An Individualized Exercise Intervention for People with Multiple Myeloma—Study Protocol of a Randomized Waitlist-Controlled Trial

Round 1

Reviewer 1 Report

The manuscript is very well written and I believe this study has significant potential. Below are my comments

Introduction

The introduction provides enough evidence to justify the need for this study however, the authors did not provide enough evidence to justify their second hypothesis. Please provide additional evidence to justify decrease in adherence to exercise to exercise after supervised exercise. (David Conroy has significant work in this)

Another thing that I believe you should mention in your introduction is the fact that patients with MM tend to lose weight fairly quickly which may be an example of cancer cachexia. Especially since many of the secondary measures that you are using in your study are measuring aspects of cancer cachexia. 

Methodology

Figure 1 and Table 1 were extremely helpful.

Why not measure exercise enjoyment for all testing days? I think it might be important to see if there was a difference between baseline, 3 months and 6 months and if supervised intervention increased/decreased enjoyment of exercise.

Another thing that you should consider controlling for is the time of day that you conduct the testing. To reduce the risk for differences in diurnal variations I'd suggest trying to test during blocked times. This might be too difficult to do, but another suggestion would be what O'Connor, Scholey, Kennedy and Boolani do in their fatigue and energy work and collect data +/- 30 minutes from baseline testing time. Once again might be a challenge, but that will definitely control for potential diurnal variations. You should look up work by Pilcher who has significant work on diurnal effects on many cognitive measures (multiple studies report evidence that cognitive performance influences balance). Pilcher provides evidence for even using block times to control for diurnal variations.

When describing the surveys please provide what measures were used for testing the validity and reliability of those surveys and the scores (i.e. Chronbach alpha was 0.90)

There is significant evidence of a link between cancer cachexia and mitochondrial dysfunction. From what I see you are using multiple objective measures to determine whether your exercise protocol reduced muscle loss/etc. I don't know if you have access to a research grade fNIRS, but if you do you may be able to measure mitochondrial function during your VO2 Max test and at rest. Another option might be a commercial grade (MOXY has been used in studies before) portable fNIRS which can measure SmO2 and Hb saturation. The exercise program should increase mitochondrial capacity, which in turn should be easily visible 3 months in Hb saturation at rest and changes in SmO2 at various stages of the VO2Max test. The MOXY costs ~$3000 US and has been used in published studies before. It provides good data on blood Hb saturation. You could measure at rest and during exercise

Cancer related fatigue

While I don't argue with the validity of the measure that you are using, one of the things I'd like to bring to your attention is the work by Eshragh and colleagues (Eshragh, J., Dhruva, A., Paul, S. M., Cooper, B. A., Mastick, J., Hamolsky, D., ... & Kober, K. M. (2017). Associations between neurotransmitter genes and fatigue and energy levels in women after breast cancer surgery. Journal of pain and symptom management, 53(1), 67-84.). This work finds that patients with cancer can be high fatigue and/or low energy, which have significantly different epigenetic biomarkers. Additionally, based on some of the measures that you are collecting Loy and colleagues (Loy, B. D., Cameron, M. H., & O'Connor, P. J. (2018). Perceived fatigue and energy are independent unipolar states: Supporting evidence. Medical hypotheses, 113, 46-51.) and Boolani and colleagues (Boolani, A., O’Connor, P. J., Reid, J., Ma, S., & Mondal, S. (2019). Predictors of feelings of energy differ from predictors of fatigue. Fatigue: Biomedicine, Health & Behavior, 7(1), 12-28.) provide evidence that some of your measures may be associated with feelings of energy and not feelings of fatigue. 

Although I am unaware of any validated cancer related measures that account for both feelings of energy and fatigue I'd recommend potentially finding a way to measure that nuance as you might find that chronic exercise influences both feelings of energy and feelings of fatigue in patients with cancer (O'Connor, P. J., & Puetz, T. W. (2005). Chronic physical activity and feelings of energy and fatigue. Medicine and Science in Sports and Exercise, 37(2), 299-305.). You may want to take the Eshragh route of using the POMS or perhaps use another measure that may be able to provide you with that nuance. Although my labs work is not in cancer, I do find that in other patient populations, you can have individuals who are low energy + low fatigue or high fatigue + high energy. Some things to think about. 

