Health-Related Quality of Life of Patients With Multiple Myeloma Treated in Routine Clinical Practice in France

Open AccessPublished:September 05, 2018DOI:https://doi.org/10.1016/j.clml.2018.08.019

      Abstract

      Introduction

      New therapies for multiple myeloma (MM) have improved life expectancy, but health-related quality of life (HRQoL) data from patients with MM in the real-world setting are lacking. This study, conducted in France, explored the associations between treatment outcomes and HRQoL in patients with MM.

      Patients and Methods

      This observational, cross-sectional, multicenter study enrolled patients (≥ 18 years old) with symptomatic MM who had consulted a physician at least once between February and March 2016. HRQoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life questionnaire (QLQ-C30) and the Quality of Life Multiple Myeloma module (QLQ-MY20).

      Results

      In total, 445 patients were included in the study; 402 (90%) completed the EORTC QLQ-C30 and QLQ-MY20 questionnaires. HRQoL decreased significantly with treatment line. Patients in the first treatment-free interval had relatively high scores. At later lines, patients receiving active treatment had better scores than those whose treatment had ended. High EORTC QLQ-C30 global health status scores were associated with good treatment response, few adverse events, and long duration of treatment, and were strongly influenced by the Eastern Cooperative Oncology Group performance status. Global health status scores correlated well with the 4 items of the QLQ-MY20 (future perspective, 0.46; body image, 0.41; disease symptoms, −0.57; side effects of treatment, −0.53).

      Conclusion

      Effective treatment options in MM can help maintain HRQoL by influencing treatment response levels and delaying disease progression.

      Keywords

      Introduction

      Multiple myeloma (MM), a cancer of the bone marrow, is one of the most common hematologic malignancies. The annual incidence in Europe is 4.5 to 6.0 cases per 100,000 people,
      • Moreau P.
      • San Miguel J.
      • Ludwig H.
      • et al.
      Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      and more than one third of patients are aged 75 years or older at diagnosis.
      • Palumbo A.
      • Bringhen S.
      • Ludwig H.
      • et al.
      Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN).
      In France in 2012, there were 35,000 new hematologic malignancies diagnosed, and MM was the most common diagnosis (4888 cases). In keeping with the wider European picture, the median age at diagnosis in France was 72 years for men and 75 years for women.
      Several new therapies for MM have become available during the past decade and have altered the natural course of the disease, resulting in improved overall survival.
      • Kumar S.K.
      • Rajkumar S.V.
      • Dispenzieri A.
      • et al.
      Improved survival in multiple myeloma and the impact of novel therapies.
      • Dimopoulos M.A.
      • Richardson P.G.
      • Moreau P.
      • Anderson K.C.
      Current treatment landscape for relapsed and/or refractory multiple myeloma.
      Although extending life expectancy is a primary objective of treatment, it is also important to consider the impact of treatment on patients’ quality of life while receiving therapy as well as the potential for treatment toxicity to interrupt therapy and negatively affect treatment outcomes.
      • Cleeland C.S.
      • Mendoza T.R.
      • Wang X.S.
      • et al.
      Assessing symptom distress in cancer patients: the MD Anderson Symptom Inventory.
      To this end, the European Medicines Agency recognizes the value of health-related quality of life (HRQoL) data in informing the benefit–risk profiles of new anticancer drugs.
      European Medicines Agency
      Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man. The use of patient-reported outcome (PRO) measures in oncology studies.
      Multiple factors can affect HRQoL: demographic and clinical characteristics such as age, performance status (PS), and comorbidities all have an impact. Furthermore, MM itself is associated with a high symptom burden and worsening functional performance. In a Danish study, patients reported a mean of 5.6 symptoms or functional problems, of which 2.3 were severe.
      • Johnsen A.T.
      • Tholstrup D.
      • Petersen M.A.
      • Pedersen L.
      • Groenvold M.
      Health related quality of life in a nationally representative sample of haematological patients.
      Symptoms such as pain, fatigue, dyspnea, nausea, vomiting, and peripheral neuropathy are all associated with worsening HRQoL in patients with MM,
      • Mols F.
      • Oerlemans S.
      • Vos A.H.
      • et al.
      Health-related quality of life and disease-specific complaints among multiple myeloma patients up to 10 yr after diagnosis: results from a population-based study using the PROFILES registry.
      and patients with a high number of comorbidities tend to report the worst HRQoL.
      • van der Poel M.W.
      • Oerlemans S.
      • Schouten H.C.
      • van de Poll-Franse L.V.
      Elderly multiple myeloma patients experience less deterioration in health-related quality of life than younger patients compared to a normative population: a study from the population-based PROFILES registry.
      Although treatment can improve HRQoL initially,
      • Delforge M.
      • Minuk L.
      • Eisenmann J.C.
      • et al.
      Health-related quality of life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.
      and lengthy treatment-free intervals (TFIs) have been shown to improve HRQoL in patients with MM,
      • Acaster S.
      • Gaugris S.
      • Velikova G.
      • Yong K.
      • Lloyd A.J.
      Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey.
      treatment-related toxicities can have a negative impact on HRQoL.
      • Jordan K.
      • Proskorovsky I.
      • Lewis P.
      • et al.
      Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study.
      The best HRQoL is usually reported during the first TFI,
      • Acaster S.
      • Gaugris S.
      • Velikova G.
      • Yong K.
      • Lloyd A.J.
      Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey.
      probably because treatment-related toxicities have not yet accumulated. Treatment demands, such as the need for regular injections, infusions, tests, and painful procedures (eg, stem-cell transplantation), can compromise HRQoL and affect a patient’s sense of well-being,

      Gado K, Domjan G. Quality of life issues of patients with multiple myeloma. In: Hajek R, ed. Multiple Myeloma—A Quick Reflection on the Fast Progress. IntechOpen. 2013. Available: https://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-on-the-fast-progress/quality-of-life-issues-of-patients-with-multiple-myeloma, Accessed March 2017.

      as well as negatively affect treatment persistence.
      HRQoL is therefore a key consideration in the management of MM and in the evaluation of new therapies. The management of MM may be improved with a better understanding of how patients are affected by general and disease-specific symptoms as well as treatment-related toxicities, and how these in turn affect HRQoL.
      • Cleeland C.S.
      • Mendoza T.R.
      • Wang X.S.
      • et al.
      Assessing symptom distress in cancer patients: the MD Anderson Symptom Inventory.
      • Jordan K.
      • Proskorovsky I.
      • Lewis P.
      • et al.
      Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study.
      Despite the increasing recognition of such issues in the literature,
      • van der Poel M.W.
      • Oerlemans S.
      • Schouten H.C.
      • van de Poll-Franse L.V.
      Elderly multiple myeloma patients experience less deterioration in health-related quality of life than younger patients compared to a normative population: a study from the population-based PROFILES registry.
      • Delforge M.
      • Minuk L.
      • Eisenmann J.C.
      • et al.
      Health-related quality of life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.
      • Acaster S.
      • Gaugris S.
      • Velikova G.
      • Yong K.
      • Lloyd A.J.
      Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey.
      • Sonneveld P.
      • Verelst S.G.
      • Lewis P.
      • et al.
      Review of health-related quality of life data in multiple myeloma patients treated with novel agents.
      • Stewart A.K.
      • Dimopoulos M.A.
      • Masszi T.
      • et al.
      Health-related quality of life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma.
      HRQoL data from patients receiving care for MM in routine-care settings in Europe are limited. In addition, there is also a paucity of evidence on the correlation between HRQoL scores measured by different assessment scales in the real-world setting.
      This observational, cross-sectional, real-world study in France was conducted to explore associations between treatment factors (eg, response, duration, toxicity) and HRQoL, as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life questionnaire (QLQ-C30)
      • Aaronson N.K.
      • Ahmedzai S.
      • Bergman B.
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      and the Quality of Life Multiple Myeloma module (QLQ-MY20).
      • Cocks K.
      • Cohen D.
      • Wisloff F.
      • et al.
      An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma.

      Patients and Methods

       Study Design

      This was an observational, cross-sectional, multicenter study conducted in France from February to March 2016.

       Physician Selection

      Physicians working in hospitals and private clinics in France were recruited by telephone by an epidemiology research assistant. Invited physicians had participated in a previous study of MM treatment patterns and were managing at least 15 patients with symptomatic MM on average per month, so as to enable the inclusion of up to 14 patients per physician.

       Patient Inclusion and Exclusion Criteria

      Adults (≥ 18 years old) with symptomatic MM who had had at least one consultation during the inclusion period with a participating physician (outpatient or inpatient) were eligible for the study. Patients were excluded if they had never received specific antimyeloma drug treatment.

