Health-related quality of life after autologous stem cell transplantation for multiple myeloma

Abstract

Autologous stem cell transplantation (ASCT) is an integral part of the frontline therapy in eligible multiple myeloma (MM) patients. The impact of ASCT on health-related quality of life (HRQoL) in myeloma has not been well described. We performed a systematic literature search to identify studies evaluating the impact of ASCT on HRQoL. Our search retrieved 12 relevant studies: 10 manuscripts and 2 conference abstracts. There was a widespread heterogeneity across studies in instruments used to measure HRQoL, time-points of measurement and statistical analysis. Only one study was a randomized controlled trial with HRQoL as a prespecified secondary end-point. The common theme that emerged from most studies is that ASCT leads to an immediate deterioration in HRQoL and increase in symptom burden. However, baseline HRQoL and symptom scores are regained as early as 1–2 months post-transplantation. Furthermore, an improvement in HRQoL and pain on long-term follow-up was noted in some studies. We describe opportunities for further research in this area, including routine incorporation of HRQoL as an end-point in transplant related clinical trials and need for trials investigating interventions that may improve short and long-term HRQoL in myeloma ASCT recipients.

Introduction

The overall survival (OS) in patients with multiple myeloma (MM) has significantly increased in the last decade due to the introduction of several agents, including proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) along with a wider incorporation of autologous stem cell transplantation (ASCT) in eligible patients ^1–3. In patients receiving 3-drug induction regimen containing a PI and an IMiD followed by ASCT, the 4-year OS rate exceeds 80%⁴. Multiple myeloma, however, remains an incurable disease and an important goal of therapy is to help patients live longer with a good health related quaity of life (HRQoL)⁵. HRQoL is a multidimensional entity and implies patients’ perception of the impact of disease and treatment on physical and mental aspects of their daily life. HRQoL can be measured by a variety of instruments, the most commonly used being the one developed by European Organization for Research and Treatment of Cancer (EORTC). Patients with MM are known to have a high symptom burden and poor HRQoL compared to those with other hematologic malignancies⁶. More than half of MM patients have fatigue and pain due to bone lesions and about a third may experience shortness of breath, appetite loss, insomnia and constipation⁶. Patients’ self-report of a clinical outcome without interpretation by a caregiver, also known as patient-reported outcomes (PROs), is an important way to capture HRQoL, and is increasingly becoming an integral part of clinical care. PROs incorporate multiple dimensions of patient function, including physical, emotional and social as well as symptom burden⁷.

A review on HRQoL data in MM clinical trials has shown widespread heterogeneity in the analysis and presentation of data⁸. The methodology and selection of end-points vary across studies, which makes it difficult for clinicians to interpret at the point-of-care. Since longitudinal assessment of PROs has been shown to improve quality of life and prolong OS^9,10, it is being used as an endpoint in several studies and has been endorsed by the Food and Drug Administration as a valid effectiveness endpoint for clinical trials¹¹. Guidelines for collecting, analyzing and reporting of HRQoL data in MM has been published in an effort to generate meaningful information for patients and clinicians regarding comparative effectiveness of therapeutic agents⁸.

High-dose melphalan (HDM) followed by ASCT is an effective consolidation therapy in MM and is likely to stay as a frontline therapy due to its demonstrated superiority in the era of PIs and IMiDs^4,12. MM patients undergoing ASCT are unique in the sense that most have not been exposed to traditional cytotoxic chemotherapy prior to high-dose melphalan. Hence, most patients have not experienced adverse events such as alopecia, prolonged hospitalization, mucositis, anorexia, and severe nausea or vomiting prior to ASCT. Hence, it would be useful for patients to better understand the potential impact of ASCT on HRQoL. This may also help in making an informed decision on whether to pursue frontline ASCT or delay it until first relapse, especially, when OS may be similar with either approach⁴.

The focus of this review is to summarize the current state of knowledge on the impact of ASCT on QoL in MM, identify the gaps in the literature and outline an agenda for future research.

