Symptom clusters and quality of life in ambulatory patients with multiple myeloma

The aim of this study was to investigate symptom clusters and associated clinical factors in ambulatory multiple myeloma patients undergoing medication therapy. We also aimed to determine the correlations between symptom clusters and patient quality of life. A total of 174 multiple myeloma patients hospitalized in the haematology day unit were included in this study. A cross-sectional survey was conducted to examine symptoms and quality of life. Symptoms were assessed by the Chinese version of the Condensed Memorial Symptom Assessment Scale. Quality of life was measured with the Functional Assessment of Cancer Therapy-General. Principal component analysis was used to identify symptom clusters. Independent-samples t tests and chi-square tests were used for comparisons between groups. Spearman’s rank correlation analysis was used to identify correlations. We identified three symptom clusters in multiple myeloma patients: psychological; pain, dry mouth, and difficulty sleeping; and fatigue symptom cluster. For each symptom cluster, the patients could be categorized into a severe-symptom group or a mild-symptom group based on the distress of symptoms. The patients in each group exhibited differential demographic and clinical features. Symptom cluster distress was adversely correlated with patients’ quality of life. Ambulatory multiple myeloma patients undergoing anticancer medication therapy experience multiple symptoms, which can be categorized into three symptom clusters. For each symptom cluster, level of distress was associated with patients’ demographic and clinical characteristics. The presence and level of distress of these symptom clusters have adverse impacts on patients’ quality of life.


Introduction
Multiple myeloma (MM) is a commonly seen haematological malignancy without cure [1]. Since 1990, the incidence of MM has increased uniformly in different countries [1]. In 2020, there were over 32,000 estimated new MM cases in the USA, and approximately 13,000 MM-related patients were lost [2]. Although MM remains incurable, MM patients' survival time has been significantly prolonged in recent decades because of the application of new drugs and advances in disease management [3]. Kumar et al. reported that the median survival of MM treated with modern therapy was nearly 6 years [4]. After disease diagnosis, the aim of MM nursing care includes symptom control and quality of life (QOL) maintenance. Dodd et al. first proposed the concept of a 'symptom cluster' (SC) in oncology [5]. An SC was defined as 'concurrent and related symptoms that may or may not have a common aetiology' [6]. Previous studies have shown that cancer patients often experience multiple symptoms, and some symptoms cluster together as SCs [7][8][9]. The symptoms in an SC may share similar physiological or pathological mechanisms, thus providing ideas for more efficient interventions targeted to SCs [10]. MM patients may experience various symptoms that depend on the patient's stage of disease and treatment regimen. Jordan et al. reported that fatigue, bone pain, sleepiness, hypoaesthesia or paraesthesia, and muscle cramps were the most commonly observed symptoms in MM patients [11]. Ramsenthaler et al. found that MM patients experienced different levels of fatigue, pain, drowsiness, tingling in hands/feet, and sleeping problems from baseline to 8 months [12]. Ramsenthaler et al. also showed that the four most prevalent symptoms in MM (prevalence ≥ 50%) were fatigue, constipation, pain, and tingling in the hands/ feet [13]. However, SCs in MM had not yet been demonstrated. Hereby, we initiated this study to investigate MM SCs, determine the influencing factors of SCs, and analyse the correlations between SCs and QOL in MM patients.

Design and participants
We conducted a cross-sectional survey to assess the symptoms and QOL of MM patients who had been admitted to the haematology day unit of West China Hospital, Sichuan University, from June 27, 2019, to January 31, 2020. Patient inclusion criteria were as follows: (1) diagnosed with MM, without any other coexisting cancers; (2) age ≥ 18 years; (3) receiving myeloma anticancer medication therapy during the survey; (4) not receiving haematopoietic stem cell transplantation or bone marrow transplantation during the survey; (5) estimated length of stay ≤ 24 h; (6) normal cognitive ability and capable of listening, speaking, reading, and writing; and (7) willing to participate in the study. Patients admitted to the day unit more than once only participated in this study once. Eligible patients were identified by registered nurses who worked in the haematology day unit at the hospital. The study's objectives and patients' rights were explained to the eligible patients. Written informed consent was obtained from the participants by a research assistant. A total of 248 MM patients were invited to join the study, and 186 patients agreed to participate. Among the 186 participants, 12 (6.45%) MM patients were excluded because > 20% of their data were missing. A total of 174 MM patients were finally enrolled. This study was preapproved by the Biomedical Research Ethical Committee of West China Hospital (no. 2019504) and was conducted in accordance with the principles of the Declaration of Helsinki.

