Across diseases with transplant-eligible patients, multiple myeloma diagnoses make up 35% of autologous stem cell transplants (ASCT) [1,2]. Due to advancements in this routine noncurative therapy that replaces diseased bone marrow with healthy blood stem cells, life expectancy has been extended by an estimated 5-10 years in patients with multiple myeloma [3]. However, patients with multiple myeloma who receive ASCT often experience physical deconditioning prior to ASCT [4], which leads to a reduced ability in activities of daily function [5] that may contribute to loss of muscle mass and strength. Lowered skeletal muscle mass, a characteristic of sarcopenia, prior to ASCT is correlated with postoperative complications [6]. Patients receiving ASCT, who can experience sarcopenia or sarcopenic obesity at the time of transplant, have an increased risk of worsened overall survival [7].

Patients with multiple myeloma who participate in the ~150 minutes of exercise, as recommended by the American College of Sports Medicine [8,9], experience better clinical outcomes including revised myeloma comorbidity index scores, treatment tolerance, length of hospital stay, remission status, overall survival, and progression-free survival compared to age-matched inactive patients [10]. Physical fitness outcomes, such as muscle strength and cardiovascular fitness, along with quality of life and fatigue, are improved in patients with multiple myeloma who undergo aerobic and resistance exercise training [11]. Previous trials have shown progressive aerobic and resistance exercise training as safe with no adverse events [12], particularly when implemented post-ASCT in patients with multiple myeloma [11,13]. Moreover, preliminary feasibility data indicates challenges with in-person attendance during the pre-ASCT phase and presents the opportunity to study a digitally supervised prehabilitation model to support already suppressed activity levels in this population [14]. With the intent to optimize muscle strength and physical fitness, precise exercise prescription (ie, intensity, duration, and frequency) is currently unclear, given the different exercise program modalities used in patients with multiple myeloma over the past 2 decades [12,13,15-20].

The goal of this randomized controlled trial, “Prehabilitation Exercise Training in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation: The PROTECT (Prehabilitation Exercise Training in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation) trial (Figure 1),” is to assess the impact of digitally supervised, individually tailored prehabilitative aerobic and resistance exercise in patients with multiple myeloma undergoing ASCT (Figure 1) on lower limb muscle strength (primary objective) in the exercise group compared to the waitlist control group. The secondary and tertiary objectives will examine physical capacity (physical function and cardiorespiratory fitness) and patient-reported outcomes (fatigue and quality of life), cardiometabolic health outcomes (biomarkers and body composition), along with posttransplant clinical outcomes including Hematopoietic Cell Transplantation-Comorbidity Index, length of hospital stay, readmission rates, and treatment-related adverse events. Finally, due to the nonprofound changes given the limited intervention period, the exploratory objective is to evaluate the exercise intervention completed post-ASCT on muscle strength, physical capacity, patient-reported outcomes, and cardiometabolic health outcomes. We hypothesize that prehabilitative aerobic and resistance exercise will improve lower limb muscle strength prior to receiving ASCT and 30 days posttransplant in the exercise group compared to the waitlist control group.

The PROTECT trial is a prospective, single-center, two-arm randomized controlled trial conducted at the Dana-Farber Cancer Institute (Boston, Massachusetts). Patients with multiple myeloma scheduled to receive ASCT are randomly assigned to one of two groups: exercise group or waitlist control group. The study schema and timeline (Figure 2) involve an 8-week intervention with a 30-day posttransplant follow-up. This study protocol is in accordance with the Consolidated Standards of Reporting Trials guidelines [21].