Materials and Methods

A systematic literature review was performed to identify all relevant articles on HRQoL in patients with MM undergoing ASCT. The search was restricted to articles in English language and those involving human subjects. Literature search was conducted by an experienced librarian from Ovid-Medline (1946-present) and Embase (1974-present) databases. Search terms included “hematopoietic stem cell transplantation”, “autologous transplantation”, “bone marrow transplantation” “multiple myeloma”, “quality of life” and “patient-reported outcomes”. Detailed search strategy is shown in the Supplementary Appendix. The search retrieved 169 potential citations, including journal articles and conference abstracts. Studies directly measuring the impact of ASCT on HRQoL were included for analysis. Exclusion criteria included studies which measured the impact of a secondary intervention (e.g. exercise, acupuncture) on HRQoL and studies not reporting QoL data on MM patients separately. Subsequently, relevant studies were reviewed in depth and references were searched to identify additional studies. A total of 12 articles which had measured the impact of ASCT on HRQoL in MM were retrieved, including 10 articles in manuscript form and 2 conference abstracts.

The commonly used instruments to measure HRQoL included the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT), Short Form 36-Survey (SF36), European Quality of Life 5 Dimensions (EQ-5D) and the M. D. Anderson Symptom Inventory (MDASI) questionnaires. The EORTC QLQ-C30 questionnaire includes 5 functional scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain and nausea/vomiting) and a global health and QoL scale along with 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact)¹³. FACT-BMT is a 47-item questionnaire which contains subscales to assess physical, functional, emotional and social well-being along with BMT-specific concerns¹⁴. SF-36 is a 36-item survey containing several domains (physical functioning, role functioning, bodily pain, general health perceptions, vitality, social functioning and general mental health), which generates a physical and mental component summary¹⁵. EQ-5D is a generic questionnaire used to measure overall health status which contains 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression)¹⁶. MDASI-BMT questionnaire consists of 14 symptoms (pain, weakness, fatigue, diarrhea, shortness of breath, nausea, mouth sores, physical sickness, disturbed sleep, loss of appetite, sadness, distress, loss of concentration, bleeding) and 5 inteference factors (mood, activity, life enjoyment, relaptionship, walking) specific to patients undergoing blood and marrow transplantation¹⁷.

Data from Selected Publications

The study design, methodology and findings of included studies^18–29 are summarized in Table I. Here we will review the key conclusions and critique of important studies which measured the impact of ASCT on HRQoL in MM.

Table I.