       Data Source

      Each physician reported data on up to 14 patients with MM whom they saw in consultation during the enrollment period and who met the general eligibility criteria; this number of patients was selected to ensure practicality and to provide an even distribution of patient recruitment across participating physicians. Patients were selected on the basis of an assigned quota according to the current or most recently completed line of treatment: up to 3 patients were selected from each treatment line (first, second, third, and fourth or later lines); up to 2 patients were selected from those receiving supportive care only (no further antitumor treatment planned). These numbers were selected to ensure that there would be sufficient patients in each line to conduct analysis by line of therapy.
      Data were collected using case report forms (CRFs), which recorded patients’ demographic and clinical characteristics, treatment, adverse events (AEs), best treatment response in current line, and their latest treatment response. The nature, status (either ongoing or resolved), and grade (3 or 4) of AEs were recorded; AEs included were limited to those observed from the beginning of the current treatment line. All patients for whom the physician completed a CRF were invited to complete the HRQoL questionnaires. Patients provided verbal consent to be included in the CRF portion of the study; informed written consent was obtained before completion of the HRQoL questionnaires.
      This observational study was approved by the Comité Consultatif sur le Traitement de l’Information en Matière de Recherche dans le Domaine de la Santé (Advisory Committee on Information Processing in Material Research in the Field of Health), and the Commission Nationale de l’Informatique et des Libertés (National Commission for Information Technology and Liberties).

       Study Variables

      HRQoL was assessed using the EORTC QLQ-C30
      • Aaronson N.K.
      • Ahmedzai S.
      • Bergman B.
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      and QLQ-MY20,
      • Cocks K.
      • Cohen D.
      • Wisloff F.
      • et al.
      An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma.
      which have been validated in patients with MM.
      • Delforge M.
      • Minuk L.
      • Eisenmann J.C.
      • et al.
      Health-related quality of life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.
      The EORTC QLQ-C30 is a disease-specific questionnaire for patients with cancer and is one of the most widely used HRQoL tools in clinical trials.
      • Nielsen L.K.
      • Jarden M.
      • Andersen C.L.
      • Frederiksen H.
      • Abildgaard N.
      A systematic review of health-related quality of life in longitudinal studies of myeloma patients.
      It comprises 5 functional scales (physical, role, emotional, cognitive, social functioning), 3 symptom scales (fatigue, pain, nausea and vomiting), 6 questions that assess additional symptoms and financial difficulties, and a global health status scale.
      • Aaronson N.K.
      • Ahmedzai S.
      • Bergman B.
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      Scores range from 0 to 100, with higher global health status scores and functional domain scores, and lower symptom domain scores associated with better HRQoL.
      • Aaronson N.K.
      • Ahmedzai S.
      • Bergman B.
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      A change in score of 6 points or more is considered a clinically meaningful difference.
      • Kvam A.K.
      • Waage A.
      Health-related quality of life in patients with multiple myeloma—does it matter?.
      The EORTC QLQ-MY20 module was developed as an addition to the QLQ-C30 for use specifically in MM. It has 4 domains (disease symptoms, side effects of treatment, body image, future perspectives). Scores range from 0 to 100; good HRQoL is indicated by high scores for future perspective and body image, and low scores for disease symptoms and side effects of treatment.
      • Cocks K.
      • Cohen D.
      • Wisloff F.
      • et al.
      An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma.

       Statistical Analyses

      Of the maximum 14 patients per physician for whom data were collected on the CRF, it was estimated that between 60% and 80% would complete the HRQoL questionnaires.
      Data were analyzed using DAISIE 2.4 software for descriptive and bivariate analyses. Quantitative variables (eg, PS score) were described using means and standard deviations (SD), medians, first quartiles, third quartiles, and minimums and maximums. Qualitative variables (eg, practice setting, current treatment status, sex) were summarized by numbers and percentages of patients in each variable subgroup. For quantitative and qualitative variables, the proportion of patients with missing data (eg, patients who did not complete an HRQoL questionnaire) were recorded, reported (eg, as unspecified) and included in percentage calculations.
      All analyses were descriptive, and as such an estimation of sample size was not conducted to allow for formal hypothesis testing on differences in HRQoL between subgroups of interest. All the P values presented here are nominal. Exploratory subgroup analyses were performed by the chi-square test, t test, or 1-way rank ANOVA to test between K-independent samples, as appropriate. A standardized change in score of at least 6 points was considered to be the minimum clinically important difference for the EORTC QLQ-C30.
      • Kvam A.K.
      • Waage A.
      Health-related quality of life in patients with multiple myeloma—does it matter?.
      The normality of the data distribution was tested on the total sample size for the EORTC QLQ-C30 and QLQ-MY20 using the Shapiro-Wilk normality test (P < .05). Patient baseline characteristics among those who agreed or declined to complete a questionnaire were analyzed to evaluate whether the sample obtained was representative.
      To investigate any correlations between EORTC QLQ-C30 and QLQ-MY20 scores, Pearson correlation coefficient calculations were performed. A multivariate regression analysis of EORTC QLQ-C30 global health status scores was conducted to evaluate the relative impact of variables on HRQoL. The potential explanatory variables considered were: age, sex, type of management (eg, hospitalization, day patient), time since diagnosis, International Staging System score at diagnosis, G-8 score, treatment line, comorbidities (including history of neuropathy), current treatment (and maintenance treatment) status, best response, last response, time since beginning of treatment line, and grade 3/4 toxicities. The multivariate analysis was performed by ANOVA with R 3.2.4 software. The linear regression analysis enabled the impact of the variables to be measured independently of one other. A backward elimination approach was used in order to reach the final model. Two models were generated, one including Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores, and one excluding ECOG PS scores to remove the effect of this variable, given that ECOG PS has been shown to be significantly and independently associated with HRQoL.
      • Ramsenthaler C.
      • Osborne T.R.
      • Gao W.
      • et al.
      The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.
      • Leleu X.
      • Petrucci M.T.
      • Welslau M.
      • et al.
      Psychometric performance of the EORTC Quality-of-Life Core Questionnaire (QLQ-C30) and QLQ–Multiple Myeloma (QLQ-MY20) in relapsed/refractory multiple myeloma (RRMM).

      Results

       Physician Characteristics

      In total, 84 physicians from across France were contacted, and 41 agreed to participate in the study (Supplemental Table 1 in the online version). The most common speciality was hematology (24, 58.5%). More than one third of physicians practiced in hospital centers (14, 34.1%), 31.7% (n = 13) in university hospital centers and 19.5% (n = 8) in private clinics (Supplemental Table 1 in the online version).