This trial includes patients diagnosed with multiple myeloma who are scheduled to receive ASCT with the full inclusion and exclusion criteria depicted in Textbox 1. Potential participants will be identified at the Dana-Farber Cancer Institute through various recruitment strategies including screening hematologic oncology clinic lists, and use of patient advertisements in waiting areas. A study coordinator contacts the patients’ treating providers or oncologists to request permission to contact potential participants who are identified through patient lists. Further screening of potentially eligible participants is conducted by study staff in person or by phone to confirm remaining eligibilities, which includes the use of the Godin Leisure-Time Exercise Questionnaire [22] to assess physical activity history and using questions similar to the Physical Activity Readiness Questionnaire to assess patient’s health status [23]. Patients interested in participating are scheduled for a digital or in-person visit to review the protocol and sign informed consent, with the option to sign consent electronically.

Approval of the trial protocol was obtained from the institutional review board at the Dana-Farber Cancer Institute (22-403) and registered at ClinicalTrials.gov (NCT05706766). All participants review and sign an informed consent document that includes the option to opt-out at any point during the trial. Per Dana-Farber Cancer Institute policy, all patient identification information is deidentified. Participants are provided compensation (US $25) for each testing visit completed in the form of a cash spending card.

Participants are randomly assigned to either the exercise group or the waitlist control group in a 1:1 ratio following the completion of baseline assessments. Prior to the trial start, the study biostatistician prepared the randomization schema and provided the randomization allocation to staff through a web-based application (REDCap [Research Electronic Data Capture]; Vanderbilt University) [24] to blind study investigators to the randomization process. The nature of the exercise intervention prevents blinding the study participants, interventionists, and outcome assessors. However, study investigators adhere to a set protocol to standardize outcome assessments and avoid bias.

Participants are evaluated for potential adverse events (eg, pain, muscle soreness, nausea, and bone pain) during each exercise session in the study period. Phone numbers for study staff are provided to report potential intervention-related adverse events. The National Cancer Institute Common Terminology Criteria for Adverse Events V5 is used to assess participants and documented by the study staff at each exercise session. Study progress and injuries are reported upon during weekly meetings through in-person updates, phone calls, or weekly email updates. Adverse events, both serious and nonserious, and deaths encountered from initiation of study intervention, throughout the study, and within 30 days of the last study intervention sessions, are followed to resolution, or until the principal investigator determines the participant as stable or the event as irreversible, or the participant is lost to follow-up.

We anticipate recruiting 1-2 participants per month, based on the accrual rates (3 to 4 participants per month) of previous exercise intervention studies [48]. A total of 30 eligible participants will be entered into this study and randomly assigned to the intervention and the control groups in a 1:1 ratio (15 per group). The sample size is based on general recommendations (24 to 50) for pilot studies in general [49-51] and this study provides 80% power to detect the effect size of Cohen d=1.15 (taking account of 10% dropout) at .05 two-sided α level.

The primary analysis is a mean difference in percent change from baseline (week 0, preintervention), between the intervention and the control groups in lower leg muscle strength over 2 time points: pretransplant (week 9, postintervention), and posttransplant (week 14-15, 30-day post-ASCT follow-up). Linear mixed-effects models are used to compare the between-group differences at postintervention and follow-up after adjusting for baseline value of the outcome and covariates, where the intervention indicator and time are included as fixed effects and participants are included as random effects. From previous studies, the estimated standard deviation of change in muscle strength (measured through leg press) from baseline to pretransplant is 16.8 kg. Thus, this study will detect a between-group mean difference of 19.3 kg with 80% power. The primary analyses will be based on the intention-to-treat principle including all randomized participants. The same analyses will also be performed with the per-protocol population.

To test hypotheses related to differences in physical capacity, patient-reported outcomes, and cardiometabolic health outcomes across groups at study completion, standard statistical techniques are used to assess within-group differences among each end point (ie, 2-tailed t test or Wilcoxon signed rank test, proportions, and corresponding 95% exact CI, etc) and between-group differences (ie, 2-tailed t tests, two-sample Wilcoxon tests, generalized linear mixed-effects model for longitudinal measurements, and so on). As an exploratory analysis to assess group differences, each clinical outcome as continuous variables (ie, length of hospital stay and the number of comorbidities) and categorical variables (ie, hospital readmission) is analyzed using 2-sample t tests for continuous variables and Fisher exact test will be used for analyzing categorical variables. An exploratory analysis to assess differences in the postintervention self-elected exercise for the waitlist control group will be assessed for end points of aim 1-2 using paired t tests and Cohen d is calculated to determine the effect size.