Studies evaluating the impact of ASCT on QoL in MM

Study author; Year; Reference	Study design	Treatment regimen/schema	Number of patients	Age	QoL Instrument used and time-points of measurement	Key findings
Gulbrandsen et al; 2001; 18	Non-randomized multicenter trial evaluating impact of HDM-ASCT on QoL; Comparison with historical control group	ASCT arm: VAD induction x 3 cycles→ High-dose cyclophosphamide and G-CSF with stem cell harvest→HDM followed by ASC infusion→Maintenance interferon, started 2 month post-engraftment Control group: Intermittent melpahlan-prednisone with or without addition of interferon	ASCT trial: 274 Historical control: 113	Mean age: ASCT: 52 Control: 55	EORTC QLQ-C30 v 1.0 Baseline, then on 1, 6, 12, 24 and 36 months from diagnosis	• At a mean of 52 days after HDM (6-month from diagnosis), ASCT patients had a significantly lower global QoL score, role functioning, and social functioning compared to patients in the control group. • At 36 months, there was significantly less fatigue and pain in the ASCT group compared to the control group.
Uyl-de Groot et al; 2005; 19	Prospective longitudinal study	VAD or VAMP × 2 cycles→ HDM and transplantation of whole blood → Bu/Cy-ASCT	35	Mean age: 53 years (range, 31–65)	EORTC QLQ-C30 and the EuroQol 5-D. Baseline (2 week after VAD/VAMP chemotherapy; T1)→ Day of hospital discharge after HDM (T2)→1 months after HDM (T3)→Day of hospital admission for PBSCT (T4)→Day of hospital discharge following PBSCT (T5)→ 6 and 12 months after hospital discharge following PBSCT (T6 and T7 respectively).	• Increased symptom burden was noted at T2 and T5, which subsequently resolved at T6 and T7. • Physical, role and social functioning was higher at T6 and T7 compared to T1.
Khalafallah et al; 2011; 20	Prospective longitudinal study	Induction therapy →Tandem ASCT with Mel 140 mg/m2 for patients ≤60 years and 100 mg/m2 for patients >60 years.	18	Median age 49 years (range, 37–70 years)	EORTC-QLQ-C30 Administered after each transplant and every 3 monthly therafter.	• The mean global health score and global quality of life significantly improved at 3-month follow-up, compared to baseline. • Patients experienced financial distress, decreased social functioning and increased symptom burden during both transplants.
Sherman et al; 2009; 21	Prospective longitudinal study	Single ASCT	Baseline: N=135 Post-transplant follow-up: N=94	Mean age: 56 (range, 34–74)	FACT-BMT, BSI Anxiety and Depression, Satisfaction with Life Scale Administered at stem cell collection and immediately post-transplant	• During the immediate post-transplant follow-up, there was a significant worsening of depression and overall life satisfaction and significant improvement in pain scores.
Etto et al; 2011; 22	Prospective longitudinal study	Single ASCT	N=29 (at diagnosis); N=27 (Post-induction/Pre-ASCT) N=14 (Day+100 ASCT)	Mean age: 55 years	SF-36 and EORTC-QLQ-C30 Administered at diagnosis, at post-induction/pre-transplant and at day+100 post-transplant	• Significant improvement in physical functioning, role functioning, fatigue, pain and constipation was noted at day 100 post-transplant compared to diagnosis.
Frodin et al; 2011; 23	Prospective longitudinal study	Single ASCT with HDM	N=60 (At baseline); N=28 (At 3-year follow-up)	Mean age: 60	EORTC-QLQ-C30 Baseline (the day before the start of conditioning), once a week during weeks 1–4, once a month during months 2 and 3, at 6 month and once every six months up to year 3 after SCT.	• There was a significant decline in global QoL and physical/role/social/cognitive functioning at week 2 compared to baseline. • Baseline QoL and symptom scores were regained at 2 month mark.
Ludwig et al; 2012; 24	Randomized phase II study	Arm-A: VTD × 4 21-day cycles→HDCT-ASCT (single or double) Arm-B: VTDC × 4 21 day cycles→HDCT-ASCT (single or double)	N=92 (At baseline) and N=55 (At post-ASCT follow-up).	Median age: 57 years in VTD arm (range, 35–65) and 58 years in VTCD arm (range, 33–68)	EORTC QLQC30 and EuroQoL EQ-5D Administered at screening visit, on Day 1 of every induction cycle, at the end of cycle-4, following recovery from SCT, and during the short-term follow-up period.	• In patients randomized to the VTD arm, a steady improvement in global health score was noted, exceeding the threshold for clinical significance at the first post-transplant follow-up visit.
Ashok et al; 2015 [Conference Abstract]; 25	Prospective longitudinal study	Single ASCT	N=31 (At baseline)	Not given	EORTC-QLQ-C30 Administered at diagnosis, after induction therapy, and at day +100 after ASCT	• The scores for global health, physical functioning, role functioning, social functioning and pain were superior at day 100, compared to prior time points.
Campagnaro et al; 2008; 27	Prospective longitudinal study	Single ASCT (Conditioning with Melphalan 200 mg/m2 in 86%)	N=64 (At baseline) Complete follow-up data available for 56 (88%) patients	Mean age: 55 years (range, 30–74)	MDASI-BMT at baseline (day-36 to day-3), day 0 (stem cell infusion), nadir of counts (individualized) and day 30	• MDASI global symptom and interference score significantly increased at nadir and returned to baseline at day 30. • The only significant predictive factor for MDASI score at nadir was baseline MDASI score (P=0.02). Patients with prolonged time to transplantation and females had higher MDASI scores at nadir.
Wang et al; 2015; 26	Prospective longitudinal study	Single ASCT with (n=22) or without (n=29) lenalidomide maintenance post-transplant	N=51 (At baseline)	Mean age: 59.4 years in low symptom group and 58.9 years in high symptom group	MDASI-MM at baseline (3 months post-ASCT and then weekly for up to 6 months)	• Based on trajectory analysis of 5 symptom scores, 35% of patients consistently reported severe symptoms during the study period. • Baseline TOT-α level in serum predicted high symptom severity. There was no impact of Len-maintenance on severity of symptoms.
Anderson et al; 2007; 28	Prospective longitudinal study	Single ASCT	N=66 (At baseline)	Mean age: 53.6 years	MDASI-BMT at baseline (Before conditioning), 3rd–4th day of conditioning regimen, Day 0 (stem cell infusion), nadir (individualized), day 30 post-transplant	• Symptoms including fatigue, sleep disturbance, lack of appetite and pain peaked at nadir of blood counts and returned towards baseline at day 30.
Williams et al; 2017 (abstract); 29	Randomized controlled trial	Arm A: Single ASCT with Busulfan-Melphalan conditioning Arm B: Single ASCT with Melphalan conditioning	N=165 (completed at least 1 assessment)	Median age: 57 years	MDASI-MM at baseline (Before initiation of conditioning therapy) and subsequently every week for 4 weeks post-ASCT	• Patients in the Bu-Mel arm had a significantly higher severity of pain, drowsiness, dry mouth, constipation, mouth sores, rash and interference with physical function, working and walking in the 4 weeks post-ASCT compared to those in Mel-arm.