       Baseline Patient and Disease Characteristics

      A total of 445 patients with MM were included in the study. Baseline patient and disease characteristics are presented in Table 1. Of note, there was no significant difference in the proportion of patients included across the different treatment lines. The mean age of patients at enrollment was similar across treatment lines, with the exception of a higher mean [SD] age in those receiving supportive care (77.3 [8.2] years) compared to active treatment lines (P = .0002); the mean [SD] age of the total population was 71.4 [10.1] years (Table 1). A greater proportion of patients aged at least 80 years were receiving supportive care (18/43, 41.9%) compared to younger patients (P = .003).
      Table 1Patient and Disease Characteristics
      CharacteristicTotal (N = 445)First Line (N = 117)Second Line (N = 103)Third Line (N = 94)Fourth Line or Later (N = 88)Supportive Care (N = 43)
      Proportion of total (%)1002623212010
      Sex
       Female214 (48.1)53 (45.3)48 (46.6)45 (47.9)47 (53.4)21 (48.8)
       Male231 (51.9)64 (54.7)55 (53.4)49 (52.1)41 (46.6)22 (51.2)
      Age (years), median (Q1–Q3)72.7 (64.5-78.5)70.0 (62.1-78.3)71.5 (64.4-75.9)74.6 (66.5-79.4)71.3 (63.7-76.8)77.5 (70.8-83.1)
      Age (years), mean (SD)71.4 (10.1)69.5 (11.6)70.5 (9.8)72.9 (9.0)70.5 (9.2)77.3 (8.2)
      Age Distribution
      < 65 years108 (24.3)37 (31.6)25 (24.3)18 (19.1)23 (26.1)5 (11.6)
       65-74 years138 (31.0)32 (27.4)40 (38.8)26 (27.7)32 (36.4)8 (18.6)
       75-79 years98 (22.0)24 (20.5)21 (20.4)24 (25.5)17 (19.3)12 (27.9)
       ≥ 80 years101 (22.7)24 (20.5)17 (16.5)26 (27.7)16 (18.2)18 (41.9)
      Time since diagnosis (months), median (Q1–Q3)39.8 (12.8-71.3)6.1 (3.7-11.7)
      One data point is missing in first line.
      36.5 (22.2-56.5)56.5 (39.3-82.8)71.7 (47.0-98.0)50.3 (23.3-73.6)
      ECOG PS
       0-1287 (64.5)104 (88.9)80 (77.7)52 (55.3)50 (56.8)1 (2.3)
       299 (22.2)11 (9.4)19 (18.4)32 (34.0)28 (31.8)9 (20.9)
       3-458 (13.0)2 (1.7)3 (2.9)10 (10.6)10 (11.4)33 (76.7)
       Unspecified1 (0.2)0 (0)1 (1.0)0 (0)0 (0)0 (0)
      ISS Stage at Diagnosis
      Characteristics measured at diagnosis.
       I106 (23.8)36 (30.8)25 (24.3)21 (22.3)19 (21.6)5 (11.6)
       II143 (32.1)30 (25.6)41 (39.8)29 (30.9)31 (35.2)12 (27.9)
       III187 (42.0)47 (40.2)35 (34.0)44 (46.8)35 (39.8)26 (60.5)
       Unspecified9 (2.0)4 (3.4)2 (1.9)0 (0)3 (3.4)0 (0)
      No. of Comorbidities
      Comorbidities included: renal insufficiency, diabetes mellitus, history of neuropathy, hypertension, previous deep vein thrombosis, previous stroke, respiratory failure, coronary heart disease, heart failure, other.
       ≥ 1268 (60.2)50 (42.7)56 (54.4)69 (73.4)52 (59.1)41 (95.3)
       0177 (39.8)67 (57.3)47 (45.6)25 (26.6)36 (40.9)2 (4.7)
      Type of Management
       Consultation220 (49.4)42 (35.9)68 (66.0)48 (51.1)44 (50.0)18 (41.9)
       Day patient190 (42.7)71 (60.7)35 (34.0)42 (44.7)37 (42.0)5 (11.6)
       Inpatient35 (7.9)4 (3.4)0 (0)4 (4.3)7 (8.0)20 (46.5)
      Practice Setting
       University hospital center152 (34.1)38 (32.5)33 (32.0)33 (35.1)35 (39.8)13 (30.2)
       Hospital center146 (32.8)41 (35.0)38 (36.9)30 (31.9)24 (27.3)13 (30.2)
       Private not-for-profit clinic15 (3.4)4 (3.4)3 (2.9)3 (3.2)3 (3.4)2 (4.7)
       Private clinic81 (18.2)22 (18.8)17 (16.5)16 (17.0)16 (18.2)10 (23.3)
       Regional cancer center51 (11.5)12 (10.3)12 (11.7)12 (12.8)10 (11.4)5 (11.6)
      Time Since Start of Treatment Line
      Time elapsed since start of each treatment line was measured and categorized in whole months.
      N = 402N = 117N = 103N = 94N = 88NA
       0-2 months85 (21.2)18 (15.4)20 (19.4)22 (23.4)25 (28.4)NA
       3-5 months134 (33.3)42 (35.9)29 (28.2)32 (34.0)31 (35.2)NA
       6-11 months105 (26.1)35 (29.9)25 (24.3)25 (26.6)20 (22.7)NA
       ≥ 12 months78 (19.4)22 (18.8)29 (28.2)15 (16.0)12 (13.6)NA
      Data are presented as n (%) unless otherwise indicated.
      Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; ISS = International Staging System; NA = not applicable; Q = quartile; SD = standard deviation.
      a Characteristics measured at diagnosis.
      b Comorbidities included: renal insufficiency, diabetes mellitus, history of neuropathy, hypertension, previous deep vein thrombosis, previous stroke, respiratory failure, coronary heart disease, heart failure, other.
      c Time elapsed since start of each treatment line was measured and categorized in whole months.
      d One data point is missing in first line.
      Patients in supportive care (n = 43) were more likely to be hospitalized (20/43, 46.5%) than those receiving active treatment (15/402, 3.7%; P < .0001). Patients in supportive care had typically already received between 2 and 4 lines of treatment (first line, 9.3%; second line, 23.3%; third line, 25.6%; fourth line, 30.2%; fifth line or more, 11.6%). Overall, patients were most commonly seen as part of a clinical consultation (49.4%) or as a day patient (42.7%). Most patients (60%) had at least one comorbidity (Table 1).
      We did not collect data about the reasons why the physicians did not prescribe any active treatment and decided to provide supportive care only. However, the characteristics of these patients (77% with an ECOG score of 3 to 4, 51% with renal impairment, 33% with diabetes, 23% with heart failure) supports that their condition seemed to be a major obstacle to the prescription of an active treatment.

       MM Treatment

      Most patients (91.5%) were receiving active treatment at the time of the study (Table 2). Compared to patients at later lines, more patients receiving first-line therapy were in a TFI (17.1% in first line vs. 2.9% in second line, 8.5% in third line and 3.4% in fourth line; P = .004) (Table 2). One-third of patients (31.7%) had undergone a stem-cell transplantation at the first or second line (Table 2).
      Table 2Multiple Myeloma Treatment Characteristics
      CharacteristicTotal (N = 445)First Line (N = 117)Second Line (N = 103)Third Line (N = 94)Fourth Line or Later (N = 88)Supportive Care (N = 43)
      Current Treatment StatusN = 402N = 117N = 103N = 94N = 88N = 43
       Currently treated368 (91.5)97 (82.9)100 (97.1)86 (91.5)85 (96.6)NA
       Treatment completed34 (8.5)20 (17.1)3 (2.9)8 (8.5)3 (3.4)NA
      SCT Status
       SCT in first and or second line141 (31.7)29 (24.8)29 (28.2)36 (38.3)38 (43.2)9 (20.9)
       SCT planned23 (5.2)16 (13.7)7 (6.8)0 (0)0 (0)0 (0)
       Eligible for SCT but did not receive9 (2.0)1 (0.9)3 (2.9)2 (2.1)1 (1.1)2 (4.7)
       Not eligible for SCT272 (61.1)71 (60.7)64 (62.1)56 (59.6)49 (55.7)32 (74.4)
      Administered Treatments
       Lenalidomide based141 (31.7)12 (10.3)73 (70.9)34 (36.2)8 (9.1)NA
       Bortezomib based118 (26.5)63 (53.8)12 (11.7)21 (22.3)14 (15.9)NA
       Bortezomib- and thalidomide based38 (8.5)32 (27.4)4 (3.9)0 (0)2 (2.3)NA
       Bortezomib- and lenalidomide based18 (4.0)5 (4.3)9 (8.7)0 (0)4 (4.5)NA
       Thalidomide based8 (1.8)5 (4.3)1 (1.0)0 (0)1 (1.1)NA
       Bendamustine based30 (6.7)0 (0)0 (0)10 (10.6)13 (14.8)NA
       Pomalidomide based66 (14.8)0 (0)2 (1.9)21 (22.3)36 (40.9)NA
       Other26 (5.8)0 (0)2 (1.9)8 (8.5)10 (11.4)NA
      Evaluation of Tumor Response in Current Line
       Evaluated326 (73.3)88 (75.2)71 (68.9)68 (72.3)57 (64.8)42 (97.7)
       Not evaluable/not evaluated115 (25.8)29 (24.8)29 (28.2)26 (27.7)30 (34.1)1 (2.3)
       Unspecified4 (0.9)0 (0)3 (2.9)0 (0)1 (1.1)0 (0)
      Toxicity
      Toxicities were grade 3/4 adverse events and included: neuropathy, diarrhea, anemia, neutropenia, thrombocytopenia, renal failure, infection, pneumopathy, or other.
       ≥ 1102 (22.9)15 (12.8)18 (17.5)23 (24.5)26 (29.5)20 (46.5)
       0343 (77.1)102 (87.2)85 (82.5)71 (75.5)62 (70.5)23 (53.5)
      Last Treatment Response Recorded in Current LineN = 348N = 93N = 80N = 73N = 60N = 42
       Complete response and very good partial response145 (41.7)55 (59.1)39 (48.7)29 (39.7)18 (30.0)4 (9.5)
       Partial response142 (40.8)34 (36.6)35 (43.8)33 (45.2)30 (50.0)10 (23.8)
       Stable disease31 (8.9)2 (2.2)5 (6.3)8 (11.0)12 (20.0)4 (9.5)
       Progressive disease30 (8.6)2 (2.2)1 (1.3)3 (4.1)0 (0)24 (57.1)
      Data are presented as n (%).
      Abbreviations: NA = not applicable; SCT = stem-cell transplantation.
      a Toxicities were grade 3/4 adverse events and included: neuropathy, diarrhea, anemia, neutropenia, thrombocytopenia, renal failure, infection, pneumopathy, or other.
      Bortezomib-based treatment was the most common therapy at the first line (100/117, 85.5%), including a regimen in combination with thalidomide or lenalidomide. Lenalidomide-based treatment was the most common therapy at the second (73/103, 70.9%) and third (34/94, 36.2%) lines, whereas pomalidomide-based treatment was the most common therapy at fourth or later lines (36/88, 40.9%; Table 2).
      The best response to treatment was evaluated for 73.3% of patients (Table 2). The proportion of patients with very good partial response (VGPR) or better as the last response recorded for their current treatment line was 59.1% at the first line and decreased with increasing treatment lines (Table 2).

