommends (Figure 2A, green columns).

Muscle strengthening activities at least twice a week were performed by 39% of patients (Figure 2B). Combining both requirements, WHO recommendations were fulfilled by 17% of our patients at the time of the assessment (Figure 2C), whilst 47% of them had fulfilled WHO recommendations before the MM diagnosis (2.8-fold higher). Most patients with MM limited themselves to metric (76%) and/or compositional (55%) sports. Rebound games and target shooting games were very rarely practiced, in line with the median patient age.

Subjective fitness levels before the myeloma diagnosis and at the time of our survey

Before the ID of MM, 98% rated their physical fitness as sufficient or better (Figure 3A). With the myeloma diagnosis, however, fitness levels substantially deteriorated: in particular, the proportion of patients who described their fitness as poor or unsatisfactory increased significantly (from 2% to 34%; Figure 3B).

Willingness to participate in sport programs

The patients were asked whether they could imagine participating in guided sport groups at the CCCF. While 38% were interested in participating, 62% could not imagine joining. The “time commitment” was the most common factor against participating in supervised sport interventions (66%). Many patients also named the long distance from home to the clinic and would rather participate in nearby sport groups. “Osteolyses,” “too much effort” or “lack of motivation” were reasons against participation in 14%, while 11% stated that they were able to exercise on their own and saw no need to participate in supervised sport interventions at our clinic.

Knowledge of effects and of specific exercises beneficial for patients with MM

Eighty-two percent of patients in the survey were aware of positive effects of PA, while only 27% had knowledge on safe, feasible, and useful exercises (Figure 3C). Most patients stated that they had gained this knowledge in clinics or during rehabilitation programs. Notably, 77% of patients affirmed that dedicated sport knowledge would be a substantial motivational factor to engage themselves in exercises.

Comparison of patients with MM meeting WHO recommendations vs not

Patient characteristics were compared between those patients who fulfilled WHO criteria vs not to gain insight into potential differences (Table 2). The strongest statistical significance was found in the fulfillment of WHO recommendations before the ID: WHO-compliant patients who were highly physically active before the ID of MM, tended to preserve their high PA levels. The assessment of subjective fitness levels also showed differences: in the “WHO-compliant group,” the proportion of patients who rated their fitness as “very good or good” was significantly higher; vice versa, those who described their fitness as “poor or insufficient” were significantly increased in the “WHO-non-compliant group.” In line, there was a significant difference between fit, intermediate-fit and frail patients: fit patients were more likely to be in the WHO-compliant group (43% fit patients vs 28% in the WHO-non-compliant group). Vice versa, frail patients were more likely to be in the WHO non-compliant group (15% vs 3% in WHO-compliant group, Table 2). Mean R-MCI scores in the WHO-compliant vs -incompliant group were significantly different with 3.8 vs 4.5, respectively.

The number of CRAB criteria at ID, ISS, and R-ISS were not statistically different. Thus, patients with unfavorable prognostics (ie, higher R-ISS, ISS or Durie & Salmon stages) were not necessarily less active than those with more favorable MM. The median BMI did not differ between groups. While 23 of 112 male patients (21%) fulfilled the WHO recommendations, 89 (79%) did not. Twelve of 99 female patients (12%) fulfilled the WHO recommendations, while 87 (88%) did not (Table 2). Since there were slightly more male patients (53%) than female patients (47%) in the study, there were more males in the WHO-compliant group naturally. Although males appeared more active, with 66% of WHO-compliant patients being male, the percentage of males fulfilling WHO recommendations (21%) compared to females fulfilling WHO recommendations (12%) was only 9% higher. The gender distribution within the WHO-compliant compared to the WHO-non-compliant group was not statistically significant (P = .1458).

While just over half of the patients in the “WHO-compliant group” were undergoing anti-MM-treatment, even more with 77% were under treatment in the “WHO-non-compliant group.” The percentage of patients, who received ASCT was significantly higher in the WHO-compliant vs -incompliant group (94% vs 62%, respectively; Table 2).

Progression-free survival and OS

The median PFS of the cohort was ~4 years and the 5-year PFS 43% (Figure 4A). This corresponded to typical PFS data of patients with MM seen in referral clinics,³⁵ albeit the 5-year OS of the cohort appeared much too favorable with 96%, due to an immortal time bias (Figure 4B). The latter reflected our selected group of patients, often with long-term remission⁴ (according to the R-ISS, the 5-year OS of our cohort was estimated with 62%).

Figure 4.

Progression-free survival and overall survival of 211 patients with multiple myeloma. (A) Progression-free survival of 211 patients with MM. (B) Overall survival of 211 patients with MM. Abbreviations: MM: multiple myeloma.