The primary purpose of the PROTECT Trial is to investigate if an 8-week digitally supervised prehabilitative exercise intervention improves lower limb muscle strength in patients with multiple myeloma. The PROTECT Trial provides a comprehensive assessment of physical capacity, patient-reported health outcomes, and cardiometabolic health as secondary outcomes, and evaluates patient posttransplant outcomes as tertiary outcomes. Furthermore, we will examine the effects of the patient’s self-elected exercise intervention following the ASCT recovery period to explore the benefits of prehabilitative versus rehabilitative exercise.

Outcomes from the PROTECT Trial will provide vital information on muscle strength development using a prehabilitative exercise modality in a patient population with low health status. Various exercise modalities targeting muscle strength have been assessed across cancers, with the most highly studied in breast, prostate, and colorectal cancers, and few interventions implemented within patients with multiple myeloma.

The goal of the proposed exercise intervention in the PROTECT Trial is to improve muscular strength in patients with multiple myeloma, a population more advanced in age (ie, 31.2% aged 65-74 years) [52]. The development of sarcopenia, as a result of disease-related physical inactivity due to immobility or disability (ie, fatigue in response to induction therapy, bone pain as a result of lesions due to disease progression) [53], is associated with post-ASCT complications in patients with multiple myeloma [7] and is indicated by decreased muscle strength [54]. Additionally, inflammation contributes to muscle wasting and may result from tumor cells releasing cytokines, though the biological mechanism of exercise and the inflammatory response is presently unclear in multiple myeloma [55,56]. Chronic low-grade inflammation, common in older adults (inflammaging), may also contribute to decreases in muscle mass, strength, and function (sarcopenia) through multiple pathways, primarily, mTORC1-mediated protein synthesis, metabolism, and mitochondrial biogenesis [56,57].

Proposed mechanisms for counteracting sarcopenia include reducing inflammation, promoting exercise-induced muscle hypertrophy, and decreasing fat infiltration following exercise (sarcopenic obesity) [58-60]. In fact, exercise training attenuates protein degradation signaling pathways and stimulates muscle protein synthesis, with overall anti-inflammatory and antioxidative effects that can mitigate both the sarcopenic effects and cancer-induced muscle wasting that occur [61,62]. In older adults specifically, muscle mass and function are improved with exercise, which increases the expression of insulin-like growth factor 1 and the subsequent increase of muscle protein synthesis [63]. Improved muscular function and strength following aerobic and resistance exercise interventions have been demonstrated in healthy adults and hematologic oncology populations [12,15,64]. Taking these processes and clinical populations into account, we hypothesize the proposed prehabilitative aerobic and resistance exercise intervention will target muscle protein synthesis to improve muscle strength in patients with multiple myeloma scheduled for ASCT.

Current evidence suggests muscle hypertrophy occurs with an estimated number of 18 resistance training sessions, performed over 6-10 weeks [65], which will be captured in the eight-week training period of the proposed exercise intervention. Effective resistance training oriented for hypertrophy consists of mechanical tension and metabolic stress [66] and promotes muscle protein synthesis in relation to muscle protein degradation [67]. The combination of increased muscle protein synthesis, decreased muscle protein degradation, and overall motor learning are supportive of pathways at the molecular level that lead to increased muscle mass, increased muscle force production, and overall physical strength [67]. Furthermore, resistance exercise has been implicated in stimulating the mTORC1 pathway (master growth regulator that senses and integrates diverse nutritional and environmental cues including growth factors, energy levels, cellular stress, and amino acids), which may improve mitochondrial function, increase muscle mass, and improve metabolic health, all in support of the development of muscular strength [62]. Hence, applying said principles of exercise to patients with multiple myeloma supports the primary outcome measure, improving muscular strength, of the PROTECT Trial.