       Adverse Events

      Physicians had not reported any toxicities (grade 3/4 AEs) for three quarters of patients (77.1%) since the initiation of their current/most recent treatment (Table 2). The proportion of patients having at least one grade 3/4 AE increased significantly with increasing treatment line, ranging from 12.8% (15/117) at the first line to 29.5% (26/88) in the fourth line or later (P < .001, χ2 test). Of patients receiving supportive care, 46.5% (20/43) experienced at least one grade 3/4 AE. Overall, the most common AEs were hematologic: anemia (12%), neutropenia (10%), and thrombocytopenia (9%). Neuropathy occurred in 6% of patients (data not shown).

       Evaluation of HRQoL

      Most patients (402, 90%) agreed to complete a questionnaire (though one patient subsequently changed their mind). Willingness to do so decreased significantly with later treatment lines; 97% of patients at first line completed a questionnaire, compared to 86% in line 4 or later and 72% of those receiving supportive care (Supplemental Tables 2 and 3 in the online version). There were no significant differences in patient baseline characteristics among those who agreed or declined to complete a questionnaire.

       HRQoL by Treatment Line

      Mean [SD] EORTC QLQ-C30 global health status scores decreased from 63.0 [19.0] at first line to 59.7 [17.1] at second line, 52.6 [20.2] at third line, 53.6 [21.4] at fourth line or later, and 32.8 [20.7] for patients receiving supportive care (P < .0001; P = .0005 excluding supportive care, ANOVA) (Figure 1). The mean differences exceeded the minimum clinically important difference between third and second line (−7.1) and between supportive care and fourth line or later (−20.8). Scores for all 5 functional scales were lower in later treatment lines; a significant effect was observed when including (P < .05 for all functional scales) or excluding (P < .0001 for all functional scales) supportive care (Table 3). When including supportive care, there were significant differences between symptom scores for all scales except financial difficulties. When excluding supportive care, significant differences were observed between the symptom scores for fatigue and dyspnea (Table 3). Symptom scores for fatigue and pain were particularly high in patients receiving supportive care (Table 3).
      Figure thumbnail gr1
      Figure 1EORTC QLQ-C30 Global Health Status Scores. Data Presented are Means, First Quartiles, Third Quartiles, and Minimums and Maximums. Open Circles Denote Extreme Values. Higher Scores for EORTC QLQ-C30 Global Health Status Score Indicated Higher Quality of Life. Excluding Supportive Care, Effect of Line on QLQ-C30 Global Health Status Score Was P = .0005 by ANOVA
      Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; QLQ-C30 = Core Quality of Life questionnaire.
      Table 3EORTC QLQ-C30 Functional and Symptom Scale Mean Scores
      CharacteristicTotalFirst LineSecond LineThird LineFourth Line or LaterSupportive CareP Excluding Supportive CareP Including Supportive Care
      Functional Scale
      Higher scores indicate a higher level of functioning compared to lower scores.
      Physical Functioning
       N37510592777229
       Mean (SD)64.3 (27.3)74.7 (20.9)67.7 (24.3)63.9 (24.6)61.2 (27.1)24.1 (26.4).001< .0001
      Role Functioning
       N38710894807431
       Mean (SD)57.7 (32.2)68.7 (29.3)62.1 (29.8)58.8 (28.3)51.4 (31.7)18.3 (25.5).002< .0001
      Emotional Functioning
       N38011092796930
       Mean (SD)68.3 (25.4)75.3 (21.5)71.7 (25.3)66.7 (22.5)64.3 (28.0)45.8 (25.3).01< .0001
      Cognitive Functioning
       N39010895837331
       Mean (SD)72.1 (24.4)79.0 (18.8)75.1 (23.4)70.3 (25.1)70.5 (25.2)47.8 (24.6).03< .0001
      Social Functioning
       N38910895817530
       Mean (SD)66.1 (30.2)75.0 (26.9)67.9 (26.5)66.5 (28.4)63.8 (30.6)33.3 (32.8).04< .0001
      Symptom Scale
      Lower scores indicate a better health state and fewer symptoms than higher scores.
      Fatigue
       N38910895817530
       Mean (SD)49.3 (27.2)40.9 (25.1)46.0 (24.9)50.5 (26.3)51.8 (26.5)80.3 (21.3).02< .0001
      Nausea/Vomiting
       N38810896817330
       Mean (SD)9.2 (15.0)6.9 (14.4)7.8 (12.3)10.7 (13.4)7.8 (14.1)21.7 (22.8).29< .0001
      Pain
       N39210895847431
       Mean (SD)39.4 (30.2)35.0 (28.1)35.6 (28.1)35.7 (28.9)41.4 (30.3)71.5 (27.5).46< .0001
      Dyspnea
       N39310995837531
       Mean (SD)31.8 (28.0)25.7 (28.1)26.7 (27.6)34.9 (25.8)33.3 (24.3)57.0 (27.0).04< .0001
      Insomnia
       N39311095827531
       Mean (SD)30.6 (28.9)25.8 (27.9)29.8 (31.1)30.9 (28.4)31.1 (23.3)48.4 (31.5).51.0046
      Appetite Loss
       N39110896817531
       Mean (SD)26.2 (29.4)19.4 (26.5)21.5 (25.9)28.8 (30.0)25.8 (27.5)58.1 (30.5).10< .0001
      Constipation
       N39510995857630
       Mean (SD)24.8 (28.8)20.5 (27.8)26.0 (29.9)25.9 (30.0)22.4 (23.8)40.0 (31.5).44.02
      Diarrhea
       N39311095837431
       Mean (SD)12.7 (22.9)8.2 (19.2)14.4 (23.0)12.4 (23.0)14.0 (23.3)21.5 (28.8).17.046
      Financial Difficulties
       N39811096857631
       Mean (SD)14.1 (25.6)11.8 (26.4)14.9 (25.9)13.7 (22.5)13.2 (23.6)22.6 (32.1).84.346
      Significance was assessed by 1-way rank ANOVA.
      Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; QLQ-C30 = Core Quality of Life questionnaire; SD = standard deviation.
      a Higher scores indicate a higher level of functioning compared to lower scores.
      b Lower scores indicate a better health state and fewer symptoms than higher scores.
      Mean EORTC QLQ-MY20 scores were also lower for patients receiving later treatment lines and supportive care than for those at early treatment lines, indicating worse HRQoL (Figure 2). Scores for future perspective and body image were lower (worse) (Figure 2A and B) and scores for disease symptoms and side effects of treatment (Figure 2C and D) were higher (worse) at later compared to early treatment lines.
      Figure thumbnail gr2
      Figure 2EORTC QLQ-MY20 Status Scores by Domain. (A) Future Perspectives, (B) Body Image, (C) Disease Symptoms, and (D) Side Effects of Treatment. Data Presented are Means, First Quartiles, Third Quartiles, and Minimums and Maximums. Open Circles Denote Extreme Values. Higher Scores for Future Perspectives and Body Image Indicate Higher HRQoL; Lower Scores for Disease Symptoms and Side Effects of Treatment Indicate Better HRQoL
      Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; HRQoL = health-related quality of life; QLQ-MY20 = Quality of Life Multiple Myeloma module.