Abbreviations: ASCT: Autologous stem cell transplantation; QoL: Quality of Life; MM: Multiple Myeloma; HDM: High-dose melphalan; VAD: Vincristine-Adriamycin-Dexamethasone; G-CSF: Granulocyte-Colony Stimulating Factor; EORTC-QLQ: European Organization for Research and Treatment for Cancer-Quality of Life Questionnaire; EuroQol-5D: Euro Quality of Life-5 dimension; VAMP: Vincristine-Adriamycin-Methotrexate-Prednisone; VTD: Bortezomib-Thalidomide-Dexamethasone; VTCD: Bortezomib-Thalidomide-Cyclophosphamide-Dexamethasone; HDCT: High-dose chemotherapy; SF-36: Short-Term 36 health; Len: Lenalidomide; TNF: Tumor Necrosis Factor.

The Nordic Myeloma Study Group compared HRQoL in patients undergoing ASCT with a historical control group treated with intermittent melphalan-prednisone¹⁸. Baseline HRQoL was comparable in the 2 groups. At the 6-month mark from diagnosis (52 days after high-dose melphalan), ASCT patients had significantly lower global QoL scores (54 vs 62, P=0.003), role functioning (44 vs 65, P< 0.001) and social functioning (60 vs 67; P=0.017) and higher appetite loss (28 vs 15; P<0.001) compared to patients in the control group. There were no significant differences in these domains at 12, 24 and 36 months. However, at the 36 month time-point, patients reported significantly less fatigue (32 vs 43; P=0.04) and pain (28 vs 40; P=0.03) in the ASCT group compared to the control group. Furthermore, patients in the ASCT arm reported a higher impact on their financial situation at baseline and up to 1 year from diagnosis compared to the control group. In conclusion, this study demonstrated the adverse impact of HDM-ASCT on HRQoL and symptom burden immediately post-transplant, with improvement in most domains at subsequent follow-ups. An important caveat is that the study was conducted prior to the era of PIs and IMiDs and a higher percentage of patients in the ASCT group were on interferon maintenance (started 2 months post-ASCT) compared to the control group (75% versus 30% respectively), which could potentially influence the impact of ASCT on HRQoL at later time-points. The ASCT group had a superior overall response rate (75% vs 38%) and median OS (62 vs 44 months; P=0.001) in this study, which likely explains the improvement in long-term symptom burden (fatigue and pain) in the ASCT group due to better disease control.

Another prospective longitudinal single-arm study conducted in the Netherlands evaluated the impact of intensive “total therapy” with tandem ASCT on HRQoL and patient-reported symptoms¹⁹. The study showed increased symptom burden, including mouth sores, change of taste, nausea/vomiting, appetite loss and diarrhea shortly after conditioning chemotherapy, which resolved at 6 and 12-month follow-up post-transplant. Notably, physical, role and social functioning was higher at 6 and 12 months post-ASCT compared to baseline. However, the baseline time-point in this study was 2 weeks after the completion of alkylator-based induction therapy, which is more toxic compared to the induction regimens used currently. Hence, the findings may not be as relevant in the context of current anti-myeloma therapy.