You may also want to examine TNF-alpha. Our work finds that TNF-alpha levels increase with increased feelings of fatigue only (we've primarily studied healthy populations, but there is also literature in cancer and fatigue to justify it).  I'd also recommend examining IL-1B as that has shown significant changes after fatiguing and anti-fatiguing conditions, especially in patients with a cancer diagnosis.

You should also examine measuring sleep quality. Our lab has significant evidence in patient populations (not cancer, but other patient populations) that poor sleep may negate the anti-fatiguing effects of exercise. You may be able to use the PSQI for self-reported and perhaps use another Actigraph that can also objectively measure sleep quality. 

Another thing that you might want to keep in mind is using variance as well as mean for physical activity data. Mean can sometimes be deceiving as I can exercise for 100 minutes a day for 3 days and then be sedentary for 4 days and still meet ACSM guidelines for being extremely physically active (although not likely in your population, but something to think about). The variation in PA levels over the course of the week may provide you with evidence as to whether maintaining consistent PA levels over the course of the week is more important than just getting the prescribed >150min to meet PA guidelines (i.e. someone performing 30 min/day of PA for 5 days vs someone performing 50 min/day for 3 days). Additionally, with sedentary behavior you could also look beyond means and also examine variance. Although not yet published some of our work is finding that those will large variations in PA levels (i.e. exercise a lot for 2 days vs exercise consistently for 5-6 days) influence the intensity of positive mood responses of chronic exercise in healthy populations. Something to think about. 

Discussion

I think the discussion is great!

 

 

 

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript is well written, congratulations. The topic is very interesting and could represent a very important contribution to science.

 

Regarding this first version, I place below some comments and suggestions aiming the manuscript improvement, point by point, with page indication.

 

92,93 - "with a 17% (HR, 92 0.83; 95% CI, 0.72-0.95) lower risk of MM compared to low levels of physical activity" – Please consider the phrase “reconstruction” aiming readers quick understanding.

 

92-98 – Please try to standardize paraphrase size in all manuscript and each section.

 

112 – Please align the beginning of the paragraph according to the template and instructions for authors.

 

116 – “WHO” and “ICMJE” should be presented in full.

 

176 – Please confirm the alignment in the beginning of the paragraph according to the template and instructions for authors.

 

206 – The first time “AEP” appearance should be in full.

 

223 – “Prior to supervised sessions” – Who will supervise? With what functions? This is very important.

 

223 – Are the participants active and familiarized with the training tasks? Will it be necessary a familiarization period? Please describe in detail.

 

223 – HR (abbreviation) is suggested herein and throughout the manuscript.

 

225 – Please confirm if more than one space before “Each”.

 

229 – 20-minutes? (before always with “-“). Please confirm and standardize throughout the manuscript.

 

229 – “peak heart rate” should be abbreviated.

 

233-234 – “maximal exercise capacity (V̇O2max) and peak exercise capacity (V̇O2peak)”. The physiological concepts are associated in the text to “exercise capacity”, although, VO2 is associated to oxygen uptake. This should be carefully addressed and explained to the readers since “exercise capacity” may be associated to other limitations, such as the motor.

 

273 - Please confirm if more than one space before “Exercise”.

 

326-328 – Please evaluate if the best option is caps or “  “.

 

350 – “uptake” is suggested instead of “consumption”.

 

352 – “FEO2 and FECO2” – Please describe.

 

365 – How was “low intensity” determined individually for each participant? Please describe.

 

363-381 – How many researchers were present in data collection and with what functions? This should be described in detail as indicated on page 223.

 

404 – BMI should be abbreviated here and not in line 408.

 

459, 474, 482, 503 – Please confirm line spacing.

 

560 – MVPA – Please describe.

 

645 – Where will be data collected? What about conditions (temperature, humidity)? Time of day? Circadian effect? These details can influence data.

