T Cell Exhaustion Markers in Multiple Myeloma Patients are Lower After Physical Activity Intervention.

PURPOSE: There is compelling evidence that CD4+ and CD8+T cells are dysfunctional in multiple myeloma, compromising their ability to control disease progression. Pre-clinical models suggest that exercise represents a non-pharmacologic means to reduce immune exhaustion, but no studies to date have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in multiple myeloma patients. PATIENTS AND METHODS: The current study includes 24 multiple myeloma patients who participated in a six-month physical activity intervention, consisting of supervised strength training (n = 12) and unsupervised home-based walking arms (n = 12). Comprehensive flow cytometry was utilized to assess the frequency of CD4+ and CD8+T cells and subpopulations expressing the markers of exhaustion PD-1, TIGIT, TIM3 and/or LAG3. Ratios of exhausted to non-exhausted cell populations, and percentages of exhausted to total populations of the same lineage, were calculated for the baseline and final timepoints. RESULTS: Eighteen of 20 exhaustion measures were lower at the end of the intervention than at baseline, and several were significantly or borderline significantly reduced in the entire sample or in one of the arms. The entire sample saw improvements in the ratios of CD4+ TIGIT+ to non-exhausted CD4+ (0.7 [0.6] to 0.6 [0.4], P = .04) and CD8+ PD1+ to non-exhausted CD8+ (1.8 [2.6] to 1.5 [2.0], P = .06), and in total exhausted CD8+ as a percent of total CD8+ (72.9 [21.9] to 68.3 [19.6], P < .01). CONCLUSIONS: This pilot study suggests that physical activity induces changes in MM patients' immune systems, potentially rendering a less exhausted T cell state.

Effects on the Physical Functioning of Two Exercise Interventions in Patients with Multiple Myeloma: A Pilot Feasibility Study.

Because of the high prevalence of bone destruction in patients with multiple myeloma (MM), physical exercise is oftentimes discouraged by healthcare providers. The goal of this prospective trial was to investigate the feasibility of two six-month exercise interventions in patients with MM (N = 42): a remotely prompted home-based walking intervention or a supervised strength training intervention. Physical function and pain were assessed with the Activity Measure for Post-Acute Care (AM-PAC) Basic Mobility Short Form raw score, a six-minute walk test (6 MWT), a 30-second sit-to-stand test (30 SST), a timed up-and-go (TUG) test, a visual analog scale (VAS) for pain, handheld dynamometer tests, heart rate at rest, blood oxygen saturation at rest, and body mass index. No intervention-related serious adverse events were observed. Adverse events mostly affected the musculoskeletal system. In the resistance training group (n = 24), patients showed significant improvements in AM-PAC, TUG, 6 MWT, and 30 SST, with all effects but the 6 MWT sustained six months after the intervention. The walking group (n = 18) saw improvements in the AM-PAC, TUG, 6 MWT, and 30 SST, with a sustained change in the AM-PAC and TUG. This trial shows the feasibility of both exercise interventions with a sustained beneficial effect on the physical functioning of a six-month strength training intervention and, to a lesser extent, a six-month unsupervised walking intervention. A larger study building on these findings is currently underway.

Physical Activity and Patient-Reported Outcomes in Monoclonal Plasma Cell Disorders.

INTRODUCTION: Plasma cell disorders (PCD) are a group of conditions characterized by disproportionate proliferation of a single clone of B lymphocytes. Multiple myeloma (MM) is a malignant type of plasma cell disorders. Improvements in MM survival have led patients and physicians to pursue strategies to improve quality of life for those living longer with this disease. Bone disease and instability associated with MM have made physicians reluctant to recommend physical activity (PA) to this patient population. The goal of this study was to examine the relationship between PA and physical and psychosocial patient-reported outcomes in patients with MM and precursor conditions. METHODS: We used a cross-sectional study design. Questionnaires on PA, demographics, fatigue, distress, and other aspects of quality of life were posted on the HealthTree® Cure Hub website, a patient portal through which individuals with MM and related disorders obtain support, track laboratories and other information about their diseases, and participate in research. RESULTS: A total of 794 individuals, including 664 with MM, are included in the current analysis. We observed potential inverse associations between PA and poor quality of life, including problems with sleep, fatigue, neuropathy, distress, and several psychosocial states. On average, patients reported that their PA levels have declined since diagnosis and that they would like to be even more active in the future than they were before their diagnosis. CONCLUSIONS: In our cross-sectional study, regular PA was associated with multiple quality-of-life indicators and other patient-reported outcomes, including better sleep and less fatigue, neuropathy, and distress. The findings of this study can help guide the design of prospective studies of the role of PA in MM survivorship.

Physical Activity in Multiple Myeloma: A Review of the Current Literature.

One of the major issues patients with multiple myeloma (MM) suffer from is bone instability and the resulting difficulties that come along with it, such as pain and immobility. Few studies have been performed in this patient group to investigate the effects of physical exercise on outcomes such as muscle strength, quality of life, fatigue, and pain. A PubMed search was conducted by entering the search terms "multiple myeloma" and "exercise," and "multiple myeloma" and "physical activity" that yielded 178 and 218 manuscripts, respectively. Limiting the search results to clinical trials left 13 and 14 manuscripts, respectively, and 7 studies (1 retrospective chart review, 1 questionnaire study, and 5 prospective clinical trials). The majority of these studies (5) were published in the past decade. The outcomes of several studies of exercise in MM show that physical exercise is feasible for MM patients. Compared with the control groups, the most active participants show better outcomes, such as improvements in their blood counts and in quality-of-life parameters such as fatigue, pain, sleep, and mood. One trial found that MM patients were in much poorer condition than people in a normative standard group. Some of the reported outcomes of exercise in MM have been promising but need to be substantiated in a broader setting with more diverse participants, for a longer duration, and include more endpoints. Due to the disease-inherent risk of bone-related complications, an individualized, supervised training protocol could be a preferable tool.

