Health-Related Quality of Life in Multiple Myeloma Patients Treated with High- or Low-Dose Lenalidomide Maintenance Therapy after Autologous Stem Cell Transplantation—Results from the LenaMain Trial (NCT00891384)

Simple Summary High-dose therapy with melphalan followed by autologous stem cell transplantation and lenalidomide maintenance has long been the standard of care for newly diagnosed patients with multiple myeloma. However, it is unclear how lenalidomide dosage or experienced side effects govern patients’ quality of life during long-term treatment. The LenaMain trial (NCT00891384) investigated lenalidomide maintenance at a high (25 mg) and a low dose (5 mg) and demonstrated that dosage had no impact on patients’ quality of life. Instead, high baseline scores for global health were maintained throughout the trial without difference between treatment arms which supports the feasibility of continuous lenalidomide treatment with a dose tailored to patients’ quality of life. Abstract Introduction: The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. Materials and Methods: Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. Results: Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: −1.905 (range: −5.78–1.97); end of year 2: 16.071 (range: 5.72–26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. Conclusion: High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients’ HR-QoL.


Introduction
Patients with multiple myeloma (MM) typically experience a high burden of symptoms, which can significantly impair their health-related quality of life (HR-QoL) [1][2][3].Moreover, therapy-related side effects can negatively impact HR-QoL [4][5][6][7].Improvements in the efficacy of MM treatment have made HR-QoL an increasingly important endpoint in clinical trials and a relevant factor for patients and physicians in choosing the most appropriate treatment [8].
High-dose therapy with melphalan followed by autologous stem cell transplant (ASCT) has long been the standard of care for newly diagnosed MM in clinically fit adults [9].ASCT may lead to the short-term worsening of the HR-QoL but the baseline HR-QoL is generally regained as early as 2 months post-transplant, with long-term improvement in the HR-QoL and pain [10,11].In contrast to tumor debulking, maintenance therapy aims to delay the disease progression after ASCT, when the disease burden is minimal.Continuous lenalidomide maintenance until progression leads to significantly improved progression-free and overall survival [12,13].However, treatment-related toxicities, like infections, rash, fatigue, diarrhea/constipation, or neuropathy, could negatively affect patients' HR-QoL, ultimately leading to discontinuation [14][15][16].
The LenaMain trial (NCT00891384) was an investigator-initiated, randomized, openlabel, phase-III trial that randomized patients to either receive lenalidomide at 5 mg (Len low) or 25 mg (Len high) [17].To date, the LenaMain trial is the only clinical trial to show that a higher dosage of lenalidomide maintenance post-transplant benefits patients by extending the time of remission.
Previous real-world data from the Connect ® MM registry, a U.S. non-interventional, prospective registry, have highlighted that lenalidomide maintenance after ASCT has no adverse impact on HR-QoL [18].But while a maintenance dose of 10-15 mg is approved in most areas as the standard of care, a dose-finding study has never been performed.Therefore, it remains unclear whether a higher dose of lenalidomide maintenance affects HR-QoL.
HR-QoL assessment using the global health status/quality of life (GHS/QoL) scale of the European Organisation for Research and Treatment of Cancer (EORTC) was a predefined secondary endpoint in the LenaMain trial.Here, we present the full HR-QoL results from cross-sectional and longitudinal analyses of the secondary and exploratory HR-QoL endpoints.Furthermore, this is the first time that the HR-QoL is compared between two cohorts receiving different dosages of lenalidomide maintenance (25 and 5 mg).

Study Design and Treatment
The LenaMain trial recruited patients from 4 June 2009 to 1 February 2015 in six hospitals in Germany.Details were previously published [17].Briefly, patients were randomized 1:1 to either receive lenalidomide at a 5 mg (Len-low) or 25 mg (Len-high) maintenance treatment (Len MT) after first-line therapy with autologous stem cell transplant.Patients in both treatment arms first entered a uniform consolidation period and received 6 cycles of lenalidomide at 25 mg (for 21 days every 28 days), after which they started their respective maintenance therapies.