       EORTC QLQ-C30 Global Health Status Scores by Treatment Factors

      At the first treatment line, overall mean [SD] EORTC QLQ-C30 global health status scores were higher in patients in a TFI (67.1 [17.5]) than in those whose treatment was ongoing (62.2 [19.1]; Table 4). However, this trend was reversed for patients receiving second-line therapy or later, with higher scores recorded for patients whose treatment was ongoing. With the data from all treatment lines combined, the score was significantly higher in patients with ongoing treatment compared to those in a TFI (57.8 [19.6] vs. 45.1 [25.0]; P < .0115; difference greater than the minimum clinically important difference; t test; Table 4).
      Table 4EORTC QLQ-C30 Global Health Status Bivariate Analyses
      ParameterNQLQ-C30 Global Health Status Score, Mean [SD]P
      Current Treatment Status
      Total
       Ongoing33657.8 [19.6].0115
       Treatment-free interval6045.1 [25.0]
      First Line
       Ongoing9262.2 [19.1]
       Treatment-free interval1867.1 [17.5]
      Second Line
       Ongoing9459.8 [16.7]
       Treatment-free interval254.2 [29.2]
      Third Line
       Ongoing7653.4 [19.9]
       Treatment-free interval744.1 [20.8]
      Fourth Line or Later
       Ongoing7454.2 [21.4]
       Treatment-free interval233.3 [8.3]
      Toxicity
       Total39655.9 [21.0]< .0001
       At least one toxicity
      Toxicities included any grade 3/4 adverse event.
      8743.9 [21.0]
       None30959.3 [19.7]
      Age
       Total39655.9 [21.0].0353
       < 70 years15258.7 [21.7]
       ≥ 70 years24454.1 [20.3]
      Time Elapsed Since Start of Treatment Line
      Time elapsed since start of each treatment line was measured and categorized in whole months.
       Total33657.8 [19.6].03
       0-2 months7852.1 [20.0]
       3-5 months12058.7 [18.3]
       6-11 months8659.9 [20.3]
       12 months or more5260.6 [18.6]
      Last Response
      Recorded in current or previous active treatment line.
       Total39655.9 [21.0]
       CR and VGPR13161.8 [19.3]
       PR13156.8 [20.1]< .0001
      Excludes NE.
       Stable disease2148.0 [16.8]
       PD2328.3 [18.8]
       NE9054.7 [19.6]
      Significance of independent variables was assessed by 1-way rank ANOVA.
      Abbreviations: CR = complete response; EORTC = European Organization for Research and Treatment of Cancer; NE = not evaluable; PD = progressive disease; PR = partial response; QLQ-C30 = Core Quality of Life questionnaire; SD = standard deviation; VGPR = very good partial response.
      a Toxicities included any grade 3/4 adverse event.
      b Time elapsed since start of each treatment line was measured and categorized in whole months.
      c Recorded in current or previous active treatment line.
      d Excludes NE.
      According to the EORTC QLQ-C30 global health status score, patients for whom the last response evaluated was VGPR or better reported higher HRQoL than those who had a worse response (P < .0001) (Table 4). The mean differences in mean EORTC QLQ-C30 global health status scores were calculated: partial response − complete response + VGPR = −5.03; stable disease − partial response = −8.79; progressive disease − stable disease = −19.76.
      Patients who had experienced any grade 3/4 AE since initiation of the current treatment line had worse HRQoL than patients who had not experienced any such AEs as well as the overall patient population (P < .0001; Table 4). The mean differences in mean EORTC QLQ-C30 global health status score was 15.38.
      For these variables (treatment status, response to treatment, AEs), the significant differences in EORTC QLQ-C30 global health status scores observed between groups were also seen for all EORTC QLQ-C30 functional scales (data not shown).
      Mean EORTC QLQ-C30 global health status scores increased significantly with time since the beginning of treatment line (P = .03); patients who had been treated within a treatment line for over a year had a mean [SD] score of 60.6 [18.6], compared to 52.1 [20.0] for those who were treated for up to 2 months (Table 4). In this case, the significant association was not reflected in the EORTC QLQ-C30 functional scales (data not shown).

       Correlation Between EORTC QLQ-C30 and QLQ-MY20

      The correlations between the EORTC QLQ-C30 global health status score and the 4 items of the QLQ-MY20 are shown in Supplemental Figure 1 in the online version. Positive correlations were found for future perspective (0.46) and body image (0.41), and negative correlations for disease symptoms (−0.57) and side effects of treatment (−0.53).

       Multivariate Regression Analysis of EORTC QLQ-C30 Global Health Status Scores

      A multivariate regression analysis of EORTC QLQ-C30 global health status scores for 396 patients was conducted with and without ECOG PS scores. The model with the best fit included, rather than excluded, ECOG PS scores, as indicated by multiple R2 values of 0.3313 versus 0.2477, respectively. From the model, the variables that best explained the QLQ-C30 global health status score including ECOG PS were treatment last response progressive disease (ie, last response recorded in current or previous active treatment line), ECOG PS score (≥ 2), and grade 3/4 hematologic toxicity. The variables that best explained the QLQ-C30 global health status score excluding ECOG PS scores were treatment line (third line of therapy or higher, or supportive care), treatment response (progressive or stable disease, or not evaluable), grade 3/4 hematologic toxicity, history of neuropathy, and age (Supplemental Table 4 in the online version).

      Discussion

      According to the World Health Organization, health is “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.”
      • World Health Organization
      Constitution of WHO: principles.
      Improvements in overall survival achieved in recent years with new therapies for MM are, of course, great achievements.
      • Kumar S.K.
      • Rajkumar S.V.
      • Dispenzieri A.
      • et al.
      Improved survival in multiple myeloma and the impact of novel therapies.
      However, it is vital that the quality of any life expectancy gained is considered. Data from clinical trials suggest that the benefits of new MM treatments may outweigh the negative effects of toxicities and disease progression,
      • van der Poel M.W.
      • Oerlemans S.
      • Schouten H.C.
      • van de Poll-Franse L.V.
      Elderly multiple myeloma patients experience less deterioration in health-related quality of life than younger patients compared to a normative population: a study from the population-based PROFILES registry.
      • Delforge M.
      • Minuk L.
      • Eisenmann J.C.
      • et al.
      Health-related quality of life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.
      • Acaster S.
      • Gaugris S.
      • Velikova G.
      • Yong K.
      • Lloyd A.J.
      Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey.
      • Sonneveld P.
      • Verelst S.G.
      • Lewis P.
      • et al.
      Review of health-related quality of life data in multiple myeloma patients treated with novel agents.
      • Stewart A.K.
      • Dimopoulos M.A.
      • Masszi T.
      • et al.
      Health-related quality of life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma.
      but the available data are limited, and the extent to which these benefits affect HRQoL in real-world practice remains unclear.
      This study identified treatment patterns consistent with those from other recent observational studies in European clinical practice
      • Ramsenthaler C.
      • Osborne T.R.
      • Gao W.
      • et al.
      The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.
      • Yong K.
      • Delforge M.
      • Driessen C.
      • et al.
      Multiple myeloma: patient outcomes in real-world practice.
      • Raab M.S.
      • Cavo M.
      • Delforge M.
      • et al.
      Multiple myeloma: practice patterns across Europe.
      and provides novel data on HRQoL across treatment lines for patients with MM managed in French health care settings. Our findings show that patients with MM receiving later lines of treatment have worse HRQoL than those at earlier treatment lines. HRQoL scores for patients receiving supportive care only (who had typically already received between 2 and 4 lines of treatment) showed the biggest difference compared to those for patients at other treatment lines, which highlights the importance of patients receiving active treatment for as long as possible. The data suggest that early and effective treatment of MM offers the best opportunity to improve or maintain HRQoL, but that the considerable deficits in HRQoL experienced at later stages of the disease (which could be due to disease progression or increased age) also deserve recognition in treatment decisions. Our findings are consistent with the results from a US survey of nearly 200 patients, which showed a trend for EORTC QLQ-C30 global health status scores to decrease with the number of treatment lines, although the relationship was not statistically significant.

      Hu HX, Katic BJ, Lowe M, Purnomo L, Gibson C, Rodrigues AM. Health-related quality of life in patients with multiple myeloma in relation to line of treatment and response. Poster E1459 presented at the 21st Annual European Hematology Association Congress, Copenhagen, Denmark, 2016.

      Our descriptive and exploratory analysis suggests a beneficial effect of deep treatment response on HRQoL. HRQoL scores were greater among patients who had a VGPR or better, compared to those who had a worse or no response to treatment. Again, this finding is consistent with the US survey, in which patients reporting their most recent disease status as complete response had a significantly higher EORTC QLQ-C30 global health status score than those whose response was partial or under control/stable, and those reporting relapsed/recurred or progressive disease.

      Hu HX, Katic BJ, Lowe M, Purnomo L, Gibson C, Rodrigues AM. Health-related quality of life in patients with multiple myeloma in relation to line of treatment and response. Poster E1459 presented at the 21st Annual European Hematology Association Congress, Copenhagen, Denmark, 2016.