Association of resilience with health-related quality of life and depression in multiple myeloma and its precursors: results of a German cross-sectional study.

OBJECTIVES: To investigate the relation between resilience, health-related quality of life (HRQOL) and depression in multiple myeloma (MM) and its premalignant stages. MM is one of the most frequent haematological disorders. It is regularly preceded by asymptomatic stages of the disease namely monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM). Survivors have to cope with mental and physical impairment in terms of HRQOL and depression. The concept of resilience refers to a person's ability to adapt to adversity. DESIGN: Cross-sectional study. SETTING: MM outpatient department at a University Hospital in Germany (tertiary care). PARTICIPANTS: 292 consecutive patients from our MM outpatient department. OUTCOME MEASURES: HRQOL, depression and psychological resilience were assessed with validated questionnaires. RESULTS: Regression analyses were performed to determine associations between resilience, HRQOL and depression. 98 patients (33.6%) had a new diagnosis of active MM, 106 patients (36.3%) were already treated for MM and 88 patients had the diagnosis of a precursor (MGUS or SMM; 30.1%) of MM. Multivariate linear regression analyses revealed a strong positive impact of resilience on physical (b 7.20; 95% CI 4.43 to 9.98; p<0.001) and mental (b 12.12; 95% CI 9.36 to 14.87; p<0.001) HRQOL. Ordered logistic regression analysis showed that the odds for higher depression severity were lowered for individuals with a high level of resilience in comparison to the individuals with a low level of resilience (OR 0.11; 95% CI 0.06 to 0.19; p<0.001). CONCLUSIONS: Resilience may be a protective factor in the disease trajectory of MM and its precursors. As a next step, future research should focus on longitudinal assessments at various time points to elucidate the role of resilience in one of the most frequent haematological malignancies.

Association between magnetic resonance imaging patterns and baseline disease features in multiple myeloma: analyzing surrogates of tumour mass and biology.

OBJECTIVE: To assess associations between bone marrow infiltration patterns and localization in magnetic resonance imaging (MRI) and baseline clinical/prognostic parameters in multiple myeloma (MM). METHODS: We compared baseline MM parameters, MRI patterns and localization of focal lesions to the mineralized bone in 206 newly diagnosed MM patients. RESULTS: A high tumour mass (represented by International Staging System stage III) was significantly associated with severe diffuse infiltration (p = 0.015) and a higher number of focal lesions (p = 0.006). Elevated creatinine (p = 0.003), anaemia (p < 0.001) and high LDH (p = 0.001) correlated with severe diffuse infiltration. A salt and pepper diffuse pattern had a favourable prognosis. A higher degree of destruction of mineralized bone (assessed by X-ray or computed tomography) was associated with an increasing number of focal lesions on MRI (p < 0.001). Adverse cytogenetics (del17p/gain1q21/t(4;14)) were associated with diffuse infiltration (p = 0.008). The presence of intraosseous focal lesions exceeding the mineralized bone had a borderline significant impact on prognosis. CONCLUSIONS: Diffuse bone marrow infiltration on MRI correlates with adverse cytogenetics, lowered haemoglobin values and high tumour burden in newly diagnosed MM whereas an increasing number of focal lesions correlates with a higher degree of bone destruction. Focal lesions exceeding the cortical bone did not adversely affect the prognosis. KEY POINTS: • Diffuse MRI correlates with adverse cytogenetics, lowered haemoglobin and high tumour burden. • Higher numbers of MRI focal lesions correlate with increasing degree of bone destruction. • Focal lesions exceeding the cortical bone borderline significantly influence survival. • Moderate/severe diffuse infiltration and more than 23 focal lesions adversely affect survival.

A magnetic resonance imaging-based prognostic scoring system to predict outcome in transplant-eligible patients with multiple myeloma.

Diffuse and focal bone marrow infiltration patterns detected by magnetic resonance imaging have been shown to be of prognostic significance in all stages of monoclonal plasma cell disorders and have, therefore, been incorporated into the definition of the disease. The aim of this retrospective analysis was to develop a rapidly evaluable prognostic scoring system, incorporating the most significant information acquired from magnetic resonance imaging. Therefore, the impact of bone marrow infiltration patterns on progression-free and overall survival in 161 transplant-eligible myeloma patients was evaluated. Compared to salt and pepper/minimal diffuse infiltration, moderate/severe diffuse infiltration had a negative prognostic impact on both progression-free survival (P<0.001) and overall survival (P=0.003). More than 25 focal lesions on whole-body magnetic resonance imaging or more than seven on axial magnetic resonance imaging were associated with an adverse prognosis (progression-free survival: P=0.001/0.003 and overall survival: P=0.04/0.02). A magnetic resonance imaging-based prognostic scoring system, combining grouped diffuse and focal infiltration patterns, was formulated and is applicable to whole-body as well as axial magnetic resonance imaging. The score identified high-risk patients with median progression-free and overall survival of 23.4 and 55.9 months, respectively (whole-body-based). Multivariate analyses demonstrated that the magnetic resonance imaging-based prognostic score stage III (high-risk) and adverse cytogenetics are independent prognostic factors for both progression-free and overall survival (whole-body-based, progression-free survival: hazard ratio=3.65, P<0.001; overall survival: hazard ratio=5.19, P=0.005). In conclusion, we suggest a magnetic resonance imaging-based prognostic scoring system which is a robust, easy to assess and interpret parameter summarizing significant magnetic resonance imaging findings in transplant-eligible patients with multiple myeloma.