HR-QoL Assessments and Endpoint
The EORTC Quality of Life Questionnaire, QLQ-C30, is the most frequently used instrument for cancer-specific HR-QoL assessment in myeloma patients [19][20][21] and includes 30 items comprising one global health status (GHS) scale, five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, nausea and vomiting, and pain), and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).Higher scores represent better GHS and functioning but also greater (i.e., worse) symptoms.The primary patient-reported outcome (PRO) hypothesis presumed similar HR-QoL for the two different lenalidomide doses during maintenance.The minimally important difference (MID) threshold for clinically meaningful change from baseline was defined a priori based on the published literature, with a value of ≥5 points considered as clinically significant [22].Evidence-based guidelines were used to interpret the longitudinal change from baseline within the groups [23] as well as the cross-sectional scores [24] (see Appendix A for further details).Patients completed the questionnaires on day 1 of each cycle.A total of 194 patients were enrolled in six German centers and 188 patients were randomized to receive Len maintenance.
The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Heinrich Heine University (Approval Date: 16 January 2009, Approval Number: MC-LKP-300).

Patient Population
From 4 June 2009 to 1 February 2015, 194 patients were enrolled in six German centers and 188 patients were randomized to receive lenalidomide maintenance.The patient demographics were balanced across the treatment groups in terms of baseline characteristics such as age, gender, risk scores, and prior therapy, without statistically significant differences.The median age at enrolment was 59 years.The QLQ-C30 domain values and utility values were balanced between the arms at both the consolidation baseline and maintenance baseline without statistically significant differences, which suggests no significant departure as a result of the differing effects of treatment with lenalidomide at 25 mg during the consolidation period (Table 1).

Compliance
The compliance rates were high, with 95.7% of all randomly assigned patients completing the QLQ-C30 questionnaire at baseline (Appendix B Figure A1a).During the consolidation period, the compliance rates remained high, with a return of more than 80% of the expected responses.During the maintenance period, the compliance rates remained close to 70% or above.Slight differences between the treatment groups were expected after correction for dropouts due to progressive disease (Appendix B Figure A1b).The GHS/QoL was high at the consolidation baseline, with a mean of 65.78 (range: 0-100).The median GHS/QoL scores were constant over 6 months of consolidation (Appendix C Figure A2a).The mean change from baseline (CFB) over time was very small, and there was no obvious trend over the six cycles (baseline: −0.98 (range: −2.16-0.2),p > 0.05; cycle 6: 1.123 (range: −4.54-2.3),p > 0.05; Appendix C Figure A2b).
Similarly, the utility was high at the consolidation baseline, with a mean of 0.7 (range: 0-1).Little variation was seen in the median utility values across the consolidation cycles (Appendix C Figure A2d).The mean CFB over time was very small, and there was no obvious trend over the six cycles (baseline: 0.003 (range: 0.01-0.02),p > 0.05; cycle 6: 0.014 (range: −0.01, 0.04), p > 0.05; Appendix C Figure A2e).

EORTC QLQ-C30 Domain Scores
At study entry, the EORTC QLQ-C30 scores were high for functioning and low for symptoms.Most CFBs in the domains were less than 5 points and therefore not considered relevant.However, some domains show a few noteworthy changes over time: Appetite loss symptom scores appear to generally become worse, with an average increase of approximately 7 points at cycle 6, surpassing the MID (baseline: −0.49(range: −1.47-0.49,p > 0.05); cycle 6: 6.527 (range: 2.76-10.3,p < 0.05); Appendix C Figure A2c).Constipation appears to be the most affected symptom, with an increase from baseline in most consolidation cycles of around 10 points (baseline: 0 (range: −1.97-1.97,p > 0.05); cycle 6: 6.808 (range: 2.77-10.84,p < 0.05); Appendix C Figure A2f).

GHS/QoL
The overall median GHS/QoL scores were generally constant over 2 years of maintenance (Figure 1a).The mean change from maintenance baseline (CFMB) in the GHS/QoL over time within the arms was mostly <5 but showed a tendency for deterioration during the last cycles in both arms (Figure 1b).