      Our study additionally found that treatment-related toxicities reduced HRQoL, which was expected. However, HRQoL improved with time, which may reflect the fact that AEs generally occur in the early stage of treatment and often decline as treatment continues.
      • Mateos M.V.
      How to maintain patients on long-term therapy: understanding the profile and kinetics of adverse events.
      Furthermore, beyond the first therapy line, HRQoL was higher during current treatment than during TFIs. The opposite trend was observed at the first line, during which HRQoL was better during the first TFI than when initiating treatment for the first time. This finding is in keeping with previously reported data from patients at first line.
      • Acaster S.
      • Gaugris S.
      • Velikova G.
      • Yong K.
      • Lloyd A.J.
      Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey.
      Clearly, these data are cross-sectional and do not represent the course of an individual patient’s disease. Nonetheless, they offer a basis for hypotheses regarding the factors that could influence HRQoL throughout the disease course. Patients starting treatment for the first time will likely experience treatment-related toxicities to which they have not previously been exposed, and will also be affected by the psychologic burden of their recent diagnosis. The first TFI may be accompanied by alleviation of these toxicities and a sense that treatment has been successful, which could be reflected by improvements in HRQoL emotional function scores compared to newly diagnosed patients.
      • Ramsenthaler C.
      • Osborne T.R.
      • Gao W.
      • et al.
      The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.
      Beyond this stage, however, patients may be more resigned to their diagnosis and better prepared for the toxicities they may experience, together with the knowledge that their condition might decline as treatment continues. It is likely that monitoring (eg, for comorbidities) is less comprehensive while patients are not receiving active treatment. These factors may contribute to this apparent switch in the balance of HRQoL between active treatment and TFIs at first versus later therapy lines. Further study of the evolution of this complex disease in terms of the impact of the disease itself and its treatment on patients is warranted. It is likely that optimal HRQoL reflects a particular balance between patient-specific factors, treatment benefits and costs, and the ability of treatment to slow disease progression.
      An additional valuable output from our study is the correlation analyses of the EORTC QLQ-C30 global health status scores and the 4 items of the QLQ-MY20 in this real-world setting. There was a good correlation between the 2 modules, indicating that they are robust and can provide reliable, accurate descriptions of the HRQoL of patients with MM. The strongest correlation was between the EORTC QLQ-C30 global health status score and QLQ-MY20 disease symptoms (−0.57); information such as this may be useful in studies of HRQoL in MM by helping to establish the factors that have greatest influence on the global health status score. The possibility of response shift resulting from patients filling out the 2 forms consecutively should be considered when evaluating these data.
      Regarding the impact of variables on global health status, the model with the best fit included, rather than excluded, ECOG PS scores.
      • Ramsenthaler C.
      • Osborne T.R.
      • Gao W.
      • et al.
      The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.
      • Leleu X.
      • Petrucci M.T.
      • Welslau M.
      • et al.
      Psychometric performance of the EORTC Quality-of-Life Core Questionnaire (QLQ-C30) and QLQ–Multiple Myeloma (QLQ-MY20) in relapsed/refractory multiple myeloma (RRMM).
      For both models, including and excluding ECOG PS, the most important variables included ECOG PS scores (for the model including ECOG PS only), the presence of hemotoxicity, and treatment response. On the basis of the model that included ECOG PS, ECOG PS itself had the strongest explanatory power for the HRQoL of patients with MM. This is an expected yet interesting finding because the ECOG PS scale is used in most clinical studies as a standardized, physician-evaluated measure of the functional state of the patient
      • Atkinson T.M.
      • Andreotti C.F.
      • Roberts K.E.
      • Saracino R.M.
      • Hernandez M.
      • Basch E.
      The level of association between functional performance status measures and patient-reported outcomes in cancer patients: a systematic review.
      and correlates with HRQoL.
      • Ramsenthaler C.
      • Osborne T.R.
      • Gao W.
      • et al.
      The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.
      • Leleu X.
      • Petrucci M.T.
      • Welslau M.
      • et al.
      Psychometric performance of the EORTC Quality-of-Life Core Questionnaire (QLQ-C30) and QLQ–Multiple Myeloma (QLQ-MY20) in relapsed/refractory multiple myeloma (RRMM).
      While HRQoL scales are inherently designed to allow patients to self-assess the impact of their disease and its treatment over time, without interpretation by a physician, the evaluation of ECOG PS by a physician is subjective, occurs at baseline, and is subject to bias and high interobserver variability.
      • Kelly C.M.
      • Shahrokni A.
      Moving beyond Karnofsky and ECOG performance status assessments with new technologies.
      PS assessment might be influenced by various elements that may concurrently relate to the patient’s HRQoL, such as their body language and how they express any changes in their physical abilities or complaints. As such, patients within a single PS category may represent a heterogeneous population.
      • Gebbia V.
      • Galetta D.
      • De Marinis F.
      Non small cell lung cancer patients with ECOG PS2: unsolved questions and lessons from clinical trials.
      An association between ECOG PS and HRQoL has been reported previously in the cancer setting. In a study of 557 patients with MM, EORTC QLQ-C30 global health status scores were significantly and independently associated with ECOG PS.
      • Ramsenthaler C.
      • Osborne T.R.
      • Gao W.
      • et al.
      The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.
      This finding has also been observed in a study of 206 patients with relapsing–remitting MM commencing second- or third-line treatment.
      • Leleu X.
      • Petrucci M.T.
      • Welslau M.
      • et al.
      Psychometric performance of the EORTC Quality-of-Life Core Questionnaire (QLQ-C30) and QLQ–Multiple Myeloma (QLQ-MY20) in relapsed/refractory multiple myeloma (RRMM).
      In a study of patients with stage IV lung cancer, reductions in HRQoL (Functional Living Index–Cancer scale) during treatment significantly correlated with a decline in PS.
      • Finkelstein D.M.
      • Cassileth B.R.
      • Bonomi P.D.
      • Ruckdeschel J.C.
      • Ezdinli E.Z.
      • Wolter J.M.
      A pilot study of the Functional Living Index–Cancer (FLIC) scale for the assessment of quality of life for metastatic lung cancer patients. An Eastern Cooperative Oncology Group study.
      The strong relationship between ECOG PS and HRQoL scores
      • Atkinson T.M.
      • Andreotti C.F.
      • Roberts K.E.
      • Saracino R.M.
      • Hernandez M.
      • Basch E.
      The level of association between functional performance status measures and patient-reported outcomes in cancer patients: a systematic review.
      suggests that the ECOG PS assessment may have been confounded by the HRQoL information expressed by patients or observed by their physicians.
      This study had several limitations. There was potential for selection bias in physician recruitment because invited physicians were self-selecting participants of a prior MM study and agreed to participate in this study. The willingness of these physicians to participate in MM research activities may reflect a level of expertise that cannot be assumed in a wider physician population. There was also a bias in patient selection because inclusion criteria required that enrolled patients were attending regular appointments at a MM clinic; therefore, patients who were not actively seeking care were excluded from the analysis. Patient numbers, particularly in later lines and supportive care, were limited. The HRQoL analysis focused on patients who had provided written consent to be included in this part of the study, although there were no significant differences in the baseline characteristics between patients who did and did not answer the questionnaire. Compliance bias may have arisen when patients responded to certain questions in the HRQoL questionnaires because the questionnaire was administered to and collected from the patient by the treating physician even if the patient was instructed to give back the questionnaire in a sealed envelope. Data on the worst- and best-performing patients may not have been captured. In terms of the definition of response, we assumed that most patients with a nonevaluable response would have been at the early stages of treatment, although this was not specified by the questionnaire. Treatment response was also based on physician assessment and was subject to local practices (within France) rather than consistent, conventionally defined criteria, as used in clinical trials.
      • Yong K.
      • Delforge M.
      • Driessen C.
      • et al.
      Multiple myeloma: patient outcomes in real-world practice.
      The study was not designed to detect statistically significant differences in HRQoL between subgroups of interest, and adjustments were not made for multiplicity. Therefore, the exploratory statistical analyses presented here should be interpreted with caution. Furthermore, it was not possible to assess the effect of AEs on HRQoL because the study was not powered to evaluate the impact of specific AEs or to differentiate between resolved and ongoing AEs. Toxicities were only identified since the initiation of the most recent treatment, with the exception of history of peripheral neuropathy; the potential impact of AEs related to previous treatment could not be fully estimated with the exception of neuropathy, which negatively affected patient HRQoL independent of treatment line. More generally, correlation between HRQoL and previous treatment experience (time to progression, response, AEs) should be further explored. Relapse may also be associated with a negative psychoemotional state related to expected poor outcomes, and this may influence HRQoL in later treatment lines. However, its specific impact could not be quantified by the present study. The short-term impact of autologous stem-cell transplantation could not be investigated because the date of transplantation was not collected. However, the impact of prior stem-cell transplantation could be explored in future research. In a recent systematic literature review, Chakraborty et al
      • Chakraborty R.
      • Hamilton B.K.
      • Hashmi S.K.
      • Kumar S.K.
      • Majhail N.S.
      Health-related quality of life after autologous stem cell transplantation for multiple myeloma.
      showed that transplantation is associated with short-term deterioration (1 to 2 months) but long-term improvement of quality of life.