Mechanisms for improvements in physical capacity, cardiometabolic health outcomes, and patient-reported outcomes along with posttransplant clinical outcomes, are described below. Exercise, particularly resistance training as noted above, stimulates muscle protein synthesis, leading to increased muscle mass and strength. However, resistance training also has the potential to improve endurance by enhancing mitochondrial function and improving motor control by neuronal growth. Cardiovascular adaptations increase oxygen transport capacity, cardiovascular health, and metabolic regulation, mitigating the risk of chronic diseases of aging. Additionally, exercise provides mental health benefits, reducing stress and enhancing cognitive function, potentially prolonging longevity and enhancing quality of life, particularly in patients with cancer undergoing pre- and posttransplant therapy.

Prehabilitative exercise, or exercise prior to medical treatment, has been successfully deployed in presurgical candidates and other tumor sites, yet there is a paucity of evidence on the effect of prehabilitation in patients receiving transplant; IMPROVE-BMT is an ongoing investigation to address this topic [68]. A recent study shows that a multimodal intervention program with partially supervised exercise training combined with nutritional support prior to transplant is feasible and safe. Patients showed improvements in fat-free muscle mass, physical performance, and health-related quality of life [69]. Additional research is needed to assess outcomes that support quality of life, overall survival, and relevant clinical outcomes along with the challenges of delivering the exercise in hospital and outpatient settings. Importantly, recent investigations indicate the acceptability and feasibility of delivering exercise prehabilitation, in person and digitally within the ASCT pathway in myeloma, but warrant further investigation on the combined effects and at the level of personalized or individualized therapy [70].

The prehabilitation intervention investigated in this study represents a novel approach to addressing the limited evidence on the benefits of prehabilitation. Prehabilitation, broadly recognized for its potential to enhance physical and psychological resilience, holds promise in optimizing outcomes for patients with cancer. Specifically, its application in the context of multiple myeloma remains understudied. The exploratory aims intend to examine the comparative effectiveness of rehabilitation versus prehabilitation, providing valuable insights into their respective contributions to patient well-being in this clinical setting.

The design of this trial includes digitally supervised, individually tailored prehabilitative exercise intervention that is progressed over the course of 8 weeks. Digital supervision allows for participants who are immunocompromised to safely complete the exercise at home and reduces the need to travel to and from the study site, outside of testing visits that are coordinated with ongoing treatment plans. Each program is designed to progress each week at 5% increments based on baseline strength and cardiorespiratory measures. The individually tailored aspect provides flexibility for patients who experience treatment-related symptoms or are able to easily manage the prescribed exercise.

Strengths of this study design include a rigorously designed exercise intervention, taking into account exercise tolerance, bone pain, development of bone lesions, and limited mobility, and is individually tailored and supervised by a qualified exercise trainer. This approach supports gradual increases in load and volume over the training period and enhances program adherence. The training is conducted digitally, allowing individuals who cannot travel to the research site three times per week to participate and provides scheduling flexibility.

Limitations of this study design include a limited sample size, digital delivery, and short duration of exercise. Training is conducted remotely via a video communication platform Zoom (Zoom Video Communications, Inc), which may restrict the assessment of the full range of motion and utilization of alternative techniques to ensure the correct execution of each movement. Additionally, digital training limits the ability to assess the participant’s state through breathing and facial expressions, potentially impacting the reported RPE and the ability to monitor progression accurately.

The PROTECT Trial will contribute to understanding the role of prehabilitative exercise, in a digitally supervised setting, on muscular strength outcomes in patients with multiple myeloma who receive ASCT. Findings from this trial will provide information on patient health outcomes following transplant including overall functional capacity. Understanding the limitations to exercise within this population may help develop future larger-scale exercise interventions in the prehabilitative and rehabilitative spaces that support patients with multiple myeloma from the time of diagnosis into survivorship.