Utility Values
The overall median utility values were constant at most time points, with a slight downward trend toward the end of year 2 with a mean change of 0.04 (Figure 1d).The mean CFMB over time within the arms showed a slight decline in the utility over 2 years of maintenance (Figure 1e).
Analyzing the median utility by treatment arm over time, we observed the utility for patients with Len high to be generally similar to that of those with Len low (median: 0.7 for Len high (range: 0.35-0.95) and 0.71 for Len low (range: 0.36-0.96)at baseline; 0.68 for Len high (range: 0.22-0.95) and 0.68 for Len low (range: 0.27-0.96)after 2 years; p > 0.05).Analyzing the mean difference in the CFMB between the treatment arms, we found no significant difference between Len high and Len low over 2 years of treatment (p > 0.05) (Figure 1f).

Function and Symptom Scales, Single Items
Analyzing the medians and CFMB over time confirmed that there were no obvious differences for many of the functional scale domains, such as role functioning, cognitive functioning, or emotional functioning.Similarly, symptom scales, like fatigue or nausea and vomiting, were constant and low for all cycles.The single-item scores for insomnia, appetite loss, constipation, and dyspnea were consistent.
The most notable overall changes included social functioning, which showed a significant downward trend over time in both arms, leading to a mean CFMB of approximately 10 points at the end of year 2, thus surpassing the MID (baseline: 0.952 (range: −0.4-2.3);end of year 2: −10.119 (range: −16.53-−3.71);p < 0.05) (Figure 2a,b).The mean difference in the CFMB between the treatment arms showed no significant Analyzing the median GHS/QoL by treatment arm, we found no significant difference over time (median: 68 for Len high (range: 16-100) and 68 for Len low (range: 34-100) at baseline; 58 for Len high (range: 16-100) and 68 for Len low (range: 34-83) at 2 years; both p > 0.05).Analyzing the mean difference in the CFMB between treatment arms, we found no significant difference between Len high and Len low over 2 years of treatment (p > 0.05) (Figure 1c).The MID of 5 is surpassed slightly at cycles 6 and 12, yet it drops quickly to surpass 5 again at cycle 24.

Utility Values
The overall median utility values were constant at most time points, with a slight downward trend toward the end of year 2 with a mean change of 0.04 (Figure 1d).The mean CFMB over time within the arms showed a slight decline in the utility over 2 years of maintenance (Figure 1e).
Analyzing the median utility by treatment arm over time, we observed the utility for patients with Len high to be generally similar to that of those with Len low (median: 0.7 for Len high (range: 0.35-0.95) and 0.71 for Len low (range: 0.36-0.96)at baseline; 0.68 for Len high (range: 0.22-0.95) and 0.68 for Len low (range: 0.27-0.96)after 2 years; p > 0.05).Analyzing the mean difference in the CFMB between the treatment arms, we found no significant difference between Len high and Len low over 2 years of treatment (p > 0.05) (Figure 1f).

Function and Symptom Scales, Single Items
Analyzing the medians and CFMB over time confirmed that there were no obvious differences for many of the functional scale domains, such as role functioning, cognitive functioning, or emotional functioning.Similarly, symptom scales, like fatigue or nausea and vomiting, were constant and low for all cycles.The single-item scores for insomnia, appetite loss, constipation, and dyspnea were consistent.