Measurement of demographic and clinical variables
Demographic characteristics, including age, gender, and educational level, were recorded 24 h after admission. Clinical characteristics, including time since MM diagnosis, Revised International Staging System (R-ISS) stage of MM [14], type of multiple myeloma, current treatment regimen, cycle number of treatment, treatment response, relapsed/refractory status, comorbidities (such as diabetes, anaemia, and skeletal lesions), and serum globulin, within 24 h after admission or in the 7 days before admission, were retrieved from the hospital information system.

Symptom measurement
Symptoms were assessed using the Chinese version of the Condensed Memorial Symptom Assessment Scale (CMSAS), a validated questionnaire to assess cancer patients' symptoms in the past 7 days [15,16]. The CMSAS consists of 14 symptom items: lack of energy, lack of appetite, pain, dry mouth, weight loss, feeling drowsy, shortness of breath, constipation, difficulty sleeping, difficulty concentrating, nausea, worrying, feeling sad, and feeling nervous. The first 11 items are physical symptoms, recording the prevalence and distress of each symptom. The distress of each symptom was assessed as follows: score of 0 for 'not present', 0.8 for 'not at all', 1.6 for 'a little bit', 2.4 for 'somewhat', 3.2 for 'quite a bit', and 4.0 for very much'. The last 3 items were psychological symptoms, recording the prevalence of each symptom as follows: score of 0 for 'not present', 1 for 'rarely', 2 for 'occasionally', 3 for 'frequently', 4 for 'almost constantly'. The average score of the 14 symptoms represented the total symptom distress [16]. Higher scores indicate more symptom distress.

Quality of life measurement
QOL was measured with the Functional Assessment of Cancer Therapy-General (FACT-G), which consists of 27 items in 4 subscales: physical well-being, social/family well-being, emotional well-being, and functional well-being [17]. Each item was scored from 0 (not at all) to 4 (very much). The score ranges were 0-28, 0-28, 0-24, and 0-28 for the physical well-being, social/family well-being, emotional well-being, and functional well-being subscales, respectively. The total QOL score is the sum of all subscales (range 0 to 108). Higher scores indicate better QOL. The Chinese version of the FACT-G has been previously validated [18].

Data collection
Two research assistants approached the patients for survey and data collection. The demographic and symptom data were collected through print-out survey forms, and participants were asked to fill out the forms at their bedside. The patients could read the questions by themselves or have them read by the assistants, according to the patient's preference. Participants' clinical characteristics were retrieved from their medical records through the hospital information system.

Statistical analysis
All data were analysed by SPSS (version 21.0). The frequency, percentage, mean, and standard deviation were calculated for the patients' demographic information, clinical features, symptom prevalence, and symptom distress. Differences between two groups were analysed by independentsamples t tests for quantitative data or chi-square tests for qualitative data. Correlations between SC and QOL were analysed by Spearman's rank correlation analysis. p < 0.05 was considered statistically significant.

Symptom cluster and subgroup identification
To identify SCs, we conducted principal component analysis (PCA), which is commonly used for SC identification [19]. First, to increase clinical significance, only symptoms with a prevalence rate ≥ 30% were included in the analysis. Second, the distress scores of selected symptoms (prevalence rate ≥ 30%) were analysed using PCA with varimax rotation. The symptoms were identified as a SC when (1) eigenvalues were > 1; (2) their factor loadings were ≥ 0.5 (if one symptom's factor loading was ≥ 0.5 in multiple components, the symptom was allocated to the component with the highest factor loading value); and (3) at least two symptoms were categorized in a component, with a Cronbach's α ≥ 0.60.
To identify the subgroups of MM patients, we conducted a K-means cluster analysis separately for each SC. K-means cluster analysis is a grouping method that can classify the samples into several groups based on the similarity measurement calculated by the squared Euclidean distance. K-means cluster analysis was used for SC subgroup identification [20]. For each SC, the patients were classified into two subgroups: a severe-symptom group and a mild-symptom group.

Symptom clusters in myeloma patients
Three SCs were identified: psychological SC (including symptoms of feeling nervous, worrying, and feeling sad); pain, dry mouth, and difficulty sleeping SC (including symptoms of pain, dry mouth, and difficulty sleeping); and fatigue SC (including symptoms of feeling drowsy, difficulty concentrating, and lack of energy). These SCs accounted for 60.32% of the total variance. Cronbach's α coefficients of the psychological SC; pain, dry mouth, and difficulty sleeping SC; and fatigue SC were 0.857, 0.608, and 0.612, respectively (Table 3).