      Conclusion

      To our knowledge, this is the first full publication of real-world data relating to HRQoL at different treatment lines in patients with MM in France. In this study, patients receiving later lines of therapy had worse HRQoL than patients at earlier treatment lines. The observed association between response and HRQoL confirms the clinical relevance to the patient of achieving a deep response to treatment. These data demonstrate that treatment options in MM do not compromise HRQoL, which is a key aspect of disease management. Caution is urged over the interpretation of the association between HRQoL and subjective measures such as ECOG PS, owing to their codependence on a number of factors. Further study of the longitudinal impact of MM and its treatment at different stages of the disease is justified in order to better understand the contributions of factors such as treatment response, duration of treatment, experience of AEs, and treatment status to overall HRQoL at different treatment lines.

       Clinical Practice Points

      • MM is a common hematologic malignancy. Although there is currently no cure, new effective treatments have recently emerged that can change the disease course and that have resulted in improved overall survival.
      • Although increasing life expectancy is the main aim of treatment, the quality of any survival gains achieved should be assessed. Indeed, the effect of treatment on patients’ quality of life is now recognized as an important consideration when determining the benefit–risk profiles of new anticancer drugs. Despite this, however, HRQoL data from patients with MM in real-world clinical practice in Europe are lacking.
      • In this study, patients with MM receiving earlier lines of treatment had better HRQoL than those in later treatment lines. This suggests that initiating effective treatment early is the most effective way to improve and sustain HRQoL.
      • Longer duration of treatment was associated with better HRQoL. Patients receiving active treatment at later lines had higher HRQoL scores than those who had stopped treatment and were receiving supportive care. This emphasizes the need for patients to receive active treatment for as long as possible.
      • Patients who experienced at least a VGPR had higher HRQoL scores than those with a poorer or no treatment response, confirming the importance of achieving a deep treatment response. As expected, treatment-related toxicities reduced HRQoL, although improvements were seen over time, as AEs often decline with continued treatment.

      Disclosure

      F.B. has received research grants, consulting fees, speaker fees, or travel support from Amgen , Roche , Eisai , Celgene , Bristol-Myers Squibb , IntegraGen , Invectys , Merck Serono , Nestlé , and Novartis . N.D., S.G.M., and F.S. are employees of Amgen and hold Amgen stock. C.T., A.F., and G.S. are employees of Kantar Health, which received funding from Amgen (Europe) GmbH to conduct this research.

      Acknowledgments

      Medical writing support was provided by Sarah Griffiths, PhD, of Oxford PharmaGenesis, funded by Amgen (Europe) GmbH. Editorial support was provided by Camilla Norrmen, PhD, of Amgen (Europe) GmbH.

      Supplemental Data

      Figure thumbnail fx1
      Supplemental Figure 1Correlation Between EORTC QLQ-C30 Global Health Status Score and 4 Symptom Scales of EORTC QLQ-MY20. Bar Charts Represent Distribution of Each Score (EORTC QLQ-C30 and Each Domain of EORTC QYL-MY20 [Future Perspective, Body Image, Disease Symptoms and Side Effects of Treatment]). Graphs Describe Correlation Between EORTC QLQ-C30 and EORTC QLQ-MY20% and 80% Confidence Intervals (Represented by Lines and Ellipses, Respectively). Numbers Represent Correlation Coefficients
      Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; QLQ-C30 = Core Quality of Life questionnaire; QLQ-MY20 = Quality of Life Multiple Myeloma module.
      Supplemental Table 1Characteristics of 41 Study Physicians
      CharacteristicN (%)
      Geographic Region
       Central3 (7.3)
       Central East6 (14.7)
       Paris Ile-de-France5 (12.2)
       North5 (12.2)
       South East4 (9.8)
       South West10 (24.4)
       West8 (19.5)
      Specialty
       Hematologist24 (58.5)
       Oncohematologist11 (26.8)
       Oncologist4 (9.8)
       Other2 (4.8)
      Practice Setting
       University hospital center13 (31.7)
       Hospital center14 (34.1)
       Private not-for-profit clinic2 (4.9)
       Private clinic8 (19.5)
       Regional cancer center4 (9.8)
      Supplemental Table 2Characteristics of Patients Asked to Complete EORTC QLQ-C30 and QLQ-MY20 by Line of Therapy
      CharacteristicTotal (N = 445)First Line (N = 117)Second Line (N = 103)Third Line (N = 94)Fourth Line or Later (N = 88)Supportive Care (N = 43)
      Agreed to answer HRQoL questionnaires
      One patient changed their mind and so did not answer questionnaire. Not all of patients who received HRQoL questionnaires answered all questions.
      402 (90.3)113 (96.6)97 (94.2)85 (90.4)76 (86.4)31 (72.1)
      Did not agree to answer HRQoL questionnaires40 (9.0)3 (2.6)6 (5.8)9 (9.6)10 (11.4)12 (27.9)
      Unspecified3 (0.7)1 (0.9)0 (0)0 (0)2 (2.3)0 (0)
      Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; HRQoL = health-related quality of life; QLQ-C30 = Core Quality of Life questionnaire; QLQ-MY20 = Quality of Life Multiple Myeloma module.
      a One patient changed their mind and so did not answer questionnaire. Not all of patients who received HRQoL questionnaires answered all questions.
      Supplemental Table 3Characteristics of Patients Asked to Complete EORTC QLQ-C30 and QLQ-MY20 by Answer or Failure to Answer
      CharacteristicTotal (N = 445)Answered (N = 401)Did Not Answer (N = 44)P
      Age (years), median (Q1–Q3)72.7 (64.5-78.5)72.4 (63.9-78.3)75.0 (67.7-80.0).0964
      Age.322
       < 65 years108 (24.3)102 (25.7)6 (13.6)
       65-74 years138 (31.0)124 (30.9)14 (31.8)
       75-79 years98 (22.0)87 (21.7)11 (25.0)
       ≥ 80 years101 (22.7)88 (21.9)13 (29.5)
      Sex.1239
       Female214 (48.1)188 (46.9)26 (59.1)
       Male231 (51.9)213 (53.1)18 (40.9)
      Type of Management.0439
       Consultation220 (49.4)196 (48.9)24 (54.5)
       Day patient190 (42.7)177 (44.1)13 (29.5)
       Inpatient35 (7.9)28 (7.0)7 (15.9)
      ECOG PS.0286
       0-1287 (64.5)265 (66.1)22 (50.0)
       299 (22.2)88 (21.9)11 (25.0)
       3-458 (13.0)47 (11.7)11 (25.0)
       Unspecified1 (0.2)1 (0.2)0 (0)
      Last Treatment Response Recorded in Current Line
       Complete response and very good partial response145 (32.6)132 (32.9)13 (29.5).0002
       Partial response142 (31.9)133 (33.2)9 (20.5)
       Stable disease31 (7.0)22 (5.5)9 (20.5)
       Progressive disease30 (6.7)23 (5.7)7 (15.9)
       Not evaluable97 (21.8)91 (22.7)6 (13.6)
      Comorbidities.0743
       ≥ 1268 (60.2)236 (58.9)32 (72.7)
       0177 (39.8)165 (41.1)12 (27.3)
      Toxicity (Grade 3/4 Adverse Event)
      Toxicities were grade 3/4 adverse events and included neuropathy, diarrhea, anemia, neutropenia, thrombocytopenia, renal failure, infection, pneumopathy, other.
      .1391
       ≥ 1102 (22.9)88 (21.9)14 (31.8)
       0343 (77.1)313 (78.1)30 (68.2)
      Data are presented as n (%) unless otherwise indicated.
      Significance was assessed by 1-way rank ANOVA.
      Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; EORTC = European Organization for Research and Treatment of Cancer; HRQoL = health-related quality of life; Q = quartile; QLQ-C30 = Core Quality of Life questionnaire; QLQ-MY20 = Quality of Life Multiple Myeloma module.
      a Toxicities were grade 3/4 adverse events and included neuropathy, diarrhea, anemia, neutropenia, thrombocytopenia, renal failure, infection, pneumopathy, other.
      Supplemental Table 4Multivariate Analysis of EORTC QLQ-C30 Global Health Status Score, Including or Excluding ECOG PS Within Model
      Model Including ECOG PS
      CharacteristicMinimumFirst QuartileMedianThird QuartileMaximum
      Residuals−61.310−10.6450.61811.54248.145
      VariableEstimateStandard Errort ValueP
      (Intercept)81.039696.5820112.312< 2e-16
      Male sex−2.724691.76889−1.540.12430
      Treatment response: PD−12.210614.35897−2.801.00535
      Treatment response: SD and NE−4.280911.99410−2.147.03244
      ECOG PS 1−6.371512.52288−2.525.01196
      ECOG PS 2−15.322142.97710−5.1474.24e-07
      ECOG PS 3−25.659553.81692−6.7236.48e-11
      ECOG PS 4−39.021298.13860−4.7952.34e-06
      Comorbidity: neuropathy−5.026173.10313−1.620.10612
      Grade 3/4 toxicity: hematology−10.931052.51872−4.3401.82e-05
      Grade 3/4 renal failure toxicity8.891246.202901.433.15256
      Age (years)−0.139920.09048−1.546.12283
      Residual standard error17.42 on 384 degrees of freedom
      Multiple R2 value0.3313
      Adjusted R2 value0.3121
      F statistic17.29 on 11 and 384 degrees of freedom