Subgroup Analysis
To analyze how external factors such as disease control, adverse events (AEs), or the burden of an extended treatment time could affect HR-QoL, we looked at utility in relation to the remission status, severity of adverse events, or time on treatment.The subgroup analysis revealed that neither the disease response ((s)CR vs. less than CR), duration of treatment, nor adverse events (AEs grade 1/2, 3/4 vs. none) affected the HR-QoL or utility (see Appendix D for further details).Also, diarrhea showed a consistent increase, leading to a significant mean CFMB at the end of year 2 exceeding the MID within the treatment arms (baseline: −1.905 (range: −5.78-1.97);end of year 2: 16.071 (range: 5.72-26.42),p < 0.05)) (Figure 2d,e).The mean difference in the CFMB between the treatment arms showed the MID to surpass 5 at cycles 9 and 18, yet it drops quickly to surpass the MID again at cycle 24.Notably, diarrhea increased slightly more for Len high by the end of year 2 without reaching statistical significance (mean difference in the CFMB between treatments for diarrhea at baseline: −3.704 (range: −11.52 −4.11, p > 0.05), and that at cycle 24: 3.922 (range: −9.87-17.571,p > 0.05) (Figure 2f).

Subgroup Analysis
To analyze how external factors such as disease control, adverse events (AEs), or the burden of an extended treatment time could affect HR-QoL, we looked at utility in relation to the remission status, severity of adverse events, or time on treatment.The subgroup analysis revealed that neither the disease response ((s)CR vs. less than CR), duration of treatment, nor adverse events (AEs grade 1/2, 3/4 vs. none) affected the HR-QoL or utility (see Appendix D for further details).

Missing Data
The number of patients on trial was similar in both arms (Figure 2).This indicates that the extent of the missing data was comparable and not missing at random, which eliminates bias in the HR-QoL toward either treatment arm (see Appendix A for further details on reasons for dropping out).

Discussion
Despite advances in the overall survival, multiple myeloma remains an incurable disease that substantially affects patients' HR-QoL.To date, the LenaMain trial is the only clinical trial to show that a higher dosage of lenalidomide maintenance post-transplant benefits patients by extending the time of remission.Here, we show that a higher Len dose does not substantially impair HR-QoL, and patients can therefore maintain the high level of functioning exhibited at study entry even at high dosages.The EORTC QLQ-C30 scores were high for functioning and low for symptoms and were similar to those of the general population, which shows a GHS/QoL between 76 and 79 [25].Thus, our study population was largely asymptomatic and had a high level of functioning at study entry.
Consolidation after autologous stem cell transplantation has long been a point of discussion [26,27].In our study, consolidation with six cycles of 25 mg of lenalidomide was feasible and no unexpected toxicity occurred.Other studies have shown significant survival benefits from lenalidomide, as well as bortezomib-containing consolidation therapy, while maintaining the HR-QoL (14 and 13 months, respectively, and both with GHS/QoL values around 70) [28,29].Thus, our HR-QoL data confirm these findings by showing very little variation in the HR-QoL, utility, and functional and symptom scores.Some domains, however, show some variation during the first cycles of consolidation, most likely reflecting some uncertainty about the upcoming therapy amid a clinical trial.
During the lenalidomide maintenance, both the GHS/QoL and utility scores were relatively stable.The overall scores declined slightly but only exceeded the previously assigned MID at the end of year 2. This suggests that the high levels of the HR-QoL and utility observed at study entry were maintained, which is consistent with previous results showing no deterioration in the HR-QoL despite continued lenalidomide maintenance [19].
When we compared the GHS/QoL and utility between both arms, we found no significant difference between Len high and Len low.Also, we found consistent values for the function and symptom scales, as well as for the majority of single items, over the course of the trial, without substantial differences between the treatment arms.Noticeable exceptions were an increase in diarrhea and a decrease in social functioning.Both exceeded the pre-specified MID in both arms by the end of year 2.
Diarrhea is a common side effect with Len treatment that can severely impact HR-QoL and may lead to the unnecessary discontinuation of therapy [30].Here, we show that diarrhea as a symptom exceeded the MID but was independent of the Len dosage.Hence, fear of diarrhea associated with decreased HR-QoL should not prevent physicians from prescribing high-dose Len MT.Instead, more supportive care should be applied.Bile acid malabsorption has recently been shown to cause Len-associated diarrhea, and treatment with a bile acid sequestrant is recommended in these cases [31].Unfortunately, these data were not yet available during our study, but they may enable more patients in the future to continue long-term treatment with Len high, achieve better disease control, and improve their HR-QoL.
The other noticeable exception we observed was an overall downward trend in social functioning without any difference between the treatment groups until the end of the 2-year observational period, when the MID for both the CFMB and CFMB between the groups was surpassed.Despite disease stability and the absence of acute treatment-related toxicity, reduced social functioning is often related to a persistent and cumulative symptom burden [32].Jordan et al., reported that social functioning was strongly affected by even moderate symptom levels [33].And while patients may achieve long-term disease control with lenalidomide maintenance, the median time to relapse is 26.9 months [34].Therefore, symptoms may begin to accumulate again after 2 years before meeting the criteria of progressive disease, further exacerbating social function deficits over time.Moreover, patients' concerns about controlling their bowels could certainly impair their social functioning, connecting both items.
Adverse effects, like treatment-related toxicities (e.g., rash, fatigue, diarrhea/constipation, neuropathy) or infections, can significantly affect HR-QoL.Alleviation of these toxicities could be reflected by improvements in the HR-QoL, just as the aggravation of these toxicities might impair the HR-QoL.Hematologic toxicities, especially grade ≥ 3 neutropenia and infections, were a common side effect in the LenaMain trial and were observed in 34.6%, 24.3%, and 12.8% of the Len-high arm during the first, second, and third years, respectively, whereas the incidence in the Len-low arm remained constant at about 9%.We found that the GHS/QoL and utility in both treatment groups were not affected by high-grade toxicity.Similarly, AEs did not lead to more patients discontinuing lenalidomide maintenance.This result is consistent with reports from other clinical trials showing that regimens that prolong progression-free survival also provide sustained stable and improved HR-QoL, suggesting that a clinically meaningful improvement in relevant symptoms outweighs the adverse effects of treatment [35,36].

