Качество жизни, связанное со здоровьем, и скорректированное на качество свободное выживание для карфилзомиба и дексаметазона после спасательной аутологической трансплантации стволовых клеток у пациентов с множественной миеломой: случайная трансплантация фазы 2 :: судебное разбирательство, проведенное Исследовательской группой Северной Европы по миеломе.

Background

Primary endpoints in clinical cancer trials are preferably objective, well-defined and measurable outcomes, such as overall survival, progression free survival and response rates [ 1 ]. However, secondary or exploratory endpoints, such as health-related quality of life (HRQL) measured through patient-reported outcomes (PROs), have become increasingly important to supplement the overall study findings [ 2 ]. PROs provide a patient-focused assessment of the impact of a treatment on patients´ symptoms and functional abilities, which can inform regulatory label claims and clinical decision making [ 3 – 5 ].

Multiple myeloma (MM) is an incurable hematological cancer associated with bone destruction, hypercalcemia, anemia, renal failure and infections [ 6 ]. Overall survival has markedly increased after the introduction of novel treatments in the past two decades [ 7 – 9 ]. A contributor to improved overall survival is high-dose melphalan with autologous stem-cell transplantation (ASCT), which is standard treatment in patients with newly diagnosed MM younger than 70 years of age without significant comorbidities [ 10 , 11 ]. High-dose melphalan causes acute toxicity of anorexia, mucositis with pain and diarrhea, neutropenia and thrombocytopenia with temporary impairment of HRQL and full recovery for some patients, 1–2 months post-ASCT, while other patients still have moderate to severe symptoms one year post-ASCT [ 12 – 15 ].

Another contributor to improved overall survival in MM is maintenance treatment, i.e. long term therapy that extends response duration [ 16 – 18 ]. An important consideration for individual decision-making about maintenance therapy is the long-term impact on patient HRQL [ 17 , 19 ]. Results from secondary PRO endpoints have shown that HRQL during maintenance varies with the specific drug used. Despite thalidomide´s prolongation of progression free survival (PFS), this drug is not approved for maintenance therapy for MM due to unacceptable impairment of HRQL [ 20 , 21 ]. Lenalidomide maintenance improves PFS and overall survival and is approved for maintenance therapy in transplant-eligible patients after ASCT [ 18 ]. Adverse event registration from clinical trials shows that lenalidomide maintenance after ASCT is tolerable, and includes mainly hematological side-effects, diarrhea and fatigue [ 22 – 24 ]. However, randomized studies comparing HRQL during lenalidomide maintenance versus observation after ASCT are lacking. Published studies allowed several drugs as maintenance therapy or were designed with another drug as comparator [ 25 – 27 ]. In one of the studies, HRQL comparison between patients receiving maintenance therapy versus no maintenance therapy after first-line ASCT was done [ 27 ]. Several maintenance drugs were included, but not carfilzomib. The overall results indicated minimal impact on HRQL by maintenance therapy, but with worsening diarrhea and reduction in future perspectives.

Eventually, almost all patients with MM will experience relapse or progressive disease and for these patients, salvage ASCT will be an option, particularly for patients who achieved a long remission after frontline ASCT [ 10 , 28 ]. After successful salvage ASCT, it would be desirable to prolong response duration with maintenance therapy, as long as that does not compromise HRQL or hamper recovery after salvage ASCT. However, there is limited randomized evidence on maintenance therapy after salvage ASCT. In the ReLApsE trial, lenalidomide maintenance therapy was included in the transplant arm; but the study was designed to evaluate salvage ASCT, not maintenance therapy [ 29 ].

To investigate the impact of maintenance therapy after salvage ASCT, the Nordic Myeloma Study Group initiated the CARFI trial in 2015 [ 30 ]. Carfilzomib, a second-generation proteasome inhibitor, was chosen for maintenance therapy in the CARFI trial, administered with dexamethasone every second week. The primary clinical endpoint of the CARFI study was time to progression; as previously reported, time to progression was significantly prolonged by eight months for the carfilzomib-dexamethasone (Kd) maintenance group (25.1 months) compared to observation (16.7 months) [ 30 ]. HRQL was one of the secondary endpoints of the CARFI trial; results of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire– Core 30 items (QLQ-C30) global health status/quality of life (GHS/QoL) subscale showed no between-group difference during the 2-year follow-up period [ 30 ]. The aim of this paper is to present an in-depth analysis of the CARFI trial PRO endpoints, as per the statistical analysis plan [ 31 ].

PRO objective, endpoints and hypotheses

The objective of the HRQL component of the CARFI trial was to assess the impact of Kd maintenance therapy, relative to observation, post salvage ASCT on a range of relevant aspects of HRQL. The primary PRO endpoint was change in overall HRQL from randomization to eight months follow-up, with the corresponding primary PRO hypothesis that there was no difference between the Kd maintenance therapy and observation groups. The primary PRO endpoint was augmented by the average overall HRQL per-patient based on all completed HRQL forms from randomization to last follow-up time-point prior to progressive disease/death/drug discontinuation/end of study (whichever came first). These two primary endpoints were supplemented by secondary PRO endpoints defined in terms of specific HRQL domains from randomization to 8 months later: (1) mean change; (2) the proportion of patients who improved, remained stable or worsened; (3) time to first recorded improvement; and (4) the proportion of patients with Kd-related symptoms. The final secondary endpoint was quality-adjusted progression free survival (QAPFS) from randomization to progressive disease/death/drug discontinuation/end of study (whichever came first). Hypotheses corresponding to each of these endpoints, including specific HRQL domains and symptoms, the questionnaires used to assess these, and the analysis and interpretation approach are presented in Table 1 .