      P < 2.2e-16
      Model Excluding ECOG PS
      CharacteristicMinimumFirst QuartileMedianThird QuartileMaximum
      Residuals−57.43−12.540.7212.8754.13
      VariableEstimateStandard Errort ValueP
      (Intercept)81.408176.7614312.040< 2e-16
      Second line−2.553182.58144−0.989.32326
      Third line−7.138292.72707−2.618.00920
      Fourth line or later−6.556082.82445−2.321.02080
      Supportive care−14.777794.92058−3.003.00285
      Treatment response: PD−16.639925.32794−3.123.00192
      Treatment response: SD and NE−5.278962.12869−2.480.01357
      Comorbidity: neuropathy−6.414143.32754−1.928.05464
      Grade 3/4 toxicity: neuropathy−5.880914.20189−1.400.16244
      Grade 3/4 toxicity: hematology−11.133322.66242−4.1823.59e-05
      Age (years)−0.221580.09398−2.358.01888
      Residual standard error18.45 on 385 degrees of freedom
      Multiple R2 value0.2477
      Adjusted R2 value0.2282
      F statistic12.68 on 10 and 385 degrees of freedom

      P < 2.2e-16
      Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; EORTC = European Organization for Research and Treatment of Cancer; NE = not evaluable; PD = progressive disease; QLQ-C30 = Core Quality of Life questionnaire; SD = stable disease.

      References

        • Moreau P.
        • San Miguel J.
        • Ludwig H.
        • et al.
        Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2013; 24: vi133-vi137
        • Palumbo A.
        • Bringhen S.
        • Ludwig H.
        • et al.
        Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN).
        Blood. 2011; 118: 4519-4529
      1. Santé publique France. Estimation nationale de l’incidence des cancers en France entre 1980 et 2012. 2013.
        (Available at:)
        • Kumar S.K.
        • Rajkumar S.V.
        • Dispenzieri A.
        • et al.
        Improved survival in multiple myeloma and the impact of novel therapies.
        Blood. 2008; 111: 2516-2520
        • Dimopoulos M.A.
        • Richardson P.G.
        • Moreau P.
        • Anderson K.C.
        Current treatment landscape for relapsed and/or refractory multiple myeloma.
        Nat Rev Clin Oncol. 2015; 12: 42-54
        • Cleeland C.S.
        • Mendoza T.R.
        • Wang X.S.
        • et al.
        Assessing symptom distress in cancer patients: the MD Anderson Symptom Inventory.
        Cancer. 2000; 89: 1634-1646
        • European Medicines Agency
        Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man. The use of patient-reported outcome (PRO) measures in oncology studies.
        (Available at:)
        • Johnsen A.T.
        • Tholstrup D.
        • Petersen M.A.
        • Pedersen L.
        • Groenvold M.
        Health related quality of life in a nationally representative sample of haematological patients.
        Eur J Haematol. 2009; 83: 139-148
        • Mols F.
        • Oerlemans S.
        • Vos A.H.
        • et al.
        Health-related quality of life and disease-specific complaints among multiple myeloma patients up to 10 yr after diagnosis: results from a population-based study using the PROFILES registry.
        Eur J Haematol. 2012; 89: 311-319
        • van der Poel M.W.
        • Oerlemans S.
        • Schouten H.C.
        • van de Poll-Franse L.V.
        Elderly multiple myeloma patients experience less deterioration in health-related quality of life than younger patients compared to a normative population: a study from the population-based PROFILES registry.
        Ann Hematol. 2015; 94: 651-661
        • Delforge M.
        • Minuk L.
        • Eisenmann J.C.
        • et al.
        Health-related quality of life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.
        Haematologica. 2015; 100: 826-833
        • Acaster S.
        • Gaugris S.
        • Velikova G.
        • Yong K.
        • Lloyd A.J.
        Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey.
        Support Care Cancer. 2013; 21: 599-607
        • Jordan K.
        • Proskorovsky I.
        • Lewis P.
        • et al.
        Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study.
        Support Care Cancer. 2014; 22: 417-426
      2. Gado K, Domjan G. Quality of life issues of patients with multiple myeloma. In: Hajek R, ed. Multiple Myeloma—A Quick Reflection on the Fast Progress. IntechOpen. 2013. Available: https://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-on-the-fast-progress/quality-of-life-issues-of-patients-with-multiple-myeloma, Accessed March 2017.

        • Sonneveld P.
        • Verelst S.G.
        • Lewis P.
        • et al.
        Review of health-related quality of life data in multiple myeloma patients treated with novel agents.
        Leukemia. 2013; 27: 1959-1969
        • Stewart A.K.
        • Dimopoulos M.A.
        • Masszi T.
        • et al.
        Health-related quality of life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma.
        J Clin Oncol. 2016; 34: 3921-3930
        • Aaronson N.K.
        • Ahmedzai S.
        • Bergman B.
        • et al.
        The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
        J Natl Cancer Inst. 1993; 85: 365-376
        • Cocks K.
        • Cohen D.
        • Wisloff F.
        • et al.
        An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma.
        Eur J Cancer. 2007; 43: 1670-1678
        • Nielsen L.K.
        • Jarden M.
        • Andersen C.L.
        • Frederiksen H.
        • Abildgaard N.
        A systematic review of health-related quality of life in longitudinal studies of myeloma patients.
        Eur J Haematol. 2017; 99: 3-17
        • Kvam A.K.
        • Waage A.
        Health-related quality of life in patients with multiple myeloma—does it matter?.
        Haematologica. 2015; 100: 704-705
        • Ramsenthaler C.
        • Osborne T.R.
        • Gao W.
        • et al.
        The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study.
        BMC Cancer. 2016; 16: 427
        • Leleu X.
        • Petrucci M.T.
        • Welslau M.
        • et al.
        Psychometric performance of the EORTC Quality-of-Life Core Questionnaire (QLQ-C30) and QLQ–Multiple Myeloma (QLQ-MY20) in relapsed/refractory multiple myeloma (RRMM).
        Blood. 2013; 121: 1721
        • World Health Organization
        Constitution of WHO: principles.
        (Available at:)
        http://www.who.int/about/mission/en/
        Date: 2005
        Date accessed: January 10, 2017
        • Yong K.
        • Delforge M.
        • Driessen C.
        • et al.
        Multiple myeloma: patient outcomes in real-world practice.
        Br J Haematol. 2016; 175: 252-264
        • Raab M.S.
        • Cavo M.
        • Delforge M.
        • et al.
        Multiple myeloma: practice patterns across Europe.
        Br J Haematol. 2016; 175: 66-76
      3. Hu HX, Katic BJ, Lowe M, Purnomo L, Gibson C, Rodrigues AM. Health-related quality of life in patients with multiple myeloma in relation to line of treatment and response. Poster E1459 presented at the 21st Annual European Hematology Association Congress, Copenhagen, Denmark, 2016.

        • Mateos M.V.
        How to maintain patients on long-term therapy: understanding the profile and kinetics of adverse events.
        Leuk Res. 2012; 36: S35-S43
        • Atkinson T.M.
        • Andreotti C.F.
        • Roberts K.E.
        • Saracino R.M.
        • Hernandez M.
        • Basch E.
        The level of association between functional performance status measures and patient-reported outcomes in cancer patients: a systematic review.
        Support Care Cancer. 2015; 23: 3645-3652
        • Kelly C.M.
        • Shahrokni A.
        Moving beyond Karnofsky and ECOG performance status assessments with new technologies.
        J Oncol. 2016; 2016: 6186543
        • Gebbia V.
        • Galetta D.
        • De Marinis F.
        Non small cell lung cancer patients with ECOG PS2: unsolved questions and lessons from clinical trials.
        Ann Oncol. 2005; 16: iv123-iv131
        • Finkelstein D.M.
        • Cassileth B.R.
        • Bonomi P.D.
        • Ruckdeschel J.C.
        • Ezdinli E.Z.
        • Wolter J.M.
        A pilot study of the Functional Living Index–Cancer (FLIC) scale for the assessment of quality of life for metastatic lung cancer patients. An Eastern Cooperative Oncology Group study.
        Am J Clin Oncol. 1988; 11: 630-633
        • Chakraborty R.
        • Hamilton B.K.
        • Hashmi S.K.
        • Kumar S.K.
        • Majhail N.S.
        Health-related quality of life after autologous stem cell transplantation for multiple myeloma.
        Biol Blood Marrow Transplant. 2018; 24: 1546-1553