An Australian study reported the impact of tandem ASCT with modified-dose melphalan (100 or 140mg/m²) as a conditioning regimen on HRQoL in 18 MM patients²⁰. Notably, 15 out of 18 patients had received PI and/or IMiD-based induction regimen and 16 had proceeded to upfront tandem ASCT. At 3-month follow-up after the second transplant, the mean global health score significantly improved from 3.44 to 4.50 (P<0.001) and the mean global quality of life also improved from 3.61 to 4.71 (P=0.001) compared to baseline. The proportion of patients with impairment of social activities decreased from 90% during both transplants to less than 40% at quarterly post-transplant follow-ups. All patients in this study had Durie-Salmon stage III disease at diagnosis indicating a high tumor burden, and one-third had high-risk cytogenetics by fluorescence in situ hybridization. Although the study was small, it demonstrated that tandem ASCT has the potential to improve long-term HRQoL in MM patients, even in those with a high disease burden at baseline.

A study from the University of Arkansas investigated the impact of a ASCT on HRQoL, distress and overall life satisfaction²¹. Notably, a total of 56% of patients in this study had received tandem ASCT on total therapy 2 protocol. At baseline, 70% of patients scored poorly for physical well-being compared to population norms. During the immediate post-transplant follow-up, there was a significant worsening of depression (P<0.05), overall life satisfaction (P<0.001) and transplant-related concerns (P<0.05). However, a significant improvement in pain scores was noted immediately post-transplant (P<0.001). Older adults in study had a superior physical, social and functional well-being at stem cell collection and also had a superior social well-being immediately post-transplantation. Furthermore, compared to contemporary transplant reference groups, decline in mood, life satisfaction and transplant-related concerns in this study was lower than anticipated. However, long-term follow-up after ASCT was not reported in this study.

Another prospective longitudinal study from Brazil evaluated the impact of ASCT on HRQoL in a cohort of patients predominantly belonging to lower socio-economic status²². Compared to diagnosis, a clinically meaningful and statistically significant improvement was seen at day 100 in the domains of physical functioning, role functioning, fatigue, pain and constipation. An important limitation in the study design was that the patient cohorts examined at diagnosis, pre-transplant and post-transplant were not completely similar, which makes head-to-head comparison at different time-points difficult to interpret.

A prospective study from Sweden on 96 consecutive patients with MM or lymphoma undergoing ASCT between 2002 and 2005 evaluated HRQoL using the EORTC-QLQ-C30 questionnaire²³. A total of 75% of patients had achieved at least a partial response prior to ASCT, reflecting a low pre-transplant disease burden. There was a clinically meaningful and statistically significant decline in physical functioning, role functioning, social functioning, cognitive functioning and global QoL at week 2 after transplant compared to baseline (which was defined as the day before conditioning). Symptom scores for sleep disturbance, pain, dyspnea and diarrhea were also significantly higher at week 2 post-transplant. However, baseline HRQoL and symptom scores were regained as early as 2 months after ASCT. Furthermore, at 3-year post-transplant follow-up, patients had a similar global QoL and superior role functioning, social functioning and emotional functioning compared to baseline. The authors concluded that patients with MM undergoing ASCT after conditioning with HDM have maximal symptom burden and adverse impact on HRQoL at week 2, followed by improvement thereafter. The study had a prospective design and screened all consecutive patients in the defined time period for inclusion, reducing the risk of selection bias. Furthermore, this study had a long and frequent follow-up after ASCT, which helped in defining the trajectory of HRQoL in transplanted MM patients. The drop-off rate at 3 years was 45% due to several reasons including patient refusal, second ASCT, illness or death, which is commonly seen in most longitudinal HRQoL studies. Data on pre-and post-transplant therapy was not provided, which limits the interpretation of long-term HRQoL after ASCT which can be influenced by different maintenance or consolidation strategies. In this study, patients with lymphoma had a superior HRQoL at 3 year follow-up compared to those with MM, which likely reflects the biology of respective diseases, as more patients with MM relapse over time after ASCT.

