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Patient‐reported pain severity and health‐related quality of life in patients with multiple myeloma in real world clinical practice

Abstract Background The association between patient self‐reported pain severity and health‐related quality‐of‐life (HRQoL) is poorly understood. Aims This real‐world study of symptomatic multiple myeloma (MM) patients sought to determine how pain severity from a single question asked during routine clinical consultation was associated with HRQoL. Methods and results Point‐in‐time data on HRQoL of 330 patients with MM (median age 70 years) receiving anti‐myeloma therapy in Germany and Italy from November 2017 through February 2018 were analyzed. HRQoL was assessed using validated questionnaires (Work Productivity and Activity Impairment [WPAI], European Organization for Research and Treatment of Cancer Quality of Life Questionnaire ‐C30 and ‐MY20). Physical pain severity was assessed during clinical consultation by a single question, asking patients to describe their pain as “no pain,” “mild,” “moderate,” or “severe.” Associations between patient‐reported pain severity and HRQoL scores were assessed by analysis of variance or χ 2 tests. Ninety‐six of the 330 patients (29.1%) reported moderate to severe pain. Increase in pain severity, from “no” to “severe” pain, was associated with significantly decreased overall HRQoL (mean score 70.2 to 33.3); significant decreases in levels of physical (82.7 to 35.1), social (81.1 to 44.4), emotional (78.1 to 48.3), and role functioning (79.5 to 38.9); and increased levels of WPAI usual activity impairment (35.4 to 71.4), and fatigue burden (26.0 to 68.9) (all p < .001). Conclusion Higher pain severity, based on a single self‐report question, was associated with poorer HRQoL in patients with MM, thereby supporting the clinical relevance of directly asking patients to self‐evaluate their pain severity.


| INTRODUCTION
Pain is a common debilitating symptom of cancer and contributes to poor health-related quality of life (HRQoL). 1 Patients with multiple myeloma (MM), especially those with relapsed/refractory disease, experience significantly more pain and poorer HRQoL (including physical, role, emotional, and social functioning) compared to an age-matched general population of the same geographical region. 2 Pain in MM is often due to myeloma bone disease, which is observed in more than 80% of patients during the course of their disease. Patients with earlier manifest or new bone disease experience discomfort or pain and a decrease in HRQoL. With effective myeloma therapy, bone pain and other myeloma-associated pain usually improves or resolves, 3 especially in patients with deep response to induction therapy and during maintenance phase. 2 Most patients unfortunately relapse after a variable length of time following successful induction therapy. A recent systematic review and meta-analysis suggest that pain is particularly prominent during uncontrolled disease at start of initial therapy and at relapse. 4 These patients require both optimal MM therapy and efficient pain management. 3 Although pain management is an integral part of cancer care, pain is underreported, misunderstood, and often undertreated. 5 A systematic review of 20 articles published from 2007 to 2013 revealed that 31.8% of patients with cancer were not receiving pain medication proportional to their pain intensity. 6 This suggests both suboptimal attention to the patient's symptoms and difficulties in assessing pain in routine practice. To provide care that is meaningful to patients with MM, capturing and understanding the patient perspective are therefore essential. Thus, every effort should be taken to integrate patientreported HRQoL into real-life MM treatment and this principle should not be hindered by cost, training, physician ability to recognize symptoms, and logistical considerations. 7,8 Information on HRQoL is important to understand the patient's symptom burden and needs. While several valid and reliable tools exist for assessment of pain severity, these tools are established in clinical trials and outcome research but not commonly used in routine clinical care, where they may be impractical due to time constraints and other reasons. 9 A simple approach to quantify pain severity in patients with MM is via self-reported assessment during routine consultation.
In this study, we examined whether patients' self-reported pain severity based on a single question relates to the magnitude of changes in QoL items such as HRQoL, functional and emotional impairment, fatigue, and work productivity in a real-world clinical setting. To our knowledge, no published study has examined the association between pain severity in patients with MM and specific other domains of HRQoL.

| METHODS
A point-in-time study was conducted using the Adelphi Multiple Myeloma Disease Specific Programme (DSP) patient-level database.
Details of the full DSP methodology have been described previously. 10 This study was an analysis of secondary data collected between November 20, 2017 and February 1, 2018 from hospital and office settings in Germany and Italy.