 

707 – “3-month” and “6-month”. Please confirm if the format is the same in all manuscript.

 

737 – Please consider other capacities evaluation, for example flexibility may be influenced by impacts. Also variables that can be determined from the incremental CPET, namely GET (gas exchange threshold) and oxygen deficit, are described in the literature to be influenced by exercise programs and are possibilities to be considered in this study, or even indicated as a possibility for future studies. Please consider.

 

772-779 – Please correct with author´s initials.

 

802 – Please correct the references according to the template and instructions for authors (e.g., journal in italic, year in bold, and other format details).

 

 

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

The submitted manuscript describes a study protocol of a randomized controlled trial utilizing an exercise intervention in patients with multiple myeloma. As the target study population has been understudied in the field, it addresses an important topic. However, there are multiple sections that need more consideration and clarifications. Further, there is a lack of justification and description about specific target population (inclusion/exclusion criteria), primary endpoint, and intervention, which need to be revised. Please see the comments below.  

Abstract

• “poorest” may be controversial. “Poor” would be appropriate.
• Author would need to describe briefly how they “individualize” the exercise training. Otherwise, it should be recommended not to use the term “individualized”
• This sentence can be confusing: “The WT will be asked to maintain their current activity levels for 12-weeks before repeating baseline testing and completing the EX group protocol.”

Does this mean WT will maintain for 12 weeks only or there will be additional weeks to maintain for completing the EX group protocol? Please revise

Introduction

• Based on the reference 2, lung cancer shows the poorest quality of life and highest psychological distress. Please revise.
• The following sentence may be overstated as significant correlation does not mean there is causality. “Therefore, interventions that improve HRQoL may also influence disease progression.”.
• Line 52-53: This is not true. The study (reference 10) reported that exercise participation produced a marked improvement in Quality of life. FACT-G scores improved from a baseline of 83.6 to 87.7 at 3 months (P<0.001). Additional results were reported in the article. Please check again and revise accordingly. In particular, HRQoL has been improved by most exercise interventions in cancer populations. It needs more clarifications why authors focus on HRQoL, instead of other outcomes that may need more evidence.
• Overall, this manuscript provides impression that authors define “individualized” as a personal training, rather than individualized frequency, intensity, type and time, volume and progression, based on line 60-62. If not, it needs more explanations. Further, authors did not provide any clear definition of individualized exercise training. Please use the term “individualized” carefully, to prevent confusion from the audience. It is strongly recommended to describe more about individualized exercise intervention as this seems the main emphasis of the paper.
• Line 65: these problems are not just limited to MM. very common in most cancer types.
• Above, authors stated only one single arm study and a RCT. Now authors add more studies line ref 13..
• Authors did not sufficiently introduce the concept of high intensity interval training (HIIT) in MM. Since HIIT has been discussed as a distinct exercise intervention in multiple patient populations including cancer, rather than a regular traditional exercise intervention, authors would need to provide more justification and description how HIIT was selected as an intervention, especially if this would be feasible in this highly disabled patient population. If feasibility is not needed, please explain why not needed.
• Line 92-98 does not flow well with previous paragraphs.

Methods

As this trial was registered years ago, concerns may arise if this study is still ongoing, especially given the small sample size. Publishing a protocol paper may need to be discouraged if the study has been completed.

2.1. trial design and setting.

- Please specify what “multi site” included in the study.

- The waitlist control group design also needs to be emphasized by ethical reason rather than preventing drop out as described by authors.

- Line 154-157: this needs to be included as a power calculation subsection. Also, please clarify the mean difference of 6.7 point would clinically mean. So if authors demonstrated this expected point of 6.7, what does that mean? Reduced mortality by a certain percentage? So target number is 44, not 65? Abstract says n=65. Please clarify.

- Inclusion criteria: Free of musculoskeletal and neurological for patients with MM would not make sense. Most patients with MM have these types of health issues. How is it possible to enroll patients free from all of these? Doesn’t it need to use a risk stratification strategy or any strategies that authors describe?