A randomized phase II study comparing the efficacy of bortezomib-thalidomide-dexamethasone (VTD) and VTD with cyclophosphamide (VTCD) in transplant eligible MM patients also reported data on HRQoL as a pre-specified secondary end-point in the study protocol²⁴. Patients in this study proceeded to a single or double ASCT after 4 cycles of PI and IMiD-based induction therapy, similar to contemporary clinical practice. The primary HRQoL endpoint was change in global health score measured by EORTC-QLQ-C30 questionnaire A total of 94% patients completed the questionnaire at screening visit, among which, 56% completed the questionnaire at the post-transplant follow-up visit. At baseline, the mean global health scores were comparable in both arms . In patients randomized to the VTD arm, a steady improvement in global health score was noted, exceeding the threshold for clinical significance (≥6 points compared to baseline) at the first post-transplant follow-up visit. Patients in the VTCD arm had a decline in global health score at the end of induction therapy, which subsequently improved at the first post-transplant follow-up visit, but did not reach clinical significance as per the prespecified criteria. Of note, ASCT led to deepening of disease response in both arms, with greater than very good partial response rate increasing from 69% pre-transplant to 86% post-transplant. Although compliance rate of HRQoL questionnaire was reported at baseline and post-transplant follow-up, no imputation for missing data was performed in this study. Nonetheless, this study showed that frontline ASCT after novel agent-based induction therapy can lead to improvement in global health score post-transplant compared to baseline.

The M.D. Anderson group had reported a prospective study on symptom burden in 64 patients with MM undergoing ASCT²⁷. The global symptom severity and median interference scores peaked at the nadir of blood counts and returned to baseline at day 30. Notably, the only statistically significant predictive factor for post-transplant symptom burden was baseline MDASI symptom and interference scores. Patients with a prolonged time from diagnosis to ASCT and females had higher global symptom and interference scores at nadir. Although prospective studies are needing for making definitive conclusions on the impact of timing of ASCT on HRQoL, this study implies that delaying ASCT until relapse might be detrimental to post-transplant QoL due to a high symptom burden immediately after transplant. Another study from M.D. Anderson measured patient-reported symptoms post-ASCT at 3–9 months and correlation with inflammatory markers²⁶. Severe symptoms, including fatigue, pain, numbness, tingling, bone pain and muscle weakness was consistently reported by around 35% of patients despite stability of the underlying disease process during this time-period. Notably, the use of lenalidomide maintenance therapy did not have any impact on the symptom severity. On biomarker analysis, elevated serum tumor necrosis factor (TNF)-α concentration at 3 months post-ASCT was able to predict subgroup with high symptom severity.

Discussion

Data from available studies demonstrate that ASCT leads to a short-term deterioration in HRQoL and symptom burden in MM. However, the adverse impact on HRQoL is short-lived and baseline health status is achieved as early as 1–2 months after ASCT. Furthermore, long-term HRQoL is often improved in patients receiving ASCT compared to baseline, likely associated with superior disease control. In the RCT evaluating VTD or VTCD followed by upfront ASCT, a statistically significant and clinically meaningful improvement in global health score was noted at the first post-transplant follow-up visit in the VTD arm²⁴. Since induction therapy with 3-drug regimens containing a PI and an IMiD is the current standard of care for both transplant eligible and non-eligible patients, the former study likely represents the impact of ASCT on HRQoL in the current era. However, it was limited by a small sample size and lack of information on HRQoL and symptom burden at several time-points after transplantation.

Measurement of PROs has been shown to be feasible in patients undergoing both autologous and allogeneic SCT. With the ease of administration of electronic questionnaires, Wood et al has shown that weekly measurement of PROs until day 100 was feasible in patients undergoing SCT,³⁰. Furthermore, patients reported a high level of satisfaction with electronic questionnaires. The drop in several HRQoL domains in the initial few weeks after ASCT is mostly related to a high symptom burden, which reinforces the importance of aggressive symptom control and supportive care post-transplant. A study evaluating the comparative efficacy of different regimens for the treatment of oral mucositis showed that superior control of mucositis was associated with a better HRQoL in the post-transplant period³¹. A recent study showed that administration of amifostine prior to high-dose melphalan leads to a significantly decreased incidence of grade 2 or higher oral mucositis (odds ratio 0.37; P=0.001) compared to a matched cohort of patients receiving high-dose melpahlan alone³². It also led to decreased incidence of diarrhea, nausea and vomiting. Due to advances in supportive care, ASCT is being performed safely and effective in elderly MM patients even in their seventh decade of life^33,34. Sherman et al, demonstrated that older patients did not fare any worse at any HRQoL domain post-transplant compared to younger patients²¹. In fact, older patients had significantly superior social functioning scores post-transplantation. Increasing data demonstrates the safety and effectiveness of transplant in older adults and supports its use for improving outcomes, including HRQoL for this population³⁵. Since the median age at diagnosis of MM is around 65 years³⁶, studies on ASCT incorporating elderly patients should have HRQoL as a pre-specified end-point.