Discussion

Our study of 211 consecutive MM patients revealed that 17% of them fulfilled the WHO exercising recommendations. While patients were more active before the cancer diagnosis and had rated their fitness as ‘good or sufficient’ in 98%, fitness levels significantly deteriorated with ID of MM. Along with ID of MM, ‘poor’ subjective fitness increased from 2% to 34%. Expectedly, patients showed high knowledge of “positive effects of PA for patients with cancer” (82%); however, most (73%) had no knowledge on feasible exercises beneficial to be performed for patients with MM.

We conducted a PubMed-based literature search on PA in patients with MM: data from Nicol et al. (12% with PA since ID, 25% before ID, and 55% interested in PA interventions)³⁶ and Craike et al. (41% interested in PA interventions, PA since ID significantly lower than before ID)³⁷ were obtained in Australia. Less data were found on European, US, or Asian patients. The type of survey varied between the use of questionnaires (self-completion or interviewer-completed) and semi-structured interviews. Expectedly, PA after the ID of any cancer significantly decreased as compared to the PA extend before the cancer diagnosis (decrease to approximately half). Disease-associated comorbidities were an important reason for patients not to engage in PA.

In comparison, the percentage of healthy individuals fulfilling the WHO recommendations varied between studies (4%-63%), depending on the country in which the study was conducted and the type and accuracy of the data collection (Table 3).^38-43 Seidu et al. found that 29% of males and 22% of females were sufficiently physically active, showing a gender difference of 7%, in line with the gender difference of 9% in our study.⁴¹ Guthold et al. used data from global population-based sample surveys, in which males were 8% more likely to be sufficiently active than females. Considering PA at work, at home, for transportation and during leisure time, a high WHO recommendation compliance (63%) was achieved compared to other studies. However, muscle strengthening was not taken into account, thus the fulfillment of WHO recommendations was overrated.⁴³ Likewise, Haider et al. had no initial data on the performance of strengthening exercises. For the cohort of Austrians, the corresponding data was extrapolated using a random sample, wherein 26.2% of participants met WHO recommendations (Table 3).⁴² As compliance with WHO recommendations varied between studies and comparison with extrapolated data seemed inaccurate, we decided to compare data on aerobic PA with others, as the data quality was much better. Thus, we compared our PA data based on aerobic activity to the Haider et al. cohort of healthy German individuals (based on aerobic PA), which closely matched the age and gender of our patients.⁴² The comparative analysis demonstrated that patients with MM are only slightly more physically inactive (0 min/week: 35%) than healthy individuals (29%). The proportion of MM patients who were physically active (1-149 minutes/week, but did not fulfill WHO definitions; 40%) was almost twice as high than in healthy individuals (23%). Only the proportion of sufficient PA according to WHO was twofold lower in MM than healthy individuals (25% vs 48%, respectively, Table 4).

The results of our study suggested that patients with MM are physically more active than assumed.⁴⁴ Only 16% of patients stated that they were inactive (no motion and no sports; 35% with no sport activities), whereas 65% exercised for at least one hour every week. Therefore, although considerably less MM patients than healthy individuals were physically active for ≥ 150 minutes/week, physical inactivity was similar between these groups. Since our data disclosed a substantial portion of patients (38%) interested in sport interventions, with adequate knowledge on the beneficial effects in 82%, but few (27%) with sufficient expertise of feasible exercises, intervention programs could favorably change this.

We hypothesize that it is easier to motivate active patients to become even more active (by increasing the knowledge of feasible exercises), than to encourage inactive patients to change this. Therefore, patients’ expertise could be increased by the offer of sport programs, improving bone stability and other comorbidities in the long run. Sport programs should ideally be offered in and outside referral clinics, be adapted to patients’ condition, disease burden, fitness levels, and personal desires and could even accompany therapy as previously shown for ASCTs by Dimeo et al or induction treatment by Möller et al.^19-22,26

Regarding sport interventions in MM, we demonstrated previously in a well-matched case-control study comparing physically active vs inactive patients, that the former had fewer disease-related comorbidities: active patients were fitter via R-MCI, showed improved treatment tolerability, improved treatment response, fewer hospitalizations, and improved PFS and OS.²² In the subsequent RCT (“REAL Fitness study”; DRKS00022250), exercise according to WHO criteria was offered by our group in newly diagnosed MM patients during induction. Patients were randomized to guide exercise over three months vs activity as usual. Actively trained patients showed significant improvements in fatigue (P = .0017), depression (P = .0203), QoL (P = .0053), timed-up-and-go-test (P = .0142), and R-MCI (P = .0078). Moreover, active patients had improved grip strength (P < .05) and biomarkers (albumin [P = .0456], HDL [P = .0259], LDL [P < .0001]). Therefore, this intervention—similar to Kitzman et al in frail cardiac patients²⁸—demonstrated that MM patients benefit from WHO-concordant personal training.⁴⁵

As a consequence, PA should be more prominently addressed by treatment teams, as recommended by Kitzman or the S3-MM guideline.^28,46 These WHO-concordant sport intervention programs should be individually planned within an interdisciplinary team: orthopedic specialists, radiation therapists and radiologists (evaluating patients’ bone stability), hematologists (evaluating patients´ remission status, AEs during treatment and comorbidities), and sport physicians (compiling feasible and safe exercises).⁴⁷ According to the results of this study, such exercise recommendations would be a motivator for sport activities for 77% of patients. Proactively addressing the topic during physicians’ visits and encouraging sport medicine services could further increase patients’ motivation and PA.