Table 1 Health-related quality of life endpoints, hypotheses, analysis and interpretation approach of the CARFI trial Endpoints HRQLdomains and/or items 1 Hypotheses Analysis and interpretation approach Primary endpoint, primary analysis Change in overall HRQL from randomization to eight months follow-up. EORTC QLQ-C30 Summary Score There will be no difference between the two groups 2 in change from randomization to eight months follow-up. Non-inferiority approach. Between-group difference in mean change per group estimated using linear mixed effect model for repeated measures. P -value < 0.01 defined as statistically significant. MID > 10 defined as clinically relevant, used as the agreement-limit for non-inferiority, i.e. an estimated between-group difference less than 10 points would accept the non-inferiority hypothesis. Missing data handled as missing at random. Supportive analysis of primary endpoint Average per-patient overall HRQL from randomization to progressive disease/death/drug discontinuation/end of study (whichever came first). EORTC QLQ-C30 Summary Score There will be no difference between the two groups 2 in per-patient mean overall HRQL averaged across all available time points from randomization to progressive disease/death/drug discontinuation/end of study (whichever came first). Non-inferiority approach comparing the mean of the average per-patient QLQ-C30-sum score between the two groups with the rank-sum test. P -value < 0.01 defined as statistically significant. MID > 10 used as the agreement-limit for non-inferiority, i.e. an estimated between-group difference less than 10 points would accept the non-inferiority hypothesis. Missing data handled as missing not at random. Secondary endpoints 1. Change in HRQL from randomization to eight months follow-up. All individual HRQL domains of EORTC QLQ-C30 and QLQ-MY20, and FACT/GOG-ntx instruments There will be no difference between the two groups 2 in HRQL, except for the domains potentially impacted by Kd-related side effects (nausea/ vomiting, fatigue, dyspnea, diarrhea, body image). Even for these five domains, the differences will not exceed the threshold for clinically relevant differences. Non-inferiority approach using linear mixed effect model for repeated measures. P -value < 0.05 defined as statistical significant. Evidence-based MID threshold used as the agreement-limit for non-inferiority of between group differences for EORTC QLQ-C30 and QLQ-MY20 domains (50, 52) and 4.4 for FACT/GOG-ntx. Missing data handled as missing at random. 2. The proportion of patients who have improved, remained stable and worsened in HRQL from randomization to eight months follow-up. Physical, role, social and emotional functioning, GHS/QoL, body image and future perspectives The proportion of patients who improved/remained stable/worsened will be similar between the two groups 2 . Superiority approach in favor of the observation group. Patient-level analysis using the responder definition threshold of 20 points for multi item domains and 33 points for body image for improvement or worsening. Chi-square test for between group comparisons. P -value < 0.05 defined as statistical significant. Missing data handled as missing completely at random. 3. The time to first recorded improvement in HRQL from randomization to eight months follow-up. Physical, role, social and emotional functioning; GHS/QoL, body image and future perspectives Patients randomized to Kd maintenance therapy will take longer time to achieve improvement in emotional functioning, role functioning and social functioning as well as in the body image domain, compared to observation, but will not differ in time to improve in physical functioning and GHS/QoL. Superiority approach in favor of the observation group for all domains except physical functioning and GHS/QoL. Patient-level analysis to assess the first time of improvement defined as 20 points for the multi item domains and 33 points for body image compared to randomization. Proportional hazards Cox regression model was used to compare between groups. P -value < 0.05 defined as statistical significant. Missing data were handled as missing completely at random. 4. The proportion of patients with Kd-related symptoms and the proportion of patients with moderate to severe Kd-related symptoms from randomization to eight months follow-up. From QLQ-C30: Fatigue, nausea/vomiting, dyspnoea, insomnia, diarrhoea. From QLQ-MY20: agitation/irritation. A larger proportion of patients randomized to Kd maintenance therapy will report more severe levels of symptoms compared to observation. Superiority approach in favor of the observation group. Patient-level analysis using the raw score thresholds for change from randomization of ≥ 33 points for Kd-related symptoms and ≥ 66 points for severe Kd-related symptoms. Chi-square test for between group comparisons. P -value < 0.05 defined as statistical significant. Missing data handled as missing completely at random. 5. Quality-adjusted progression-free survival from randomization to last follow-up time-point. Two quality-adjustment metrics: EORTC QLQ-C30 Summary Score and EORTC QLU-C10D Quality-adjusted progression-free survival will not differ substantially from the difference observed in progression free survival, since we do not expect Kd to impact significantly on overall HRQL. Non-inferiority approach. Per-patient time in QAPFS calculation for each of the metrics and multiplied with the per-patient estimated mean time to last follow-up time point. Group-level QAPFS estimated by Kaplan-Meier method and difference between group were estimated using bootstrap methods. P -value < 0.05 defined as statistical significant. Missing data handled as missing completely at random. HRQL; health-related quality of life, EORTC QLQ-C30; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire– Core 30 items, QLQ-MY20; the Multiple Myeloma module, FACT/GOG-ntx; Functional Assessment of cancer Therapy/Gynaecologic Oncolocy Group-Neurotoxity instrument, GHS/QoL; global health status/quality of life, QLU-C10D; the EORTC Quality of Life Utility Measure-Core 10 dimensions, QLQ-C30-sum; EORTC QLQ-C30 Summary, Kd; carfilzomib-dexamethasone, MID; minimal important difference, QAPFS; quality-adjusted progression-free survival 1 As assessed by items and standard scoring algorithms of the EORTC QLQ-C30, EORTC QLQ-MY20 and FACT/GOG-ntx. 2 The two groups refer to the Kd maintenance therapy group and the observation group

Methods

Design, patients and treatment

The CARFI trial was a Nordic Myeloma Study Group open-label multi-center, randomized, phase II clinical trial, using a parallel (1:1) group design (clinicaltrials.gov: NCT02572492 ). Details of the study design, trial treatment and main findings have been published elsewhere [ 30 ]. In brief, patients with MM aged 18 years or more with first relapse after prior ASCT and found eligible for salvage ASCT were included at 25 hospitals within four Nordic countries and Lithuania from January 2015 to April 2018. Key exclusion criteria were previous treatment with carfilzomib, maintenance treatment given after first ASCT, World Health Organization performance status ≥ 3, significant neuropathy (grade 3–4, or grade 2 with pain) and any comorbidity that would preclude treatment with carfilzomib or salvage ASCT.

Two months after reinduction with four cycles of carfilzomib-lenalidomide-dexamethasone followed by salvage ASCT, patients were randomized to Kd maintenance or observation. Kd maintenance was given as intravenous carfilzomib (27 mg/sqm every second week with escalation of carfilzomib to 56 mg/sqm if tolerated) and oral dexamethasone 20 mg every second week until progression, unacceptable adverse effects, withdrawal of consent or 1 September 2019 (end of study). Dose modifications of carfilzomib and/or dexamethasone were done in case of toxicity related to the drugs (described in the supplementary appendix).

PRO instruments

HRQL were assessed with three instruments: the EORTC core module (QLQ-C30) [ 32 , 33 ] and Multiple Myeloma module (QLQ-MY20) [ 34 ], and the Functional Assessment of cancer Therapy/Gynaecologic Oncolocy Group-Neurotoxity (FACT/GOG-ntx) instruments [ 35 ]. The three questionnaires and domains are described in Table 2 .

Table 2 The three questionnaires, domains, descriptions and scoring. EORTC QLQ-C30; quality of life questionnaire-core 30, EORTC QLQ-MY20; quality of life questionnaire-multiple myeloma module, FACT/GOG-Ntx; Functional Assessment of cancer Therapy/Gynaecologic Oncology Group-Neurotoxicity Health-related quality of life questionnaires Domains Description and scoring EORTC QLQ-C30 (30) Global quality of life Five functional domains (physical, role, emotional, cognitive and social) Nine symptom domains (fatigue, nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhea) Financial difficulties A 30-item, 15 domain cancer-generic questionnaire validated in patients with multiple myeloma (31). Recall period of 7 days. Four-point categorical scale: ‘not at all’, ‘a little’, ‘quite a bit’, ‘very much’. The answers are transformed into 0-100 scales (44). For the functional domains, a high score means low degree of problems. For the symptom domains, a high score means high degree of symptoms. EORTC QLQ-MY20 (32) Two functional domains (future perspective and body image) Two symptom domains (disease symptoms and side effects of treatment) A 20-item, four domain myeloma-specific questionnaire. Recall period of 7 days. Four-point categorical scale: ‘not at all’, ‘a little’, ‘quite a bit’, ‘very much’. The answers are transformed into 0-100 scales (44). For the functional domains, a high score means low degree of problems. For the symptom domains, a high score means high degree of symptoms. FACT/GOG-ntx (33) Peripheral neuropathy An 11-item questionnaire summarized as a single domain of peripheral neuropathy. Recall period of 7 days. Five-point categorical scale: ‘not at all’, ‘a little bit’, ‘somewhat’, ‘quite a bit’, ‘very much’. The answers are transformed into a 0–44 scale (45). Higher score indicating less peripheral neuropathy

PRO data collection

Patient inclusion in the PRO sub-protocol was part of the CARFI trial. HRQL was assessed with all three instruments at randomization (two months post salvage ASCT) and then every second month in the outpatient clinic at study visits. The study nurses had access to trial specific guidance in PRO data collection. If a scheduled visit was postponed (e.g. due to vacation, public holidays, acute toxicities beyond grade 2), the PRO data collection was postponed as well. From study initiation until July 2017, the study nurses administered all three PRO instruments on paper for the patients to complete in the clinic. From July 2017, electronic completion of the EORTC instruments via a tablet directly into a REDCap database became an option. Real-time monitoring of non-completion of instruments was not carried out. PRO data collection continued until end of study for each patient, defined as the time of disease progression, death, drug discontinuation or study termination (whichever came first). Study termination was defined as the last protocol visit for the last included patient, which was on 1 September 2019.

