Introduction
Multiple myeloma (MM), considered incurable, accounts for 10% of hematologic malignancies [
1]. The median age at diagnosis is 69 and 72 years in the USA and Europe, respectively [
2,
3], and a significantly shorter median survival is observed in patients ≥ 50 years of age [
4]. Immunomodulatory agents and proteasome inhibitors have increased response rates and progression-free survival (PFS). However, most patients eventually experience relapse or develop refractory disease [
5‐
8]. Current therapies aim to maintain health-related quality of life (HRQoL) while prolonging survival. Improved survival and consequent lengthening of the disease course is associated with an increased burden of disease- and treatment-related symptoms. One of the most frequent symptoms of MM impairing QoL is bone pain [
9‐
14]. Furthermore, increasingly complex/aggressive therapies are associated with an increased risk of treatment-related toxicities.
Demonstrating improvements in HRQoL is challenging in patients with advanced or chronic diseases as patients’ perceptions of their health status and responses to HRQoL-related questions can be affected by adaptations to the disease [
15,
16]. In the absence of actual HRQoL improvements, HRQoL preservation during treatment may be seen as a benefit.
An informed treatment decision requires an adequate understanding of the potential benefits and risks by both physician and patient. When treatments offer a clear survival benefit but have increased toxicity, it is important to consider the patient’s experience of treatment and HRQoL. In order to inform benefit-risk assessments, it is essential to use validated, disease-relevant, patient-reported outcome (PRO) measures in clinical studies to assess symptoms, functioning (activity limitations), health status/HRQoL, patient satisfaction, treatment preferences, and adherence.
Elotuzumab, an immunostimulatory antibody against signaling lymphocytic activation molecule F7 (SLAMF7), is indicated in combination with lenalidomide and dexamethasone (Ld) for the treatment of MM in patients who have received one to three prior therapies in the US [
17] or at least one prior therapy in Europe [
18]. In the phase 3 ELOQUENT-2 study (NCT01239797), elotuzumab in combination with Ld (ELd) was compared with Ld in patients with relapsed and/or refractory MM (RRMM) [
19]. ELd improved PFS, reducing the risk of disease progression or death by 30% versus Ld (hazard ratio = 0.70; 95% confidence interval 0.57, 0.85;
p < 0.001) [
19]. PFS was sustained over time, with a relative improvement of 44% for ELd versus Ld at 3 years [
20] and 50% at 4 years [
21]. Overall response rate (ORR) was also improved at 3- and 4-year follow-up (79% with ELd versus 66% with Ld at both analyses) [
20,
21]. Patients with a very good partial response (VGPR) or better (International Myeloma Working Group [IMWG] Uniform Response Criteria for Multiple Myeloma definition) [
22,
23] achieved longer PFS than those with minimal response or stable disease following treatment with ELd [
19], consistent with prior reports regarding depth of response and survival [
22‐
24]. ELd had a similar safety profile and discontinuation rate to Ld.
In ELOQUENT-2, PRO measures (Brief Pain Inventory–Short Form [BPI-SF], European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire–Core 30 module [QLQ-C30] and myeloma-specific module [QLQ-MY20]) were included as pre-specified secondary or exploratory endpoints. In this paper, we investigated HRQoL measures and whether there is a relationship between treatment response and patient-reported pain. These analyses, performed using data from the extended 3-year follow-up, aim to provide patients and physicians with a more comprehensive benefit-risk assessment of elotuzumab in RRMM.
Discussion
ELOQUENT-2 pre-specified PRO and HRQoL endpoints allowed us to assess the effect of elotuzumab in combination with Ld on HRQoL and patient-reported pain, identify predictors of improvements in pain and HRQoL during treatment, and examine the relationship between best response to treatment and patient-reported pain.
Adding elotuzumab to Ld did not cause a decrement to key HRQoL domains or a clinically relevant increase in patient-reported pain. Pain levels were low at baseline, consistent with a “mild pain” rating [
33], and only 9% of patients had a poor ECOG performance status of 2 [
19]. These low levels of pain were maintained during treatment with both ELd and Ld and may have limited further reductions in pain severity. This is supported by our observation that changes in mean pain scores were greater in patients with moderate-to-severe pain at baseline. The combination of low pain levels at baseline and the high thresholds for improvement used in this study (in comparison with other MM studies [
34]) meant that demonstrating clinically meaningful improvement in pain was challenging. It was therefore not surprising that differences in other domains did not emerge.
Data presented here demonstrate that differences in the pain experience occurred early in treatment (cycles 1 to 2); however, differences between treatments also emerged in later cycles, in subgroups based on age. In several patients with vertebral compression fractures, it took several months for the pain to improve. Although these results are surprising and possibly due to the heterogeneity in the data, the pattern was consistent across several pain endpoints (BPI-SF domains and pain domain of the EORTC QLQ-C30).
