Social frailty predicts worse outcomes in patients with multiple myeloma: A novelty in an old approach

Abstract Social frailty, defined as the loss of social roles and networks in the community, has never been evaluated in patients with multiple myeloma (MM). This study aimed to evaluate the usefulness of social frailty as a predictor of survival in MM. We retrospectively reviewed 237 consecutive patients with MM from 2009 to 2019. Activities of daily living (ADL), the instrumental ADL score, the Charlson Comorbidity Index, and factors to evaluate social relationships were routinely assessed at the time of initial diagnosis and first hospitalization at our center by hematological clinicians, nurses, and rehabilitation staff. Social frailty was evaluated using five social factors and was defined as a score of at least 2 points. Overall, 69 (30.0%) patients were defined as socially frail, with a median score of 0. Those who were socially frail showed significantly shorter progression‐free and overall survival than those who were not. Using the International Staging System, International Myeloma Working Group frailty score, and social frailty, we developed two staging systems, and these further demonstrated the importance of assessing frail patients with MM. Our findings have identified the usefulness for evaluating social frailty; however, to confirm our results, an independent study with larger patient numbers with an entirely prospective assessment is needed to confirm their results.

Eastern Cooperative Oncology Group performance status (ECOG PS), age, and CCI are useful predictors of survival among patients with transplant-ineligible MM [12]. The Revised Myeloma Comorbidity Index (R-MCI), developed by Engelhardt et al to weight the Initial Myeloma Comorbidity Index (I-MCI), showed a significant survival impact when 13 risk factors including organ function and MM-specific risks were considered [13]. Although these representative variables could predict patient outcomes and help identify patients who will benefit from triplet/quadruplet combination therapy or ASCT, these have not been used to evaluate a patient's relationship or role in the social community because the variables mainly assess physical ability, physical frailty, and organ function [4,11,[13][14][15][16][17].
Only recently has the concept of "social frailty" been proposed [18][19][20]. Social frailty, referred to as social isolation, indicates the loss of social roles and networks in the community and is related to physical frailty or vulnerability [20][21][22][23]. In general, elderly people become physically frail and considering the median age of 70 years at MM diagnosis, some patients may experience a decline in physical function and social relationships. The natural history and unique biology of an individual's myeloma disease presentation, comorbidities, and social environment are all relevant factors [24]. Although numerous reports regarding the biology of myeloma, both in vivo and in vitro, and physical frailty have been reported, social relationships or social frailty have never been evaluated objectively. Hence, this study aimed to evaluate social relationships and their prognostic impact in patients with MM. We hypothesized that aside from the established prognostic markers, the prognosis of patients with MM is also associated with social relationships.

Study design and patients
We conducted a retrospective review of 237 consecutive patients newly diagnosed with symptomatic MM between January 2009 and December 2019 at Kameda Medical Centre, Kamogawa, Japan.
Patients with primary plasma cell leukemia were excluded. Data on the patients' clinicodemographic characteristics and outcomes were obtained from the electronic medical records. Diagnosis and treatment response were assessed using the IMWG criteria. Highrisk cytogenetic abnormalities (CAs) that were evaluated included del(17p), t(4;14), and t(14;16) based on interphase fluorescence in situ hybridization analysis. All participants or their family members provided written informed consent for inclusion in retrospective studies.
The study was conducted according to the Declaration of Helsinki and was approved by the ethical review board of Kameda Medical Centre.

Assessment of frailty
We performed multivariable evaluations that considered pretreatment demographics, laboratory data, ECOG PS, ADL, IADL, CCI, International Staging System (ISS) stage, and presence of high-risk CAs at the time of initial diagnosis and first hospitalization at our center by hematological clinicians, nurses, and rehabilitation staff as clinical practice. ADL and IADL scales were used to assess self-care activities, household management tasks, and independence [9,10]. The CCI was used to estimate the number and types of comorbidities [8]. The IMWG   frailty score was calculated based on the combination of age, ADL, IADL, and CCI, and cutoff values (<1, ≥2) were followed as previously reported [11]. Cutoff values to predict reduced overall survival (OS) and progression-free survival (PFS) were defined as follows: ADL (>4, ≤4), IADL (>5, ≤5), and CCI (≤1, >1) [11]. OS was calculated from the date of myeloma diagnosis until the date of any-cause death, whereas PFS was calculated from the date of myeloma diagnosis until the date of progression, relapse, or any-cause death determined from the electronic medical records.
To assess social frailty, five factors regarding daily social activities, roles, and relationships were evaluated as follows [20,23]

Statistical analysis
Baseline characteristics were compared between patients with and without social frailty using the Mann-Whitney U-tests or Student t-