Rationale for PRO endpoints

In developing the statistical analysis plan, HRQL studies of patients with MM were reviewed to inform our choice of PRO endpoints and appropriate PRO measures [ 31 ]. The EORTC QLQ-C30 Summary (QLQ-C30-sum) score was chosen to assess the primary PRO endpoint because there is no standard HRQL assessment for use in MM maintenance trials, it captures the generic HRQL concepts of importance in cancer, it reduces issues with multiplicity (type I error), and it has been validated in patients with hematological malignancies [ 36 , 37 ]. Secondary PRO endpoints were specified a priori, aligned with hypotheses (Table 1 ), assessed by specific domains from the QLQ-C30, QLQ-MY20 and FACT/GOG-ntx. These included four of the functioning domains (physical, role, social, emotional) and GHS/QoL from EORTC QLQ-C30, and two domains from the QLQ-MY20 (body image and future perspectives); these were chosen because they have previously been shown to be affected after primary ASCT [ 12 – 14 ]. Based on the literature, Kd-related symptoms were identified and defined as fatigue, dyspnea, nausea/vomiting, diarrhea, insomnia, agitation and restlessness; these were included to assess the non-infusion related symptomatic impact of carfilzomib and dexamethasone treatment [ 38 – 45 ]. Time in QAPFS was included as it captures the benefits and consequences of Kd maintenance therapy in terms of both treatment efficacy (PFS) and HRQL consequences. Further details are provided in the statistical analysis plan [ 31 ].

Statistical analyses

The statistical analysis plan for the PRO endpoints was finalized and published before starting the PRO data analyses [ 31 ]; a clarifying amendment was added to the published statistical analysis plan before finalizing the PRO data analyses. The statistical analyses are described here in brief. For each patient, the study period was from randomization to that patient’s last follow-up prior to progressive disease/death/drug discontinuation/end of study (which ever came first). The analyses were based on all available questionnaires from randomized patients on protocol until last follow-up time point except for the supportive analysis of the primary endpoint where all available questionnaires were included in the analysis. The last follow-up time point was defined as the time point before the number of patients on protocol in one of the groups became less than 15 patients. Analyses were carried out using Stata 17.

Patient characteristics and PRO scores at randomization were described with summary statistics (mean and 95% confidence intervals (CI)). PRO completion rates were calculated for each assessment time point as number of randomized patients with enough completed items to calculate the QLQ-C30-sum score as a proportion of patients on protocol at that time point.

HRQL domain scores of the QLQ-C30 and QLQ-MY20 were calculated according to EORTC standard scoring [ 46 ]. The QLQ-C30-sum score was calculated from the mean of 13 of the 15 QLQ-C30 domains (excluding GHS/QoL and Financial impact defining items) [ 37 ]. The QLQ-C30-sum score ranges from 0to 100, with 100 being best. The FACT/GOG-ntx score was calculated according to the FACT manual [ 47 ].

For the endpoints involving change in HRQL, the longitudinal PRO data were analyzed with a linear mixed effect model for repeated measures. The model included patients as a random variable and time (baseline, two, four, six and eight months), treatment group and country as fixed factors. The results were tested for statistical significance at the 5% level for the primary HRQL endpoint and at the 1% level for the secondary HRQL endpoints. Statistically significant results were interpreted as clinically relevant/meaningful if they exceed the threshold for minimally important difference/change (MID). As MID has not yet been established for the QLQ-C30-sum score, a 10-point change/difference was pre-specified as indicating a clinically relevant change (within a group) and a clinically relevant difference in change between groups [ 48 , 49 ]. Within and between group changes in the individual domains of the QLQ-C30 questionnaire were interpreted according to the evidence-based guidelines for between-group differences [ 50 ] and change over time [ 51 ] using the threshold for a small difference/change. For the domains of QLQ-MY20, recommended estimates for MIDs were used (disease symptoms and side effects of treatment; 10 points, body image; 13 points and future perspectives: 9 points) [ 52 ]. For the FACT/GOG-ntx subscale, 4.4 [ 53 ] points were used as primary MID and 11.8 points were used for sensitivity analysis [ 54 ].

For the supportive analysis of the primary endpoint, the average per-patient QLQ-C30-sum score from randomization to progressive disease/death/drug discontinuation/end of study was calculated. The mean per-patient QLQ-C30-sum score was calculated for each group and compared with a rank-sum test.

To evaluate the proportion of patients who improved, remained stable or worsened in HRQL, patients were categorized as having perceived either an improvement or worsening from randomization if they experienced a change in score (in the direction of improvement or worsening, respectively) that exceeded at least 20 points [ 55 ]. For the single item domain of body image, 33 points were used [ 52 ].

Time to first recorded improvement in HRQL was calculated for each patient as time from randomization to the first time the patient reported an improvement of at least 20 points for the EORTC multi-item domains [ 55 ], and 33 points for the body image single item domain [ 52 ]. Patients who did not record an improvement at any time point were censored at end of study. Patients with no score at randomization and patients with high functioning as well as good GHS/QoL (greater than 80 points) and body image (less than 33 points) at randomization were excluded from this analysis since this left no room for improvement. The mean time to improvement was compared between groups using a proportional hazards Cox regression model with treatment, PRO score at randomization and country as covariates, and presented as a hazard ratio (HR) with corresponding 95% CI. A post-hoc analysis of average time of first recorded improvement with corresponding standard deviations was performed.

For endpoints involving the proportion of patients with Kd-related symptoms, raw item scores were converted to 0-100 scales according to the EORTC manual [ 46 ], i.e. “none at all”=0, “a little”=33, “quite a bit”=67, “very much”=100. The proportion of patients with Kd-related symptoms was defined as the number of patients experiencing any of the Kd-related symptoms corresponding to at least “a little” (≥ 33 points) divided by the total number of patients. Similarly for the proportion of patients reporting moderate to severe Kd-related symptoms, a score of at least “quite a bit” (≥ 66 points) was used. This dichotomized grading has previously been used in patients with hematological malignancies [ 56 ]. Differences between treatment groups in these proportions were analyzed as binary endpoints using chi-square tests of homogeneity.

Preference-based utility scores were calculated from the QLQ-C30 data using the utility scoring algorithm of EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D) [ 57 ], which yields a score with a maximum of one (representing the best possible health state), and is anchored at zero (representing the state of being dead). Implementing this algorithm requires a country-specific value set; as a Danish QLU-C10D value set was not available at the time of analysis, the German value set was used [ 58 ], as it was considered to be closest culturally of the country-specific value sets available at the time of analysis. The time in QAPFS was calculated using two quality adjustment metrics: the per-patient mean EORTC QLQ-C30-sum score (divided by 100, as required for quality adjustment of life years) and the per-patient mean QLU-C10D utility score [ 59 ]. Patient-level QAPFS was calculated by multiplying the per-patient estimated mean time to progression/death (censored at last follow-up time point) by each of the quality adjustment metrics. Group-level QAPFS was then estimated with the Kaplan-Meier method. The mean difference in QAPFS between the two groups was estimated using bootstrap methods for each quality-adjustment metric.

To examine potentially missing data patterns (informative drop-out) two pattern mixture model analyses were performed; (1) stratifying patients into two groups based on drop-out time early (drop-out between zero and eight months follow-up) and late (participated in the study at 10 months) per treatment group, (2) stratifying patients into three groups based on drop-out time (early, late and never drop-out) per treatment group.

A post-hoc analysis was performed to investigate compliance with Kd maintenance therapy by assessing the proportion of fully administered, reduced and omitted doses of carfilzomib and dexamethasone relative to scheduled doses.