Myeloma patient subgroup analyses based on symptom clusters
We identified two patient subgroups by K-means cluster analysis for each SC. The severe-symptom group represented the group with the higher distress score, while the mild-symptom group represented the group with the lower distress score. For each SC, the demographic, treatment, and disease characteristics in these two subgroups are presented in Table 4 and Table 5. In the psychological SC, the average patient age in the severe-symptom group was younger than that in the mild-symptom group (p = 0.033). In addition, in the severe-symptom group, there were higher ratios of female patients and patients with a treatment response < partial response (PR) and anaemia than in the mild-symptom group (p = 0.027, 0.034, and 0.024, respectively). In the pain, dry mouth, and difficulty sleeping SC, there were higher ratios of female patients and patients with a treatment response < PR, relapsed or refractory disease, diabetes, or serum globulin > 40 g/L in the severe-symptom group than those in the mild-symptom group (p = 0.044, 0.002, 0.022, 0.019, and 0.040, respectively). In the fatigue SC, there were higher ratios of patients with time since MM diagnosis ≥ 24 months, a treatment response < PR, and relapsed or refractory disease in the severe-symptom group than those in the mild-symptom group (p = 0.038, 0.000, and 0.008, respectively).

Correlations between symptom clusters and patient quality of life
In this study, Cronbach's α of the FACT-G was 0.893. The patients' total QOL score was 79.54 ± 14.46. The subscale scores for physical well-being, social/family well-being, emotional well-being, and functional well-being were 23.21 ± 4.20, 21.38 ± 5.38, 19.92 ± 3.76, and 15.02 ± 5.80, respectively. The total score and each subscale QOL score were all negatively correlated with the psychological SC; the pain, dry mouth, and difficulty sleeping SC; and the fatigue SC (all p < 0.05; Table 6).