Patient characteristics
The baseline clinicodemographic characteristics of the patients are summarized in

Prediction of OS and PFS evaluated via IMWG frailty score and social frailty
The PFS (median: 24.2 months vs 41.7 months; P < .001) and OS

Prediction of OS and PFS evaluated via combination of ISS, IMWG frailty score, and social frailty
As the assessment of frailty scores and myeloma disease status is important, we combined scores that assessed ISS stage III, IMWGfrailty, and social frailty (Disease-Physical-Social staging system) and divided the patients into three groups: stage I, II, and III included patients with zero or one, two, and all three of the parameters, respectively. There were significant differences in PFS (median: 40.6, 27.2, and 19.0 months for stages I, II, and III, respectively; P < .001, < .001, and .19 for stage I vs II, stage I vs III, and stage II vs III; respectively) and OS (median: NR, 51.2, and 28.9 months for stages I, II, and III, respectively; P < .001, < .001, and .002 for stage I vs II, stage I vs III, and stage II vs III, respectively) among the three groups

F I G U R E 3 Progression-free survival (PFS) and overall survival (OS) according to the Disease-Physical-Social staging system
Note. The patients were divided into three groups according to the presence of International Staging System (ISS) stage III, International Myeloma Working Group (IMWG) frailty, and social frailty, as follows: stage I, II, and III included patients with zero or one, two, and all three of the parameters, respectively. Median PFS: 40.6, 27.2, and 19.0 months for stages I, II, and III, respectively; P < .001, < .001, and . 19

DISCUSSION
This study demonstrated the prognostic impact of social frailty in patients with MM, in addition to the established prognostic markers.
Several studies have shown the negative impact of frailty using the physical conditions of patients or the presence of comorbidities as proxy measures [11][12][13]. However, to our best knowledge, this is the first study to evaluate and emphasize on social frailty in the assessment of patients with MM.
There have been several studies on social frailty, and thus far, five factors can be used for the objective evaluation of social relationships.
However, these five factors have different impact in patients with MM.
The first factor "Going out less frequently when compared with the pre- There are also numerous reports regarding physical frailty [11,[13][14][15]. The IMWG frailty score, which we used in this study, was devised based on data of patients included in clinical trials and was therefore reported to be slightly dissociated from real-world data [14]. We evaluated consecutive MM patients, and excluded only seven patients, and although the number of patients was relatively small to reflect real-world data, the findings were from a clinical setting. Our results on physical fragility based on ADL, IADL, and CCI were worse than those of a previous report on IMWG [11] but consistent with that of a previous prospective study [14].
By combining scores on ISS stage III, physical frailty, and social frailty, we were able to stratify the prognosis of patients with MM (Disease-Physical-Social staging system). In addition, we devised another staging system by combining physical and social frailty to create a simplified evaluation tool and to emphasize the importance of frailty in MM (Physical-Social Frailty staging system). ROC curve analysis showed no significant difference in the predictive capability

F I G U R E 4 Progression-free survival (PFS) and overall survival (OS) according to the Physical-Social Frailty staging system
Note. The patients were divided into three groups according to the presence of International Myeloma Working Group (IMWG) frailty and social frailty, as follows: stage I, II, and III included patients with zero, one, and all two of the parameters, respectively. function, included in the assessment of major physical frailty scores (I-/R-MCI) were not evaluated [14]. Third, this study was limited by its retrospective nature and heterogeneous treatments. It was conducted at a single institution, and the findings were not validated. Fourth, at our institute, there were no caregivers designated by a specific team (eg, bone marrow transplantation team) [29][30][31], and it was not possible to evaluate the influence of caregivers objectively and separately.
Finally, no absolute definition or established evaluation methods for social frailty have been identified. Despite these limitations, this study identified a novel approach for evaluating social frailty in patients with MM. Prospective studies with a larger sample size are needed to confirm our findings.
In summary, we stratified patients with MM based on their prognosis using a simple social assessment and proposed a new prognostic staging system. Albeit the retrospective review and several limitations, this report identified a novel approach for evaluating social frailty in patients with MM. To confirm our results, an independent study with larger patient numbers with an entirely prospective assessment is needed.

ACKNOWLEDGMENTS
The authors would like to thank the residents of the Department of for their excellent advice. We would also like to thank the nurses and the rehabilitation staff for their assistance with data collection and patient care. We also thank Editage (www.editage.jp) for their English language editing services.

AUTHOR CONTRIBUTIONS
TT conceived, designed, and initiated the study, collected the data, performed statistical analysis, wrote the manuscript, and provided patient care. TT, DM, KN, and MT provided patient care. KM supervised the study, collected the data, wrote the manuscript, and provided patient care. All authors have reviewed and approved the final manuscript.