| Participants and measures
Consenting adults (≥18 years at time of survey) with symptomatic MM and who received either first-line or second/subsequent-line MM therapy voluntarily completed questionnaires independent of their treating physician at routine face-to-face consultations (referred to as time of survey) and were returned in a sealed envelope to ensure confidentiality.
Each physician invited their next eight consecutively consulting patients to participate in the study to minimize selection bias.
Patients were asked to rate their pain severity using a single question: "Please tick the box that best describes the level of pain that you are currently experiencing." Each patient chose one response: "no pain," "mild pain," "moderate pain," or "severe pain." Responses to this question were aligned with responses from the validated EuroQol 5-dimension 5-level (EQ-5D-5L) questionnaire on pain/discomfort 11 ; responses to the single question were also concordant with the relevant responses from the EQ-5D-5L (Appendix S1). In addition, responses to the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ) 20-item myeloma-specific questionnaire (EORTC QLQ-MY20) 12 on bone aches/pain (question 31) were also aligned with the single pain question (Appendix S1).
The EORTC QLQ-MY20 asked patients "During the past week, have you had the following symptoms or problems." Patients were considered to have bone pain in the past 7 days before the survey if they answered "A Little," "Quite a Bit" or "Very Much" to any combination of EORTC QLQ-MY20 questions 31 to 33, and 35 on bone pain/aches (question 31) or site-specific bone pain (questions 32-33, 35). Patients were considered to have bone pain/aches (non-site specific) based on positive responses to question 31, and site-specific bone pain (back, hip, and chest) based on responses to questions 32, 33, and 35, respectively.
Several dimensions of HRQoL (physical, role, emotional, and social functioning and fatigue) were assessed via the validated EORTC Core-30 Questionnaire version 3 (EORTC QLQ-C30). 13 Work productivity and activity impairment were assessed using the validated Work Productivity and Impairment questionnaire (WPAI). 14

| Patient-reported pain severity and HRQoL
To assess the association between pain severity and different HRQoL outcome measures, patients were stratified according to their current level of self-reported pain severity at the time of survey (defined as "no pain", "mild pain", "moderate pain" or "severe pain").
As the level of patient self-reported pain severity increased from no pain to severe pain, mean scores on overall HRQoL decreased from 70.2 to 33.3; this association was statistically significant (ANOVA; p < .001) (Figure 1). A higher level of self-reported pain severity was associated with poorer physical, social, and emotional functioning.
As pain severity increased from no pain to severe pain, we observed  Table S2 shows the linear regression coefficients for the association between the level of patient self-reported pain severity and HRQoL.

| Increasing pain severity associated with reductions in HRQoL and work productivity
In all patients, we observed a significant association between patients self-reported pain and HRQoL. Mean HRQoL differences between no pain and the other three pain groups were significant (p < .05) in all instances, with the exception of activity impairment due to a problem and social functioning in those with self-reported mild pain. These results indicate that increasing self-reported pain was associated with poorer overall health status and functioning, increased work and activity impairment, and fatigue.

| DISCUSSION
This real-world study examined how patients' self-reported pain severity, from a single question asked during clinical consultation, is associated with HRQoL in symptomatic MM patients receiving antimyeloma therapy in routine practice. Higher pain severity self-reported by patients with MM via the single question was associated with significantly poorer overall HRQoL, poorer physical, social, and emotional functioning, and greater functional impairment and fatigue burden.
Although MM remains a largely incurable condition, the introduction of novel therapies has significantly improved clinical outcomes.
For many patients, MM is a long-term chronic condition characterized by a remitting and relapsing course. 18 A study on MM patients in England across all disease stages revealed that general symptom level, pain, and anxiety predicted declining HRQoL. 19 Previous research has shown that higher grades of chemotherapy induced peripheral neuropathy were correlated with worse HRQoL outcomes, 20 and that patients with MM experience a high symptom burden and low HRQoL. 21 Therefore, an accurate and thorough assessment of pain in MM is crucial for identifying the underlying etiology and for developing a treatment plan.
An accepted standard of care, recently reinforced by a guide from the European Society for Medical Oncology, is that healthcare professionals should routinely assess patient's cancer pain by asking them to rate their pain on a scale of 0 to 10, where 0 is no pain at all and 10 is the worst pain imaginable. Patients who find it difficult to give their pain intensity a number are asked to use linear analogue scales, which allows them to mark their individual pain severity between the extremes of no pain and very severe pain. 22 In our study, responses to a single question were consistent with responses to validated questionnaires (EQ-5D-5L, EORTC QLQ-MY20), indicating that a straightforward single question can provide an accurate perspective of the patient's pain severity.
Due to the lack of common sampling across studies and region, interpretation of the patient-reported outcomes data from our study compared to other published studies is limited. A recent study 23 22,27 or to consider the impact of these medications on the pain severity experienced by the patients.
As this was an analysis of secondary data, the base size of certain subgroups was small, such as those with "severe pain" and those in