Relevance
Continuous therapy for multiple myeloma is often associated with a plethora of side effects.Thus, physicians might hesitate to use lenalidomide at the recommended dose, especially out of fear of infections or neuropathy.Some myeloma patients might also prioritize quality of life over a long-term response, further prompting dose reductions.We were the first to show that high-dose lenalidomide extends the progression-free survival but is associated with an increase in grade 3/4 infections in comparison to lower dosages of lenalidomide.Here, we show that a higher Len dosage is well tolerated, and the quality of life is not dose-dependent.Severe AEs, like infections, also did not impact the long-term quality of life.This result argues for titrating Len maintenance up to the best-tolerated dose in order to reach the optimal efficacy.Others have also argued for an individualized approach based on the disease characteristics, response to induction and ASCT (or even non-ASCT consolidation approaches, such as CAR-T-cell therapy or bispecific antibodies), as well as patient preferences [37].Newer data from the DETERMINATION trial have also taken QoL into account [38].This trial investigated the effect of adding ASCT to triplet therapy (lenalidomide, bortezomib, and dexamethasone) followed by lenalidomide maintenance and showed superior progression-free survival in the transplant group.Although the investigators observed a transient but clinically meaningful decrease in the quality of life associated with ASCT, the mean QoL scores subsequently recovered.In fact, the mean improvements from the maintenance baseline remained numerically higher in the post-transplant group throughout the maintenance therapy.This further supports that a more effective therapy results in better QoL, which emphasizes that personalized approaches are paramount when considering the toxicities and treatment effects on the QoL.But our results could also apply to the relapsed setting.With the advent of triplet combinations for relapsed patients, physicians might use dose-reduced Len to prevent side effects.By establishing high-dose Len maintenance as independent of grade 3/4 adverse events, our data also argue for a higher dose in the relapsed setting in order to achieve fast and durable responses.