The adverse impact of ASCT on the financial burden of patients and subsequent influence on HRQoL and outcomes remains an area in need of further exploration. Khalafallah et al. had demonstrated that 70% of patients experienced financial difficulty at the time of transplant compared to 40% at post-transplant follow-up, indicating a significant financial burden of ASCT. This study was performed prior to the era of maintenance therapy. Hence, it did not take into account the cost of post-transplant PI and IMiD therapy. In the era of novel agents, each costing more than $100,000 per year and a changing paradigm from finite duration of therapy to continuous therapy, patients often face financial burden and distress in addition to the toxicity of therapies, which can impact their HRQoL. Although upfront ASCT has been shown to be more cost-effective compared to delayed ASCT in the treatment of newly diagnosed MM³⁷, the cost of a 3-drug induction regimen, upfront ASCT and prolonged maintenance therapy until progression is approximately $500,000 in the United States³⁸. Significant improvement in HRQoL is usually seen with frontline therapies for MM, compared to therapies for relapsed disease³⁹. In addition, delayed ASCT until first relapse might not be feasible in certain patients due to a high symptom burden later in the course of disease⁴⁰. Furthermore, the symptom burden at post-transplant nadir increases with increase in time from diagnosis to ASCT, as shown by the M.D. Anderson group²⁷ Further trials are needed to measure the impact of novel agents and ASCT on HRQoL in MM and the interaction between socio-economic status, financial impact and HRQoL with different therapeutic modalities.

Gaps in literature and future perspectives

Our review shows that there is a paucity of prospective data on the impact of ASCT on HRQoL in the era of novel-agents. The studies were heterogeneous in patient populations included, pre- and post-transplant therapies and instruments used for measuring HRQoL. The criteria for patient selection and statistical handling of missing data were not clearly mentioned in most studies.

Guidelines for measuring and analyzing data on HRQoL in MM in the era of novel agents have been summarized elsewhere⁸. Studies measuring PROs in the context of hematopoietic cell transplantation most commonly being FACT-BMT, EORTC-QLQ-C30 and SF-36 questionnaires for measurement of HRQoL and symptom burden⁴¹. Patients with MM have unique symptoms due to the disease itself and the therapy received. Hence the use of myeloma specific instruments like EORTC QLQ-MY20⁴² to measure HRQoL in these patients might be beneficial in capturing and tracking meaningful information. The PRO of MDASI-Walking interference is another validated measure for physical functioning in post-ASCT MM patients and correlates well with the 6-minute walking test, with a higher completion rate⁴³. Commonly used instruments like EORTC QLQ-C30 and FACT-BMT miss certain symptoms specific to MM, like numbness/tingling as an adverse effect of PIs or IMiDs. Hence guidelines should be established for the homogeneous use of single or a combination of instruments for comprehensive assessment of relevant PROs in patients with MM undergoing ASCT. Furthermore, PRO metrics need to be adjusted to the hematologic response status and the patients’ knowledge of their response status.

A list of current studies in MM incorporating ASCT and HRQoL as a primary or secondary end-point has been summarized in Table II. Notably, all of these studies are focusing on short term symptoms after ASCT, predominantly in the first 60 days after stem cell infusion. Acupuncture has been shown to reduce symptom burden during ASCT and at day 15 and 30 after transplantation in a sham-controlled trial⁴⁴. Increased stem cell infusion dose has been tested in a RCT and did not seem to have any impact on symptom burden in patients with MM or amyloidosis undergoing ASC⁴⁵. Since the median OS in MM is increasing with the availability of new drugs, studies with longer follow-ups are needed to measure longitudinal HRQoL. Post-transplant maintenance therapy leads to further deepening of response after ASCT and prolongs the duration of remission without adversely impacting HRQoL, as shown in a real world registry study⁴⁶. HRQoL at several time-points in patients receiving upfront ASCT versus those continuing on 2 or 3-drug regimens with PIs and/or IMiDs until 1st relapse needs to be compared head-to-head in future studies. The Food and Drug Administration has endorsed PROs as a valid effectiveness endpoint in clinical trials¹¹. Hece, HRQoL should be explored as a primary endpoint in myeloma trials, which might be especially helpful in situations where the magnitude of survival benefit is equivocal. Furthermore, studies in future should explore the relationship between HRQoL and survival in MM.