Discussion
To our knowledge, this was the first report of SC investigation in MM. In this study, we identified three SCs in 174 MM patients who had been treated in the haematology day unit in our institute. The first SC was the psychological SC, which included symptoms of feeling nervous, worrying, and feeling sad. Although the specific symptom items might differ within the cluster, the psychological SC has been demonstrated to be a common SC in patients with cancer, regardless of whether they present with a solid tumour or haematological malignancy [7][8][9]. Specific psychological symptoms in MM have been reported in previous studies [21]. Ramsenthaler et al. found that almost one-third of MM patients claimed anxiety [12].
Our data showed that in the psychological SC, the patients with severe-symptom distress were younger than those with mild-symptom distress. Van der Poel et al. also reported that elderly MM patients (> 65 years) had better emotional functioning than young patients (≤ 65 years) [22]. The reason for such a difference remains unknown. This might be because elderly patients have better coping strategies due to their more extensive life experience compared with younger patients. Furthermore, in agreement with previous studies, our data showed that more female patients reported severe-symptom distress within the psychological SC than male patients [9,23]. Finally, the distress level of the psychological SC was influenced by the patients' treatment outcome and disease characteristics. Patients with a treatment response < PR or anaemia were more likely to report severe symptom distress for the psychological SC than their counterpart patients.
The pain, dry mouth, and difficulty sleeping SC was also identified in our MM patients. Studies have shown that pain and sleep disturbance always coexist in an SC in cancer patients [24][25][26]. Krause et al. showed that sleep deprivation enhanced pain responses within the primary sensing regions in the brain and weakened the activity in other regions that modulated pain processing [27]. Such findings provide physiological evidence of the coexistence of pain and sleep disturbance in cancer patients. Symptoms of pain, dry mouth, and sleep disturbance were reported in MM patients [28][29][30]. In the pain, dry mouth, and difficulty sleeping SC, we found the ratio of female patients was higher in the severe-symptom group than that in the mild-symptom group. SD, standard deviation; MM, multiple myeloma; R-ISS, Revised International Staging System; PI, proteasome inhibitors; IMiD, immunomodulatory drugs; PR, partial response. ' ≥ PR' includes stringent complete response, complete response, very good partial response, and partial response. ' < PR' includes minimal response, stable disease, progressive disease, and clinical relapse; anaemia was defined as haemoglobin < 120 g/L in male adults or haemoglobin < 110 g/L in non-pregnancy female adults   SC, symptom cluster. The symptoms were measured by the Condensed Memorial Symptom Assessment Scale (CMSAS); four symptoms were excluded in the principal component analysis because of the prevalence < 30%: weight loss, lack of appetite, nausea, and shortness of breath The data for each symptom corresponding to each SC column represents the factor loading; factor loadings measure the relationship between each variable (symptom) and their components (SC) and can be interpreted as correlation coefficients, ranging between − 1.0 and + 1.0; symptoms included in the SCs demonstrated factor loadings ≥ 0. Studies found that females had lower pain acceptance than males [31], and being female was significantly associated with poor sleep [32]. Although it is not the common belief that there is an association of gender with pain tolerance or quality of sleep, many studies recognize that pain and quality of sleep may associate with genders. Bartley EJ et al. stated that 'Much population-based research consistently demonstrates greater pain prevalence among women relative to men, and some studies have reported greater pain severity among women than men.' [33]. Ohayon et al. reviewed more than 50 studies of insomnia based on data collected in various representative community-dwelling samples or populations, and found that insomnia prevalence is higher in women than that in men [34]. Therefore, whether the female MM patients were more likely to be bothered by the pain, dry mouth, and difficulty sleeping SC needs to be further studied. We also found that patients with type 2 diabetes reported severe distress for symptoms in the pain, dry mouth, and difficulty sleeping SC. Pain in MM patients might be associated with skeletal lesions and peripheral neuropathy induced by tumour oppression, M-protein, and myeloma anticancer medication (e.g. thalidomide, bortezomib); in MM patients with type 2 diabetes, pain might also be caused by diabetes-related peripheral nervous system damage [35]. Dry mouth in MM patients might be induced by multiple factors, such as M-protein, myeloma anticancer medication (e.g. thalidomide), and vitamin B deficiency [30]. In MM patients with type 2 diabetes, dry mouth symptoms might also be induced by hyperglycaemia-caused salivary secretion disorder by oxidative stress and inflammation [36]. Sleep Table 4 Comparison of demographic and treatment characteristics between severe-symptom and mild-symptom groups according to SCs (N = 174) Only 162 patients were analysed for treatment response because 12 patients were not assessed for response; SD, standard deviation; SC, symptom cluster; MM, multiple myeloma; PI, proteasome inhibitors; IMiD, immunomodulatory drugs; PR, partial response; ' ≥ PR' includes stringent complete response, complete response, very good partial response, and partial response; ' < PR' includes minimal response, stable disease, progressive disease, and clinical relapse; t test was used for comparing the age between the severe-symptom group and mild-symptom group, and the chi-square tests were used for variables other than age  Table 5 Comparison of disease characteristics between severe-symptom and mild-symptom groups according to SCs (N = 174) SC, symptom cluster; SD, standard deviation; MM, multiple myeloma; R-ISS, Revised International Staging System; anaemia was defined as haemoglobin < 120 g/L in male adults or haemoglobin < 110 g/L in non-pregnancy female adults; haemoglobin and serum globulin were tested within 24 h after admission or in the 7 days before admission; chi-square tests were used for comparing the variables between the severe-symptom group and mild-symptom group disorder in MM is probably associated with medication (e.g. dexamethasone) and pain; in MM patients with type 2 diabetes, diabetes-related neuropathic pain and nocturia from poor glycaemic control may also lead to sleep disorder; furthermore, diabetic neuropathy would affect central control of respiration and upper airway neural reflexes, and promote sleep-disordered breathing [37,38]. Therefore, if MM patients have type 2 diabetes, the pain, dry mouth, and difficulty sleeping SC may be more extreme. Finally, the severity of MM disease and the treatment outcome highly affected the distress associated with the pain, dry mouth, and difficulty sleeping SC. In this study, symptoms of feeling drowsy, difficulty concentrating, and lack of energy were categorized into the fatigue SC, which includes physical and cognitive fatigue. Fatigue is the most frequent symptom reported in MM patients, with a high prevalence of 55 ~ 98.8% [13,28,29]. We found that the patients with a long time since diagnosis (≥ 24 months), a poor treatment response (< PR), and relapsed or refractory disease tended to report severesymptom distress within the fatigue SC in contrast to their counterpart patients. Mols et al. found that patients with MM complained of a significant increase in fatigue from baseline to the 1-year follow-up [39]. A previous study also observed that fatigue was significantly higher in relapsed or refractory MM patients than in the control group [40].
QOL improvement is one of the most important goals for MM management. Based on our findings, the MM patients with severe-symptom distress in the psychological SC; the pain, dry mouth, and difficulty sleeping SC; and the fatigue SC had inferior QOL in all domains and overall scores. These results are consistent with previous studies in other cancers [41][42][43]. Although no studies have assessed the correlation between SCs and QOL in MM patients, the correlations between specific symptoms and QOL have been addressed in MM. For example, symptoms of pain, fatigue, anxiety, and depression correlated with QOL in MM [11,13]. With the determinant role of symptom distress in cancer patients' QOL, one unique feature of MM, compared with other cancers, was that the overall survival of MM has been significantly prolonged in recent decades, yet the disease remains incurable. Thus, living with cancer and experiencing multiple rounds of treatment might be more common in MM patients than in patients diagnosed with other human cancers. At least for some patients, MM might be considered a chronic disease, and QOL for those patients was as important as the outcome of cancer therapy. Targeting SCs rather than single symptoms allows for more thorough symptom assessment, simplified interventions, and more efficient symptom management [10]. Additionally, because individual symptoms of MM are associated with decreases in QOL [11,12], it is logical that clusters of symptoms may have a greater impact on QOL than single symptoms. Therefore, our data provided first-hand evidence to show the inter-correlations of MM disease status, SCs, and QOL. Our data also encourage health care givers to provide special attention to specific patient groups, such as young, female MM patients.