Addition of a new therapeutic agent to an existing single or double regimen may improve clinical outcomes without compromising HRQoL, as observed with the ELd combination in RRMM, and with other double and triple combinations in metastatic melanoma and metastatic pancreatic ductal adenocarcinoma [
35,
36]. Treatment may therefore be maintained over a longer period, with potential survival benefits.
The quality of PRO data collected during clinical studies is improving, as are the analyses and reporting of these data; however, there are still elements, such as dosing convenience, that may affect HRQoL but are not adequately measured by current PRO instruments [
37].
PRO data are important to demonstrate the effects of cancer and its treatment on patients’ lives; identify patients who may benefit the most from a specific therapy; and inform clinicians about the relative benefits and risks of its efficacy, toxicity, and value from the patient perspective [
38]. Several regulatory and clinical research organizations have ongoing initiatives to develop frameworks for improving benefit-risk assessment and PRO measures, as there is no widely accepted method of benefit-risk quantification [
37,
39‐
41]. High-quality PRO data will feed into future benefit-risk analyses.
Our robust, scientifically valid methodology addressed many issues common to analyses of PRO data, particularly regarding missing data. Following a pre-defined statistical analysis plan, data were analyzed from all PRO and HRQoL domains included in the study. Validated and disease-specific PRO instruments were used to measure outcomes important to patients with RRMM. We focused on the experience of pain during treatment, as patients with MM have reported that this significantly impairs HRQoL [
25], and conducted secondary analyses to assess the influence of demographic/clinical factors on patients’ perceptions of the effect of MM or its treatment on HRQoL.
Data from the ASPIRE study [
34] showed comparable levels of baseline HRQoL, as measured by the global health status/QoL domain of the EORTC QLC-C30, to those reported in ELOQUENT-2. Mean values for the ELd group (ELOQUENT-2) and carfilzomib group in ASPIRE were comparable at equivalent time points (cycles 1, 3, 6, 12, and 18), as was the magnitude of benefit seen with each treatment, although applying a lower threshold for meaningful improvement in ASPIRE (5 points) than in ELOQUENT-2 (10 points) may have implied some impact on HRQoL. Results from ELOQUENT-2 demonstrated that HRQoL is sustained in a number of domains important to patients; this was seen over an extended period of follow-up, with greater differences in certain subgroups.
This study has some limitations. The open-label trial design may have influenced investigators’ and patients’ treatment expectations during self-reported assessments. However, it is worth noting that, according to the study protocol, response was evaluated every 4 weeks from date of first dose of study drug until disease progression, death, or withdrawal of consent. Therefore, the differences seen between treatment groups in terms of patient-reported pain response at cycle 2 of treatment (Online Resource: Fig.
3) between patients with versus those without an objective response occurred at the time that the first evaluation scans were performed. As such, these PRO data seem to support a reduction in pain owing to treatment response that at this time point would not have been influenced by either patient or investigator knowledge of first evaluation scan results. Study discontinuations leading to missing data can complicate the interpretation of PRO and HRQoL results, and this study had lower completion rates at the end of treatment compared with baseline. However, additional statistical analyses were performed to compensate for this.
Compliance with ethical standards
Institutional review board or independent ethics committee approval and written informed consent from all patients for being included in the study were obtained. The study was performed in accordance with the ethical principles of the Declaration of Helsinki and in compliance with national laws.
Conflict of interest
David Cella has served as a consultant for and/or received research funding from AbbVie, Alexion, Astellas, Bayer, Biogen Idec, Bristol-Myers Squibb, Celgene, Clovis Oncology, Daiichi Sankyo, Eli Lilly, Evidera, Exelixis, FibroGen, Genentech, GlaxoSmithKline, Helsinn Therapeutics, Immunogen, Ipsen Pharma, Janssen, Lexicon Pharmaceuticals, Merck, Novartis, Onconova, and Pfizer. Jan McKendrick and Amber Kudlac are employees of PRMA Consulting Ltd. Antonio Palumbo has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Genmab, Janssen-Cilag, Millennium, Novartis, Onyx, and Sanofi, and served in a consulting or advisory role for Amgen, Bristol-Myers Squibb, Celgene, Genmab, Janssen-Cilag, Millennium, and Onyx. Abderrahim Oukessou, Teresa Zyczynski, and Catherine Davis are employees of Bristol-Myers Squibb. Ravi Vij has received honoraria from Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Onyx, and Takeda; served in a consulting or advisory role for Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Onyx, and Takeda; received research funding from Onyx and Takeda; and received travel, accommodations, and/or expenses from Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Onyx, and Takeda.
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