Evaluating the anti-tumour effects of physical activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance

Student thesis: Doctoral ThesisPhD

Abstract

A higher physical activity level is associated with reduced risk of clinically diagnosed cancers, including multiple myeloma (MM) (Moore et al., 2016). MM is preceded by two precursor stages – monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) (Landgren et al., 2009) – which carry an estimated 1% and 10% risk of progression to MM per year, respectively, and are not actively treated to avert disease progression (Kyle et al., 2010; Kyle et al., 2007; Kyle et al., 2002). A prior case study of one patient with SMM, with an elite sporting background, indicated that disease activity – measured in blood – may be reversed by regular exercise training (Boullosa, Abreu, Tonello, Hofmann, & Leicht, 2013). However, the acceptability of exercise training and its effects on disease activity biomarkers are yet to be determined in a representative group of MGUS and SMM patients. In Chapter 3, it was found that progressive exercise training for 16 weeks is feasible and safe for patients with MGUS and SMM. However, as reported in Chapter 4, in contrast to the aforementioned case study (Boullosa et al., 2013), it was found that exercise training does not reverse disease activity in people with MGUS and SMM. The finding herein that MGUS and SMM disease activity was unchanged by exercise training appears to contradict the observation that MM risk is reduced in physically active persons, particularly as a high physical activity level does not appear to reduce the risk of developing cancer precursors (Boutron-Ruault, Senesse, Meance, Belghiti, & Faivre, 2001). However, these observations are likely to be synergistic and explained by a unifying anti-cancer mechanism of exercise that remains to be defined. Indeed, as outlined in Chapter 2, numerous anti-cancer mechanisms of exercise are commonly purported, yet many lack supportive evidence. The strongest evidence indicates that exercise-induced modulation of the immune system may be the principal driver of reduced clinical cancer risk in physically active persons. As such, a key aim of Chapter 2 was to interpret findings from the exercise immunology literature in the context of cancer immunoediting, the most widely-accepted model for immune–cancer interactions, which describes elimination, equilibrium, and escape phases of tumorigenesis (Dunn, Bruce, Ikeda, Old, & Schreiber, 2002). The findings amassed in Chapter 2 indicate that regular exercise likely enhances immune competency, leading to the elimination of immunogenic cancer cells within the tumour microenvironment by effector immune cells, resulting in the maintenance of covert cancers in equilibrium (Dunn et al., 2002). It is likely that the aforementioned deductions explain why 16 weeks of exercise training had no effect on MGUS and SMM disease activity, as MGUS and SMM are poorly immunogenic and are positioned within the equilibrium phase of immunoediting (Nakamura, Smyth, & Martinet, 2020). Furthermore, in Chapter 5, it was found that 16 weeks of exercise training had no effect on immune competency in blood – including T cell senescence, exhaustion, anergy, or stemness – in patients with MGUS and SMM. It may be that exercise-induced changes to immune competency are more apparent within the tumour microenvironment, as the site of cancer–immune interactions. Future trials are required to explore the long-term effects of exercise training on time-to-progression from MGUS and SMM to MM, and on immune competency within the tumour microenvironment. Such trials will be amongst the first to investigate whether exercise training reduces clinical cancer risk in humans.
Date of Award1 Nov 2021
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorJohn Campbell (Supervisor), James Turner (Supervisor), Oliver Peacock (Supervisor) & Sally Moore (Supervisor)

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