Table II.

Clinical trials evaluating QoL in patients with MM undergoing ASCT

ClinicalTrials.gov ID	Study Title	Outcome measures	QoL instrument used	Time points for QoL measurement
NCT02274519	Novel Support Options in Autologous Stem Cell Transplant for Multiple Myeloma	Primary: Quality of life Secondary: Time to engraftment and febrile neutropenia	NIH PROMIS Short form questionnaires for pain, depression, anxiety, social isolation, and sleep	Day 1, 14 and 30 of ASCT
NCT00600353	Multi-day Doses in Prevention of Nausea and Emesis	Primary: Overall emetic response Secondary: Impact of nausea and vomiting on the QoL of patients undergoing ASCT	Modified Osoba modules	Day 1, 3 and 7 of ASCT
NCT00747877	High-Dose Melphalan and a Second Stem Cell Transplant or Low-Dose Cyclophosphamide in Treating Patients With Relapsed Multiple Myeloma After Chemotherapy	Primary: Time to disease progression Secondary: Response rate, overall survival, progression free survival, toxicity, safety and QoL	EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires	Baseline and after completion of re-induction therapy
NCT03135925	Feasibility of Pre Transplant Exercise (Pre-habilitation) for Multiple Myeloma Patients Awaiting Autologous Stem Cell Transplantation (PREeMPT)	Primary: Number of exercise sessions attended (feasibility) Secondary: Physical fitness and QoL	FACT-MM (QoL1) and EORTC-QLQ-C30 MY20 (QoL2)	At initial assessments and 6th and final exercise session, which will be between 6 and 12 weeks from initial assessment
NCT03187223	Bendamustine and Melphalan in Myeloma (BEB-2)	Primary: CR rate at 60 days after ASCT Secondary: Toxicity, engraftment, overall survival and QoL	EORTC Q30 questionnaire	At screening and at day 60 post-ASCT
NCT01487031	Music Therapy on Nausea and Pain for Autologous Stem Cell Transplantation	Primary: Patient perception of nausea and pain Secondary: QoL, narcotic medication use, monitoring of psychological responsiveness	FACT-G7	7 days after intervention
NCT01811862	Acupuncture for symptom control in hematopoietic stem cell transplantation patients	Primary: Area-under-curve for MDASI total score	MDASI	Day-2 to Day5 of ASCT

Abbreviations: QoL: Quality of Life; MM: Multiple Myeloma; ASCT: Autologous Stem Cell Transplantation; PROMIS: Patient-Reported Outcomes Measurement Information System; FACT-G7: Functional Assessment of Cancer Therapy-General-7; EORTC: European Organization for Research and Treatment of Cancer; QLQ: Quality of Life Questionnaire;

Conclusion

The therapeutic aren in MM has seen tremendous progress in recent years with the approval of several drugs with unprecedented response rates and survival. However, HRQoL remains an important consideration in addition to traditional end-points and should be meticulously measured in clinical trials to promote patient-centered cancer care. It is important for patients and caregivers to know whether delay in progression is associated with a superior HRQoL for making decision on sequencing of therapies. Although ASCT leads to a short-term deterioration in HRQoL, it could be a valuable option if it indeed leads to a superior HRQoL in the long-term, as suggested by some studies in our review. Future research should focus on rigorously measuring PROs in MM clinical trials to identify the landscape of HRQoL in the current era and the impact of different therapeutic modalities on short and long-term HRQoL.

Highlights.

• ASCT leads to short-term worsening of health-related quality of life (HRQoL).

• Baseline HRQoL is regained as early as 2 months post-transplant.

• Long-term improvement in HRQoL and pain was noted in some studies.