Our study bears several strengths, for example our substantial number of patients and comparison with prior PA-studies in MM and healthy individuals. Moreover, our study participation was exceptional: of 233 patients asked, 232 (99.6%) took part. The time expenditure for the assessment via questionnaire was short (15’), all questionnaires were performed and supervised by the same inquirer (J.R.) and data completeness was 100%. Since this study did not aim to verify the patient-reported PA, we cannot exclude that the PA amount was over- or underestimated. The sample size was determined at the beginning of the study. Since 211 patients were included in the analysis, meaningful statistical evaluations could be performed. Criticism may evolve from the fact, that the analysis was conducted with MM patients who attended the outpatient myeloma clinic at the UKF/CCCF. In some patients, the ID of MM was some time ago, so PA before ID may have been overestimated. However, it was shown that historical recall of leisure physical activity can be reasonably estimated by questionnaires over a substantial time period in older women.⁴⁸ The exclusion of inpatients and the substantial immortal time bias caused by the study design resulted in an overestimated OS.^49,50 Concentrating on patients with longer survival mirrors today’s longer survival with MM and that in very few patients, functional cure can be achieved today.^3,4

Conclusion

We conclude that this study provides important data on PA in MM, a presently still understudied setting. Our results on patients’ motivation suggest that proactively addressing the topic of ‘exercise and sport’ can increase patients’ PA. This can improve their QoL, which is increasingly relevant due to prolonged cancer (and MM) survival today.^3,4,11,32,44 Importantly, our study indicates that PA should not be underestimated in patients with MM and that physical inactivity is similarly prevalent in patients with MM (35%) and healthy individuals (29%). Patients who are already physically active (65%) may find it easier to increase their PA or perform additional muscle-strengthening exercises to meet WHO recommendations, which 17% of patients with MM already fulfilled in our analysis. Further studies in a larger, multi-center setting are needed to confirm our results, validate our questionnaire with real time PA performance, and analyze this in in- and outpatient settings.

Supplementary material

Supplementary material is available at The Oncologist online.

Acknowledgments

The authors thank DSMM, GMMG, EMN, and IMWG experts for their support and prior recommendations on this study. We thank all patients with MM who participated in this study and the MM-tumorboard and Comprehensive Cancer Center Freiburg, specifically, Prof. Dr. Georg Herget (Orthopedics), PD Dr. Jakob Neubauer (Radiation), Dr. Henning Schäfer (Radiation oncology), and AG Engelhardt/Wäsch members for their support. The results were presented in part at the “German, Austrian and Swiss annual Hematology & Oncology meetings” (DGHO). G.H.: Clinic for Orthopedics and Trauma Surgery, Department of Surgery, Medical Faculty, University of Freiburg, Freiburg, Germany. Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center, University of Freiburg. J.N.: Department of Radiology, University of Freiburg, Freiburg, Germany. Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center, University of Freiburg. H.S.: Department of Radiation Oncology (H.S.), Medical Center, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ) Heidelberg, Freiburg, Germany.

Conflict of interest

The authors declare no competing interest.

Author contributions

Conceptualization: J.R., G.I.M.-D.M., C.G., P.D., R.W., M.E. Data curation: J.R., M.E. Formal analysis: J.R., G.I. Investigation: J.R. Methodology: J.R., M.-D.M., P.D., R.W., M.E. Project administration: M.E. Resources: P.D., R.W., M.E. Supervision: M.E. Validation: J.R., G.I., M.E. Visualization: J.R., G.I., M.E. Writing—original draft: J.R., M.E. Writing—review & editing: all authors. All authors approved the final version of the manuscript.

Data availability

The data underlying this article are available in the article and in its Supplementary Material. Further data supporting the findings of this study are available from the corresponding author (M.E.) upon reasonable request.

Funding

The authors declare no funding. The authors declare no competing financial interest related to this study.

Ethics approval

The ethics committee had neither ethical nor legal reservations against the implementation of the research project (Ethics committee Albert-Ludwigs-Universität Freiburg, application number 20-1351).

Patient consent

Patients consented to participate in the study in writing before inclusion in the study. Information contained in the study is kept confidential, all identifiers have been removed prior to submission for publication.

Clinical trial registration

Trial registration was not required, since study was registered at the University of Freiburg, ethical approval # 20-1351.