Sample size in the maintenance phase of the CARFI trial was determined according to the primary trial endpoint (time to progression). According to the trial protocol, it was expected that 150 patients would continue to the maintenance phase. No formal power analysis was performed for the PROs, and no patients were involved in the design or the interpretation phase of the study.

Results

Patient population

In total, 181 patients underwent salvage ASCT, and 168 patients continued to randomization between Kd maintenance or observation; 82 were randomized to Kd maintenance and 86 to observation, constituting the population for this HRQL analysis. Reasons for drop-out before randomization have been reported previously [ 30 ]. Reasons for drop-out from randomization until eight months follow-up are presented in the CONSORT flow diagram of Fig. 1 and the supplementary appendix Figure S1 until last follow-up time point (i.e. 22 months). Patient demographics, clinical characteristics and PRO mean scores at randomization are presented in Table 3 . PRO completion rate until eight months follow-up was 93% (95% for the Kd maintenance and 91% for the observation group) and 93% until last follow-up time point (supplementary appendix Table S1 ).

Fig. 1 CONSORT flow diagram CONSORT flow diagram of the entire study period is presented in the supplementary appendix Figure S1 Kd; Carfilzomib-dexamethasone, p; patient, q; questionnaires (completed items for calculating the EORTC QLQ-C30 summary score)

Table 3 Patient characteristics and patient-reported outcomes scores at randomization. Kd; Carfilzomib-dexamethsone, IQR; Interquartile range 25-75%, MM; multiple myeloma, ASCT; high-dose melphalan with autologous stem-cell transplantation, WHO; World health organization, EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core questionnaire; EORTC QLQ‐MY20, European Organisation for Research and Treatment of Cancer Multiple Myeloma module; FACT/GOG‐ntx subscale, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale; SD, Standard deviation Kd maintenance group ( p = 82) Observation group ( p = 86) Median age , years (IQR) 60 (54–65) 63 (58–67) Gender Female/Male 39/43 32/54 Median time from MM diagnosis , months (IQR) 47 (37–65) 48 (37–60) Median time from salvage ASCT to randomization , weeks (IQR) 8.1 (7.7–8.5) 8.1 (7.8–8.8) Median time from salvage ASCT to start of Kd maintenance/observation , weeks (IQR) 9.8 (8.8–10.3) 10.8 (8.8–13.7) Myeloma status Stringent complete response Complete response Very good partial response Partial response Stable disease Progressive disease Missing 10 (12%) 13 (16%) 41 (50%) 16 (20%) 1 (1%) 0 (0%) 1 (1%) 12 (14%) 8 (9%) 50 (58%) 16 (19%) 0 (0%) 0 (0%) 0 (0%) WHO performance status 0 1 2 3 or 4 Missing 47 (57%) 29 (35%) 2 (2%) 0 (0%) 4 (5%) 45 (52%) 30 (35%) 2 (2%) 0 (0%) 9 (10%) Country of residence Denmark Sweden Norway Finland Lithuanian 26 (30%) 18 (21%) 32 (37%) 4 (5%) 6 (7%) 21 (26%) 28 (34%) 20 (24%) 4 (5%) 9 (11%) EORTC QLQ-C30 domain scores, mean (SD) Global Health Status/Quality of life 66.0 (22.3) 68.1 (18.8) Physical functioning 77.4 (19.9) 75.9 (20.0) Role functioning 65.6 (29.5) 63.0 (29.6) Emotional functioning 80.1 (21.3) 85.8 (17.9) Cognitive functioning 84.8 (18.3) 82.3 (21.7) Social functioning 74.1 (24.6) 73.6 (25.4) Fatigue 35.6 (24.2) 35.6 (21.4) Nausea/vomiting 7.7 (14.4) 9.0 (18.9) Pain 22.9 (25.4) 25.2 (27.8) Dyspnea 23.2 (25.0) 25.6 (25.7) Insomnia 23.5 (26.4) 23.5 (25.8) Appetite loss 13.0 (21.7) 16.2 (25.6) Constipation 9.0 (19.1) 7.8 (19.4) Diarrhea 17.9 (24.4) 19.7 (26.8) Financial difficulties 16.2 (26.7) 8.6 (21.9) EORTC QLQ-MY20 domain scores, mean (SD) Disease symptoms 17.5 (16.9) 17.3 (17.5) Side effects of treatment 22.2 (14.2) 20.2 (15.2) Future perspective 58.9 (29.1) 62.0 (25.9) Body image 68.4 (30.3) 70.2 (32.7) FACT/GOG-ntx domain score, mean (SD) FACT/GOG-ntx subscale 38.1 (6.7) 38.7 (5.0)

Effect of kd maintenance on HRQL

The difference in mean change from randomization between groups in QLQ-C30-sum score estimated at eight months was 4.62 points on the 0-100 scale (95% CI -8.9; -0.4, p = 0.032) was statistically significant but not clinically important (i.e. it was less than the predefined MID). The findings are visualized in Fig. 2 . Similarly, none of the differences at specific time points (two, four and six months follow-up) reached statistical significance and clinical relevance. Data until last follow-up time point are provided in the supplemental appendix Table S2 . Results of the pre-specified supportive analysis of the primary endpoint, the average per-patient mean QLQ-C30-sum score, was 81.4 (SD 12.9) for the Kd maintenance group and 82.5 (SD 12.3) for the observation group. These means were similar and did not differ statistically significantly between the groups (rank sum test, p = 0.625).

Fig. 2 Mean score change from randomization in EORTC QLQ-C30 Summary Score until 8 months follow-up. Horizontal bars illustrates 95% confidence intervals. Kd; Carfilzomib-dexamethasone

Effect of kd maintenance on the individual PRO domains

Within the observation group, the patients reported statistically significant and clinically meaningful improvements at eight months in six domains (physical, role, social functioning, appetite loss, fatigue and body image), whereas the patients in the Kd maintenance group did not report statistically significant or clinically meaningful improvements in any domains at eight months follow-up. The findings are presented in Table 4 . For these six domains, the results at eight months are presented in Fig. 3 , and mean score changes, 95% confidence intervals and p -values until last follow-up time point are presented in supplementary appendix Table S3 - S8 .

Table 4 Mean change from randomization to eight months follow-up and between-group difference. The point estimates in bold indicate a statistically significant ( p < 0.01) and clinically relevant difference/meaningful change. Improvements are indicated by positive changes for function domains and negative changes for symptom domains Kd maintenance group Observation only group Between groups Mean score change (95%CI) p -value Mean score change (95%CI) p -value Mean score difference (95%CI) p -value QLQ-C30 function domains Positive values indicate better functioning Negative values favour observation group GHS/QoL 1.77 (-5.14; 8.69) 0.615 1.36 (-3.71; 6.43) 0.599 0.41 (-8.16; 8.99) 0.925 Physical 1.13 (-3.43; 5.69) 0.628 6.47 (3.05; 9.89) < 0.001 -5.34 (-10.94; 0.26) 0.062 Role 7.74 (0.23; 15.25) 0.043 12.18 (5.39; 18.96) < 0.001 -4.44 (-14.52; 5.65) 0.389 Social 3.81 (-1.67; 9.28) 0.173 9.34 (5.07; 13.62) < 0.001 -5.54 (-12.41; 1.34) 0.114 Emotional 0.57 (-3.14; 4.27) 0.765 0.00 (-3.35; 3.35) 0.999 0.56 (-4.44; 5.57) 0.826 Cognitive -1.80 (-5.85; 2.25) 0.383 2.23 (-1.82; 6.28) 0.281 -4.03 (-9.79; 1.73) 0.170 QLQ-C30 Symptom domains Negative values indicate reduced symptoms Positive values favor observation group Appetite loss -1.11 (-8.21; 5.99) 0.76 -12.87 (-19.21;-6.52) < 0.001 11.75 (2.47; 21.04) 0.013 Constipation -0.95 (-6.00; 4.11) 0.714 -0.86 (-5.54; 3.82) 0.719 -0.09 (-7.01; 6.84) 0.980 Diarrhoea -0.86 (-7.72; 6.00) 0.806 -4.81 (-11.62; 2.01) 0.167 3.95 (-5.78; 13.67) 0.426 Dyspnoea -1.23 (-7.68; 5.22) 0.709 -6.79 (-13.60; 0.01) 0.050 5.56 (-4.01; 15.14) 0.255 Fatigue -2.53 (-8.30; 3.24) 0.390 -9.09 (-13.61; -4.57) < 0.001 6.56 (-0.72; 13.84) 0.078 Nausea and vomiting 0.34 (-4.57; 5.26) 0.891 -5.91 (-10.59; -1.22) 0.013 6.25 (-0.31; 12.81) 0.062 Pain 1.73 (-4.04; 7.50) 0.557 -1.90 (-7.14; 3.33) 0.476 3.63 (-4.07; 11.34) 0.356 Insomnia 2.76 (-3.75; 9.27) 0.406 -2.70 (-8.50; 3.10) 0.362 5.46 (-3.19; 14.10) 0.216 Financial difficulties -2.61 (-6.69; 1.47) 0.211 -0.15 (-3.13; 2.82) 0.920 -2.46 (-7.57; 2.66) 0.346 QLQ-MY20 function domains Positive values indicate better functioning Negative values favor observation group Future perspectives 7.64 (3.17; 12.11) 0.001 7.58 (3.16; 12.00) 0.001 0.06 (-6.33; 6.44) 0.986 Body image 8.24 (0.90; 15.58) 0.028 13.60 (7.05; 20.14) < 0.001 -5.36 (-15.30; 4.59) 0.291 QLQ-MY20 symptom domains Negative values indicate reduced symptoms/side effects Positive values favor observation group Disease symptoms 3.07 (-0.20; 6.35) 0.066 0.72 (-2.54; 3.97) 0.666 2.36 (-2.23; 6.94) 0.314 Side effects of treatment -5.21 (-8.53; -1.89) 0.002 -7.09 (-9.80; -4.38) < 0.001 1.88 (-2.39; 6.16) 0.388 FACT/GOG-Ntx subscale Positive values indicate less peripheral neuropathy Negative values favour observation group FACT/GOG-Ntx subscale -0.63 (-2.11-0.84) 0.399 0.85 (0.12–1.57) 0.022 -1.48 (-3.14-0.18) 0.080 Kd; Carfilzomib-dexamethasone, GHS/QoL; global health status/quality of life, QLQ-C30; quality of life questionnaire-core 30, QLQ-MY20; quality of life questionnaire-multiple myeloma module, FACT/GOG-Ntx; Functional Assessment of cancer Therapy/Gynaecologic Oncology Group-Neurotoxicity CI; Confidence interval

Fig. 3 Mean score improvement from randomization to 8 months follow-up for the six domains with statistically significant and clinically meaningful improvement at 8 months follow-up Blue* indicates time points with statistically significant and clinically meaningful improvement for the observation group. Red* indicates time points with statistically significant and clinically meaningful improvement for the carfilzomib-dexamethasone (Kd) maintenance group

Proportion of patients who improved, remained stable or worsened

Generally, the majority (range 52-93%) of patients in both groups remained stable from randomization to the eight months follow-up, with some notable exceptions. A higher proportion of patients in the Kd maintenance compared to the observation group (93% versus 81%) reported stable physical functioning at four months (odds ratio 2.99, 95% CI 1.01; 8.83, p = 0.040). Also, a higher proportion of patients in the Kd maintenance group compared to the observation group (13% versus 2%) reported worsening in social functioning at eight months (odds ratio 8.74, 95% CI 1.06; 72.2, p = 0.018). The proportions and odds ratios for all domains from randomization to two, four, six and eight months follow-up are reported in Supplementary Table S9 .

Time to first recorded improvement

There were no statistically significant between-group difference in time to first recorded improvement in any of the (EORTC QLQ-C30) functional domains, GHS/QoL scale, QLQ-MY20 body image domain or future perspectives (Table 5 ). The average weeks to first recorded improvement is displayed in the supplementary appendix Table S10 ).

Table 5 Time to first recorded improvement in the functional domains, Global Health Scale/Quality of Life and body image domains. Patients with no score at randomization and patients with high functioning as well as good GHS/QoL and body image at randomization were excluded from this analysis since high/good score at randomization leaves no room for improvement Kd maintenance group Observation group Hazard ratio (95%CI) P -value Patients included in the analysis (n) Improved n (%) Patients included in the analysis (n) Improved n (%) Global Health scale/QoL 52 24 (46) 46 17 (37) 1.42 (0.73–2.76) 0.30 Physical functioning 40 15 (38) 43 15 (35) 1.03 (0.47–2.26) 0.94 Role functioning 48 31 (65) 53 38 (72) 0.83 (0.49–1.40) 0.49 Emotional functioning 32 10 (31) 22 10 (45) 0.66 (0.25–1.74) 0.40 Social functioning 39 23 (59) 40 23 (58) 0.95 (0.51–1.78) 0.88 Body image 48 34 (71) 42 32 (76) 0.86 (0.51–1.45) 0.58 Future perspectives 59 30 (51) 62 32 (52) 0.91 (0.52–1.59) 0.74 Kd; Carfilzomib-dexamethasone, QoL; Quality of life

Proportion of patients with Kd-related symptoms

Significantly more patients in the Kd maintenance group developed Kd-related symptoms of restlessness and agitation (odds ratio 1.90, CI95% 1.01; 3.58, p = 0.046) and insomnia (odds ratio 2.60, CI 95% 1.15; 5.88, p = 0.019) during the study period (Fig. 4 and the supplementary appendix Table S11 ).

Fig. 4 Proportion of patients developing carfilzomib-dexamethasone (Kd) related symptoms during the study period for the Kd maintenance and the observation group

Quality-adjusted progression free survival

When quality-adjusting the PFS based on the QLQ-C30-sum score, the QAPFS difference between the twogroups was 3.0 months in favor of the Kd maintenance group (95% CI 0.78; 5.28, p = 0.008). Mean QAPFS based on the QLQ-C30-sum score for the Kd maintenance group was 18.0 months (95% CI 16.4; 19.6) and 15.0 months for the observation group (95% CI 13.5; 16.5). Similarly for QAPFS based on the QLU-C10D, where Kd maintenance significantly extended QAPFS by 3.5 months (95% CI 1.2; 5.9, p = 0.004) compared to observation. The mean QAPFS based on the QLU-C10D for patients in the Kd maintenance group was 17.5 months (95% CI 15.9; 19.2) and 14.0 months (95% CI 12.4; 15.5) for the observation group. The quality-adjusted progression-free-survival curves are displayed in Fig. 5 . For comparison, the unadjusted progression-free survival was 19.3 months for the Kd maintenance group (95% CI 17.9; 20.7) and 16.8 for the observation group (95% CI 15.4; 18.3) resulting in a significantly superior PFS of 2.5 months for the Kd maintenance group (95% CI 0.47; 4.5, p = 0.016).

Fig. 5 Quality-adjusted progression-free-survival based on the EORTC QLQ-C30 Summary score and EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D). Kd; Carfilzomib-dexamethansone

Impact of missing data

Concerning informative drop-out, the pattern mixture models showed a statistically significant and clinically relevant difference for QLQ-C30-sum score reported by patients dropping out early compared to patients dropping out late for the Kd maintenance group (mean difference 12.2 points, 95% CI 5.3; 19.2, p = 0.001, with patients who dropped out early having poorer scores). There were no statistically significant or clinically relevant differences between early, late and never drop-out patients for the observation group or between never and late for the Kd maintenance group.

Post hoc analysis

Our post hoc investigation revealed that 90% (2150 out of 2392) of the dexamethasone doses that were administered to the patients on protocol were full doses of 20 mg, and 83% (1983 out of 2392) of Kd maintenance doses were administered with full dose carfilzomib of 56 mg/sqm. In addition, 12% of the carfilzomib doses were administered as reduced doses (45, 36 or 27 mg/sqm), and for the remaining carfilzomib doses, treatment was omitted or data were not available. Further details of dose escalation and modification as well as administered doses of dexamethasone and carfilzomib can be found in the supplementary appendix Table S12 , S13 and S14 .

Discussion

This is the first prospective randomized trial reporting patient-reported HRQL data in patients with relapsed MM receiving maintenance therapy with Kd after salvage ASCT. Kd maintenance therapy after salvage ASCT did not affect the perceptions of overall HRQL compared to observation, confirming our primary hypothesis. When adjusting the PFS for the HRQL impact, the Kd maintenance treatment still remained beneficial compared to observation, but reduced the PFS for the Kd maintenance group from 19.3 to 18.0 or 17.5 months and from 16.8 to 15.0 or 14.0 months for the observation group depending on the quality adjustment metric. Progression-free survival based on maintenance therapy should be quality-adjusted and constitutes a relevant estimate for the maintenance therapy benefits when taking the HRQL impact into account. For health technology assessment and health reimbursement decisions, the EORTC QLU-C10D score is suitable for estimating quality-adjusted PFS and for use in cost-utility analyses because it is a preference-based HRQL metric, whereas the EORTC QLQ-C30 summary score is not.

Patients randomized in the CARFI study were recovering after salvage ASCT. Evidence-based recovery trajectories in symptoms and functioning have been documented only following primary ASCT, but not for salvage ASCT [ 12 – 14 ]. Introducing maintenance therapy after ASCT leads to concerns of hampering patient recovery and/or initiating new side effects related to the drugs included in maintenance treatment. Our study showed that salvage ASCT recovery was hampered by Kd maintenance in six domains at eight months follow-up including physical functioning and fatigue, which are considered core HRQL domains in patients with multiple myeloma. Those findings were consolidated in our findings of higher proportions of patients treated with Kd maintenance reporting stable physical function at four months follow-up, which is a time point where improvement in physical functioning is expected, as well as worsening in social functioning at eight months follow-up.

Based on the non-infusion related toxicity profiles of carfilzomib and symptomatic side-effects of dexamethasone, we pre-specified domains and items expected to be affected during Kd maintenance treatment. The analysis showed that more patients reported insomnia, restlessness and agitation during Kd maintenance treatment. Those side-effects can primarily be attributed to dexamethasone treatment [ 45 ]. Our investigation of Kd-related symptoms revealed that dexamethasone symptomatic side-effects had a greater impact on patients than carfilzomib-related symptomatic side-effects. This finding in keeping with our post hoc analysis findings of 90% of dexamethasone doses being administered as full doses of 20 mg.

Dyspnoea is a well-documented side effect of carfilzomib, as revealed by the adverse events registrations from the large phase III clinical trials ASPIRE and ENDURANCE [ 39 , 42 ]. Trajectories of patient-reported dyspnoea during carfilzomib treatment have to our knowledge not been published. Our investigation revealed no negative impact of carfilzomib maintenance on the patient-reported dyspnoea. As our findings of Kd-related symptoms are based on a patient cohort where the majority of patients received full-dose carfilzomib, dose reduction cannot be the exploration. However, in the CARFI study, the patients completed the HRQL questionnaires in the outpatient clinic on the drug administration day. The patients were asked to report symptoms experienced for the past seven days when completing the questionnaires. At that time point, it had been two weeks since the last dose of carfilzomib was administered, and the relevant side-effects might have subsided by then.

This study has several strengths. The objectives, endpoints, hypotheses and analyses methods are based on a pre-published statistical analysis plan guided by an evidence-based guideline for inclusion of PRO in clinical trials [ 31 , 60 ]. This minimizes statistical multiplicity issues, avoids cherry picking of HRQL findings and ensures high-quality PRO data results to inform clinical decision-making. Another strength is the high PRO completion rate. These factors work together to confer scientific rigor and credibility to our results.

A limitation of related research rather than this study is that an MID for the primary PRO endpoint of the QLQ-C30-sum score is not yet established. An arbitrary cutoff of 10 points was thus chosen as the MID, based on previous EORTC QLQ-C30 MID findings in patients with MM [ 61 ]. However, looking at the domain results (where we did have MIDs [ 51 ]), we suspect that an MID for QLQ-C30-sum score lower than 10 points may have been more correct. Hence, this study might have been underpowered for detection of smaller, but potentially clinically important differences. The performed sensitivity analysis investigating the impact of missing data due to drop-out suggests that the missing data are not missing at random. The patients in the Kd maintenance group leaving the study late or who were on protocol at the end of the study period reported better HRQL compared to the patients leaving the protocol early. Reasons for drop-out were imbalanced between the two randomized groups during follow-up: 53 out of 86 (62%) patients in the observation group came off study protocol due to progressive disease, while the corresponding number was smaller in the Kd maintenance group (29 out of 82 (35%)). More patients in the Kd maintenance compared to the observation group (7 versus 1) left the study due to withdrawn consent.

Conclusion

HRQL data from the phase II randomized CARFI trial demonstrate that Kd maintenance did not impair the patients´ perceptions of their overall HRQL, but Kd maintenance did delay recovery after salvage ASCT in several of the core domains of patients with multiple myeloma, specifically physical, role and social functioning, appetite loss, fatigue and body image. When adjusting the PFS for the HRQL impact, the Kd maintenance treatment still remained beneficial, and the difference in PFS between the two groups became larger when adjusting for HRQL. Progression-free survival of maintenance therapy should be quality-adjusted to be able to balance the benefits against the HRQL impact.

Electronic supplementary material

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Supplementary Material 1

Supplementary Material 2

Supplementary Material 3

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Acknowledgements

Our heartfelt thanks go to Henrik Rode Eshøj. Sadly, Henrik passed away during the time of analyzing the data and writing the manuscript. Henrik made a great contribution in rearranging the PRO data collection into electronic data capturing in the CARFI trial and other clinical trial conducted by the Nordic Myeloma Study Group. In addition, Henrik was the key manager in establishing the statistical analysis plan, which is the foundation of this work. Thank you to Sanne Kjær at the Clinical Trial Unit, Aalborg University Hospital for administrative assistance and Nana Hyldig for data preparation. Also, we would like to express our thanks to the participating patients for taking time to complete the questionnaires and to the study coordinators at the including sites for administrating the paper questionnaires.

Funding

Amgen.

Open access funding provided by University of Southern Denmark

Data availability

The data used for this manuscript are available upon reasonable request directed to the corresponding author.

Ethics approval and consent of participate

The study was conducted in accordance with ethical principles of the Declaration of Helsinki. The study was approved by North Denmark Region Committee on Health Research Ethics (N-20,130,064), Danish Health and Medicines Authority (No. 2,013,092,582) and Danish Data Protection Agency (No. 2008-58-0028). The trial was approved in each participating country by the relevant ethics committees and drug agencies. EudraCT number 2013-003789-15 and ClinicalTrials.gov number NCT02572492 . EORTC and FACT provided permission for use of the questionnaires.

Every participant gave informed consent to participation in the trial before inclusion.

Consent for publication

Not required.

Competing interests

All of the authors declare that they have no competing interests.

References

1. Delgado A Guddati AK Clinical endpoints in oncology - a primer Am J Cancer Res 2021 11 4 1121 1131 33948349 PMC8085844

2. Bottomley A Reijneveld JC Koller M Flechtner H Tomaszewski KA Greimel E Current state of quality of life and patient-reported outcomes research Eur J Cancer 2019 121 55 63 10.1016/j.ejca.2019.08.016 31561134

3. US Department of Health and Human Services Food and Drug Administration. US Food and Drug Administration. Guidance for industry: patient-reported outcome measures: Use in medical product development to support labeling claims. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf [updated December 2009

4. European Medicine Agency. The use of patientreported outcome (PRO) measures in oncology studies. Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/04/WC500205159.pdf2016 [

5. Cella D Chen CI Quek RGW Uribarren A Reaney M Mastey V Patient-reported outcomes labeling for oncology drugs: multidisciplinary perspectives on current status and future directions Front Pharmacol 2022 13 1031992 10.3389/fphar.2022.1031992 36339622 PMC9634749

6. Palumbo A Anderson K Multiple myeloma N Engl J Med 2011 364 11 1046 1060 10.1056/NEJMra1011442 21410373

7. Langseth ØO Myklebust T Johannesen TB Hjertner Ø Waage A Incidence and survival of multiple myeloma: a population-based study of 10 524 patients diagnosed 1982–2017 Br J Haematol 2020 191 3 418 425 10.1111/bjh.16674 32367512

8. Hannig LH Nielsen LK Ibsen R Arnheim-Dahlström L Kjellberg J Abildgaard N The impact of changed treatment patterns in multiple myeloma on health-care utilisation and costs, myeloma complications, and survival: a population-based comparison between two time periods in Denmark Eur J Haematol 2021 107 1 63 73 10.1111/ejh.13615 33675553

9. Thorsteinsdottir S Dickman PW Landgren O Blimark C Hultcrantz M Turesson I Dramatically improved survival in multiple myeloma patients in the recent decade: results from a Swedish population-based study Haematologica 2018 103 9 e412 e5 10.3324/haematol.2017.183475 29567776 PMC6119139

10. Giralt S, Garderet L, Durie B, Cook G, Gahrton G, Bruno B et al (2015) American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant.;21(12):2039-51 10.1016/j.bbmt.2015.09.016 PMC4757494 26428082

11. Lenhoff S Hjorth M Holmberg E Turesson I Westin J Nielsen JL Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study Nordic Myeloma Study Group Blood 2000 95 1 7 11 10607678

12. Chakraborty R, Hamilton BK, Hashmi SK, Kumar SK, Majhail NS (2018) Health-related quality of life after autologous stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant 10.1016/j.bbmt.2018.03.027 PMC6108907 29626515

13. D’Souza A Brazauskas R Stadtmauer EA Pasquini MC Hari P Bashey A Trajectories of quality of life recovery and symptom burden after autologous hematopoietic cell transplantation in multiple myeloma Am J Hematol 2023 98 1 140 147 10.1002/ajh.26596 35567778 PMC9659666

14. Ebraheem MS Seow H Balitsky AK Pond GR Wildes TM Sivapathasundaram B Trajectory of symptoms in patients undergoing autologous stem cell transplant for multiple myeloma: a Population-based cohort study of patient-reported outcomes Clin Lymphoma Myeloma Leuk 2021 21 9 e714 e21 10.1016/j.clml.2021.05.002 34099429

15. Cunningham D Paz-Ares L Gore ME Malpas J Hickish T Nicolson M High-dose melphalan for multiple myeloma: long-term follow-up data J Clin Oncol 1994 12 4 764 768 10.1200/JCO.1994.12.4.764 8151320

16. Zhi Y Bao S Mao J Chai G Zhu J Liu C Efficacy of maintenance treatment in patients with multiple myeloma: a systematic review and network meta-analysis Hematol (Amsterdam Netherlands) 2022 27 1 1069 1088 10.1080/16078454.2022.2121900 36125238

17. Karam D Gertz M Lacy M Dispenzieri A Hayman S Dingli D Impact of maintenance therapy post autologous stem cell transplantation for multiple myeloma in early and delayed transplant Bone Marrow Transplant 2022 57 5 803 809 10.1038/s41409-022-01631-8 35297404

18. McCarthy PL Holstein SA Petrucci MT Richardson PG Hulin C Tosi P Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a Meta-analysis J Clin Oncol 2017 35 29 3279 3289 10.1200/JCO.2017.72.6679 28742454 PMC5652871

19. Ludwig H Durie BG McCarthy P Palumbo A San Miguel J Barlogie B IMWG consensus on maintenance therapy in multiple myeloma Blood 2012 119 13 3003 3015 10.1182/blood-2011-11-374249 22271445 PMC3321864

20. Stewart AK Trudel S Bahlis NJ White D Sabry W Belch A A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 trial Blood 2013 121 9 1517 1523 10.1182/blood-2012-09-451872 23297129 PMC3587317

21. Nielsen LK Stege C Lissenberg-Witte B van der Holt B Mellqvist UH Salomo M Health-related quality of life in transplant ineligible newly diagnosed multiple myeloma patients treated with either thalidomide or lenalidomide-based regimen until progression: a prospective, open-label, multicenter, randomized, phase 3 study Haematologica 2020 105 6 1650 1659 10.3324/haematol.2019.222299 31515355 PMC7271593

22. McCarthy PL Owzar K Hofmeister CC Hurd DD Hassoun H Richardson PG Lenalidomide after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 19 1770 1781 10.1056/NEJMoa1114083 22571201 PMC3744390

23. Attal M Lauwers-Cances V Marit G Caillot D Moreau P Facon T Lenalidomide maintenance after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 19 1782 1791 10.1056/NEJMoa1114138 22571202

24. Palumbo A Cavallo F Gay F Di Raimondo F Ben Yehuda D Petrucci MT Autologous transplantation and maintenance therapy in multiple myeloma N Engl J Med 2014 371 10 895 905 10.1056/NEJMoa1402888 25184862

25. Abonour R, Wagner L, Durie BGM, Jagannath S, Narang M, Terebelo HR et al (2018) Impact of post-transplantation maintenance therapy on health-related quality of life in patients with multiple myeloma: data from the Connect(R) MM Registry. Ann Hematol. 10.1007/s00277-018-3446-y PMC6208675 30056582

26. Roussel M Hebraud B Hulin C Perrot A Caillot D Stoppa AM Health-related quality of life results from the IFM 2009 trial: treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma Leuk Lymphoma 2020 61 6 1323 1333 10.1080/10428194.2020.1719091 32090636

27. Tay J, Vij R, Norkin M, Buadi F, Kindwall-Keller TL, Roberts JS et al Health related quality of life for multiple myeloma patients according to treatment strategy after autologous stem cell transplant: a cross-sectional study using EORTC, EQ-5D and MY-20 scales. (1029–2403 (Electronic)). 10.1080/10428194.2018.1523399 30380358

28. Gimsing P Hjertner Ø Abildgaard N Andersen NF Dahl TG Gregersen H Salvage bortezomib-dexamethasone and high-dose melphalan (HDM) and autologous stem cell support (ASCT) in myeloma patients at first relapse after HDM with ASCT. A phase-2 trial Bone Marrow Transplant 2015 50 10 1306 1311 10.1038/bmt.2015.125 26121108 PMC4598614

29. Goldschmidt H Baertsch MA Schlenzka J Becker N Habermehl C Hielscher T Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE Leukemia 2021 35 4 1134 1144 10.1038/s41375-020-0948-0 32694619

30. Gregersen H Peceliunas V Remes K Schjesvold F Abildgaard N Nahi H Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: a randomised phase 2 trial by the Nordic Myeloma Study Group Eur J Haematol 2022 108 1 34 44 10.1111/ejh.13709 34536308 PMC9292771

31. Eshoj HR, King M, Abildgaard N, Gregersen H, Nielsen LK, Möller S (2020) Statistical Analysis Plan (SAP) for the CARFI trial - Analysis of secondary endpoints: patient-reported outcomes https://portal.findresearcher.sdu.dk/da/publications/statistical-analysis-plan-sap-for-the-carfi-trial-analysis-of-sec

32. Aaronson NK Ahmedzai S Bergman B Bullinger M Cull A Duez NJ 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 5 365 376 10.1093/jnci/85.5.365 8433390

33. Wisloff F Eika S Hippe E Hjorth M Holmberg E Kaasa S Measurement of health-related quality of life in multiple myeloma. Nordic Myeloma Study Group Br J Haematol 1996 92 3 604 613 10.1046/j.1365-2141.1996.352889.x 8616024

34. Cocks K Cohen D Wisløff F Sezer O Lee S Hippe E 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 11 1670 1678 10.1016/j.ejca.2007.04.022 17574838

35. Huang HQ Brady MF Cella D Fleming G Validation and reduction of FACT/GOG-Ntx subscale for platinum/paclitaxel-induced neurologic symptoms: a gynecologic oncology group study Int J Gynecol cancer: Official J Int Gynecol Cancer Soc 2007 17 2 387 393 10.1111/j.1525-1438.2007.00794.x 17362317

36. Efficace F Cottone F Sommer K Kieffer J Aaronson N Fayers P Validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Summary score in patients with hematologic malignancies Value in Health: The Journal of the International Society for Pharmacoeconomics and Outcomes Research 2019 22 11 1303 1310 10.1016/j.jval.2019.06.004 31708068

37. Giesinger JM Kieffer JM Fayers PM Groenvold M Petersen MA Scott NW Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust J Clin Epidemiol 2016 69 79 88 10.1016/j.jclinepi.2015.08.007 26327487

38. Dimopoulos MA Goldschmidt H Niesvizky R Joshua D Chng WJ Oriol A Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial Lancet Oncol 2017 18 10 1327 1337 10.1016/S1470-2045(17)30578-8 28843768

39. Dimopoulos MA Moreau P Palumbo A Joshua D Pour L Hajek R Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study Lancet Oncol 2016 17 1 27 38 10.1016/S1470-2045(15)00464-7 26671818

40. Ludwig H Moreau P Dimopoulos MA Mateos MV Kaiser M Hajek R Health-related quality of life in the ENDEAVOR study: carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed/refractory multiple myeloma Blood cancer Journal 2019 9 3 23 10.1038/s41408-019-0181-0 30796199 PMC6386751

41. Stewart AK, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R et al (2016) 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. 10.1200/JCO.2016.66.9648 PMC5791840 27601539

42. Stewart AK Rajkumar SV Dimopoulos MA Masszi T Spicka I Oriol A Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma N Engl J Med 2015 372 2 142 152 10.1056/NEJMoa1411321 25482145

43. Jakubowiak AJ Dytfeld D Griffith KA Lebovic D Vesole DH Jagannath S A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma Blood 2012 120 9 1801 1809 10.1182/blood-2012-04-422683 22665938 PMC5162553

44. Mushtaq A Kapoor V Latif A Iftikhar A Zahid U McBride A Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: a systematic review Crit Rev Oncol/Hematol 2018 125 1 11 10.1016/j.critrevonc.2018.02.008 29650268 PMC5901887

45. King T Faiman B Steroid-Associated Side effects: a Symptom Management Update on multiple myeloma treatment Clin J Oncol Nurs 2017 21 2 240 249 10.1188/17.CJON.240-249 28315528

46. Fayers P, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A (2001) The EORTC QLQ-C30 Scoring Manual (3rd Edition). Brussels: European Organisation for Research and Treatment of Cancer.

47. Administration and Scoring Guidelines www.facit.org: Functional Assessment of Chronic Illness Therapy; [FACT/GOG-Ntx Scoring Guidelines (Version 4)

48. Osoba D Bezjak A Brundage M Zee B Tu D Pater J Analysis and interpretation of health-related quality-of-life data from clinical trials: basic approach of the National Cancer Institute of Canada Clinical Trials Group Eur J Cancer 2005 41 2 280 287 10.1016/j.ejca.2004.10.017 15661554

49. Ringash J O’Sullivan B Bezjak A Redelmeier DA Interpreting clinically significant changes in patient-reported outcomes Cancer 2007 110 1 196 202 10.1002/cncr.22799 17546575

50. Cocks K King MT Velikova G Martyn St-James M Fayers PM Brown JM Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 J Clin Oncol 2011 29 1 89 96 10.1200/JCO.2010.28.0107 21098316

51. Cocks K King MT Velikova G de Castro G Jr St-James M Fayers M Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Eur J Cancer 2012 48 11 1713 1721 10.1016/j.ejca.2012.02.059 22418017

52. Sully K Trigg A Bonner N Moreno-Koehler A Trennery C Shah N Estimation of minimally important differences and responder definitions for EORTC QLQ-MY20 scores in multiple myeloma patients Eur J Haematol 2019 103 5 500 509 10.1111/ejh.13316 31444815 PMC6852250

53. Yost KJ Cella D Chawla A Holmgren E Eton DT Ayanian JZ Minimally important differences were estimated for the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) instrument using a combination of distribution- and anchor-based approaches J Clin Epidemiol 2005 58 12 1241 1251 10.1016/j.jclinepi.2005.07.008 16291468

54. Calhoun EA Welshman EE Chang CH Lurain JR Fishman DA Hunt TL Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy Int J Gynecol Cancer 2003 13 6 741 748 14675309 10.1111/j.1525-1438.2003.13603.x

55. Kemmler G Zabernigg A Gattringer K Rumpold G Giesinger J Sperner-Unterweger B A new approach to combining clinical relevance and statistical significance for evaluation of quality of life changes in the individual patient J Clin Epidemiol 2010 63 2 171 179 10.1016/j.jclinepi.2009.03.016 19615857

56. Johnsen AT Tholstrup D Petersen MA Pedersen L Groenvold M Health related quality of life in a nationally representative sample of haematological patients Eur J Haematol 2009 83 2 139 148 10.1111/j.1600-0609.2009.01250.x 19284418 PMC2730555

57. King MT Viney R Simon Pickard A Rowen D Aaronson NK Brazier JE Australian utility weights for the EORTC QLU-C10D, a Multi-attribute Utility Instrument Derived from the Cancer-Specific Quality of Life Questionnaire, EORTC QLQ-C30 PharmacoEconomics 2018 36 2 225 238 10.1007/s40273-017-0582-5 29270835 PMC5805814

58. Kemmler G Gamper E Nerich V Norman R Viney R Holzner B German value sets for the EORTC QLU-C10D, a cancer-specific utility instrument based on the EORTC QLQ-C30 Qual Life Res 2019 28 12 3197 3211 10.1007/s11136-019-02283-w 31485913 PMC6863792

59. King MT Costa DS Aaronson NK Brazier JE Cella DF Fayers PM QLU-C10D: a health state classification system for a multi-attribute utility measure based on the EORTC QLQ-C30 Qual Life Res 2016 25 3 625 636 10.1007/s11136-015-1217-y 26790428

60. Calvert M Kyte D Mercieca-Bebber R Slade A Chan AW King MT Guidelines for inclusion of patient-reported outcomes in clinical trial protocols: the SPIRIT-PRO Extension J Am Med Association 2018 319 5 483 494 10.1001/jama.2017.21903 29411037

61. Kvam AK, Wisloff F, Fayers PM (2010) Minimal important differences and response shift in health-related quality of life; a longitudinal study in patients with multiple myeloma. Health and quality of life outcomes.;8:79-7525-8-79 10.1186/1477-7525-8-79 PMC2922103 20678240