Limitations
There were some limitations in this study. First, the study was carried out in the day haematology unit of one hospital. Furthermore, MM patients receiving some treatment regimen, such as transplantation, were excluded from this study. Furthermore, in this study, only 4 patients were treated with daratumumab, and no patients were treated with selinexor or venetoclax. Thus, the results could not fully represent all MM patients who underwent treatment. Second, like many other similar studies, we assessed each symptom using only one item with a general symptom scale for cancer (not specific for MM). The limited number of symptoms included in the CMSAS can result in symptoms going unreported (e.g. diarrhoea, numbness, or tingling in hands/feet). In addition, the development of CMSAS was based on the hypothesis that 'health-related QOL might be an important criterion for identifying a set of core symptoms', and the relationship between CMSAS and FACT-G was also one of the indicators to verify the reliability of CMSAS [15]. Therefore, it is essential to choose more comprehensive and precise symptom assessment tools in future research. Third, the crosssectional survey could clarify neither the causal relationships between associated factors and SCs nor the patterns of SCs over time. A longitudinal study is needed to address these issues. Additionally, since their pharmacological and toxicological effects differ, the numbers and composition of SCs between PI and IMiD may also differ. However, only a limited number of patients were included in this study, and we cannot categorize patients according to PIs versus IMiDs.

Implications for clinical practice
Symptom management and QOL improvement are particularly important for MM patients because many patients have more than 5 years of overall survival with the cancer. We identified three SCs in MM patients: the psychological SC; the pain, dry mouth, and difficulty sleeping SC; and the fatigue SC. The correlations of patient characteristics, CS, and QOL were investigated. In general, patients with more severe disease conditions and less encouraging treatment responses show increased SC distress. Some patient subgroups, such as female MM patients and young MM patients, may experience severe SC distress. Clinical practitioners should develop individualized SC interventions based on the patients' demographic and clinical characteristics. For example, female MM patients may experience more distress from the psychological SC and the pain, dry mouth, and difficulty sleeping SC; thus, assessing psychological status, pain symptoms, and sleep quality and providing appropriate interventions are essential for these patients. Patients with a treatment response < PR might suffer from all three SCs (psychological; pain, dry mouth, and difficulty sleeping; and fatigue), and so a series of comprehensive interventions might be needed. In addition, some influencing factors of SCs and the pattern of SC changes over time are still unclear; further research is needed to provide evidence for precise symptom management.

Conclusions
We assessed the symptoms in ambulatory MM patients undergoing medication therapy in the day unit of our hospital and identified three SCs: the psychological SC; the pain, dry mouth, and difficulty sleeping SC; and the fatigue SC. SC distress was associated with patients' demographic and clinical characteristics. In MM patients, for each SC, distress was negatively correlated with QOL. Since the symptoms within an SC are interconnected, targeting the cluster might benefit patients' QOL and thus improve health care quality.