Conclusions
The lenalidomide dosage during long-term maintenance had no impact on the quality of life in multiple myeloma patients.Instead, high baseline scores for global health and utility were maintained throughout the trial, without differences between the treatment arms.Thus, the HR-QoL was not governed by the higher rate of infectious toxicity caused by high-dose lenalidomide, which supports the feasibility of continuous Len treatment with a dose titrated on an individual basis and tailored to patients' HR-QoL.Legends: patient characteristics (GHS: global health status; QoL: quality of life; CFB: change from baseline; N/n: number; SD: standard deviation; BL: baseline).Note: the range (r) is the difference between the maximum and minimum possible values of the raw score (e.g., for an item scored 1-4, r = 3); all items except for those contributing to the global health status/QoL scales are scored from 1 to 4.
The QLQ-C30 scoring manual describes the process for calculating the scores from the individual questionnaire responses:

•
Raw scores (RSs) are calculated as the mean of the responses that belong to each scale or item (e.g., for the physical function, this would be the mean of the responses for questions 1-5); • Standardized scores (Ss) are calculated using a transformation such that they vary at an interval from 0 to 100.
Note: If items are missing, then the following process should be followed: 3.
If at least half of the items that contribute to a scale have been answered, then calculate the score as above, ignoring the missing items; 4.
If more than half are missing, then the scale is set to missing; 5.
Single items will always be set to missing.

3. 3 .
Quality of Life during the Consolidation Phase 3.3.1.Global Health Status/Quality of Life (GHS/QoL) and Utility Values

Figure 1 .
Figure 1.GHS/QoL and utility: (a) median GHS/QoL by treatment and cycle and patient number analyzed by treatment and cycle; (b) mean change from maintenance baseline (CFMB) in GHS/QoL by treatment and cycle; (c) mean CFMB between treatments (mean (range), n = patients analyzed, p-value); (d) median utility by treatment and cycle and patient number analyzed by treatment and cycle; (e) mean CFMB in utility split by treatment and cycle; (f) mean difference in CFMB between treatments (mean (range), n = patients analyzed, p-value).

Figure 1 .
Figure 1.GHS/QoL and utility: (a) median GHS/QoL by treatment and cycle and patient number analyzed by treatment and cycle; (b) mean change from maintenance baseline (CFMB) in GHS/QoL by treatment and cycle; (c) mean CFMB between treatments (mean (range), n = patients analyzed, p-value); (d) median utility by treatment and cycle and patient number analyzed by treatment and cycle; (e) mean CFMB in utility split by treatment and cycle; (f) mean difference in CFMB between treatments (mean (range), n = patients analyzed, p-value).

Figure 2 .
Figure 2. Social functioning (a) median by treatment and cycle and patient number analyzed by treatment and cycle; (b) mean change from maintenance baseline (CFMB) by treatment and cycle; (c) mean difference between treatments in CFMB (mean (range), n = patients analyzed, p-value) diarrhea; (d) median by treatment and cycle and patient number analyzed by treatment and cycle; (e) mean CFMB by treatment and cycle; (f) mean difference between treatments in CFMB (mean (range), n = patients analyzed, p-value).

Figure 2 .
Figure 2. Social functioning (a) median by treatment and cycle and patient number analyzed by treatment and cycle; (b) mean change from maintenance baseline (CFMB) by treatment and cycle; (c mean difference between treatments in CFMB (mean (range), n = patients analyzed, p-value) diarrhea; (d) median by treatment and cycle and patient number analyzed by treatment and cycle; (e) mean CFMB by treatment and cycle; (f) mean difference between treatments in CFMB (mean (range), n = patients analyzed, p-value).

Figure A3 .
Figure A3.Estimated utility during MT by cycle and grouped by (a) non-complete responders (vgPR, PR, SD) and (b) complete responders (CR, sCR), by severity of experienced AEs: (c) grade 1 and 2 or (d) 3 and 4, and by time of treatment for (e) Len high and (f) Len low (color coding for time and MT treatment).

Figure A3 .
Figure A3.Estimated utility during MT by cycle and grouped by (a) non-complete responders (vgPR, PR, SD) and (b) complete responders (CR, sCR), by severity of experienced AEs: (c) grade 1 and 2 or (d) 3 and 4, and by time of treatment (e) Len high and (f) Len low (color coding for time and MT treatment).