-Exclusion i needs more clarification. Specify abnormal ECG finding that suggest the increased risk of exercise induced cardiac event, like 2^nd or 3^rd degree heart block? Please provide more information.

Exclusion iv. Again, most MM patients would possibly have physical disability.. Needs more clarification.

-Based on inclusion/exclusion criteria, the potential patient cohort could be possibly more smoldering multiple myeloma without any further clarifications. Also authors did not consider how they will approach patients before or after hematopoietic cell transplant or chemotherapy in inclusion/exclusion criteria. This will make the whole different picture of target population and affect intervention and outcome measures.

- So stratified randomization based on disease stage means 4-5 patients per each? How does this work in n=22 per group? Please provide more information and how power calculation could explain this.

2.5. exercise intervention

Although authors emphasize this intervention as an individualized exercise training but there is no specific information about individualization. Importantly, no safety precautions about exercise training for patients with MM described in this section.

-Does low impact aerobic activities mean non-weight bearing exercise? Please clarify. Also what does it mean by “determined by bone metastases site” It is unclear how authors could determine warm up based on bone metastases site. 60-85% peak heart rate needs to be RPE 12-15? Is that what implies? Needs more clarifications

-Now it is shown as a high intensity interval training. Need more information and justification about HIIT in the introduction. Especially, most patients with MM are frail, meaning they would not be able to perform HIIT + resistance exercise.

-Based on experience, most patients with MM could not achieve true VO2max so VO2peak has been measured. If the estimated peak heart rate will be used, what is the point of doing CPET? Not using ventilatory threshold to prescribe exercise sessions?

-Any other specific resistance training method, rather than focusing on major trunk, upper and lower body muscle groups? This is just a regular RT for anyone.. More consideration with MM would be needed.

-Cost-effectiveness analysis is an important approach, but the main concept was not introduced well in the manuscript until 5.1. section. This is presented all of sudden.

-Again, metabolomic and lipidomic analyses need more information. Targeted or untargeted, what pathway, phenotypes, candidate risk factors are the authors investigating?

Data analysis: this study design would need two-way repeated measures ANCOVA. Please check with biostatistician.

Discussion
Authors would need to discuss expected problems and limitations of the study.

Needs more discussion why HRQOL versus other measure is primary endpoint. It is heavily demonstrated previously that HRQOL is improved by exercise, and ACSM now published their strong recommendation of exercise for all cancer survivors including hematologic cancer to improve HRQOL, but other important markers such as VO2peak or muscular, bone health are still understudied.

Conclusion

If this is a randomized controlled trial, safety, feasibility, and acceptability should have already been demonstrated. It is very unclear which phase this study is. The following article may be helpful for the authors to clarify the phase of the study. PMCID: PMC4522392. From Ideas to Efficacy: The ORBIT Model for Developing Behavioral Treatments for Chronic Diseases. Although multiple studies have shown the feasibility of general exercise interventions in different cancer types, HIIT may need additional safety and feasibility information, especially for MM, given severe physical disabilities. Please provide more considerations on this.

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

I'd like to thank the authors for responding to all of my comments. I look forward to eventually reading the results of the study. 

Author Response

We thank Reviewer 1 for their comments.

Reviewer 2 Report

The authors are to be congratulated, the article has considerably improved and is close to suggestion for publication.

 

Below some changes are suggested line by line. These should be associated with a careful and detailed reading of the entire document prior to the new submission, desirably the last before suggestion for acceptance and publication.

 

144-150 – Please review the template format.

145 – Please place the figure 1 legend according to the journal template.

154-161 – Please review format (for example the justified text).

161-165 – Please review. Too much space, please confirm the journal template.

167-168 – Please review and correct (in bold it seems to be a subtopic).

173 – It is believed “;” is missing.

441-453 – The text format does not seem according to the template, please confirm in these lines and throughout all manuscript.

805-808– “and….” – In all cases without space - Please correct.

832 – References do not seem according to the journal template, please carefully review: in bold the year and not journal number; space between lines, hyperlink; justified text, upper and lower case in journals (in some cases in one format and in others in another).

 

My best wishes for good work in this final stage.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf