Impact of elotuzumab treatment on pain and health-related quality of life in patients with relapsed or refractory multiple myeloma: results from the ELOQUENT-2 study

Treatment of relapsed/refractory multiple myeloma (RRMM) aims to prolong survival while maintaining health-related quality of life (HRQoL) by managing disease-related symptoms and complications—one of the most frequent and debilitating being bone pain. In the ELOQUENT-2 study (NCT01239797), which evaluated the addition of elotuzumab to lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone, pain and HRQoL were assessed in patients with relapsed/refractory disease using the Brief Pain Inventory–Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 module (QLQ-C30) and myeloma-specific module (QLQ-MY20). Mean baseline pain scores were low and remained so throughout treatment with both regimens; mean HRQoL scores did not change substantially from baseline. A significantly higher proportion of patients with objective response than without had clinically meaningful improvements in worst pain over two consecutive treatment cycles (29 versus 12%; p < 0.001). Patients with very good partial response (VGPR) or better reported reduced scores for pain severity and worst pain; those with progressive disease reported increased scores for these domains and pain interference. These findings show that previously reported improvements in progression-free survival and response rate with elotuzumab are achieved without detriment to HRQoL, which is maintained over time. Electronic supplementary material The online version of this article (10.1007/s00277-018-3469-4) contains supplementary material, which is available to authorized users.

problems during the previous week [4]. In the current study, HRQoL measures were scored in accordance with the manual [3].

Handling of missing and incomplete data for the PRO instruments
Mean Pain Interference scores and mean HRQoL domain scores were calculated if at least 50% of the items that construct the domain had been answered. If more than 50% of the items were missing, the domain score was considered missing. The mean Pain Severity score was calculated based on all four severity items; missing items were not imputed at an individual patient level [2]. Thus, the score was not calculated if any items were missing.
Missing domain-level data or data for the entire instrument were assumed to be missing at random; no adjustments were made to account for any missing domains or assessments.

Meaningful change from baseline
The minimal important difference (MID) is the smallest difference in the domain of interest that patients consider beneficial and that would mandate a change in the patient's management, in the absence of troublesome side effects and excessive cost [5].
The MID needs to be met or exceeded at the group level in order for reported changes to be considered meaningful. The MID defines meaningful change for patients and should not be interpreted as clinically relevant. The method of calculation of MID thresholds for the BPI-SF, EORTC QLQ-C30, and QLQ-MY20 are described below.

BPI-SF
An MID has not been established for the BPI-SF in MM. Distribution-based methods were used to calculate MM-specific MIDs for the Worst Pain item and the Pain Severity and Pain Interference baseline scores using two methods: one based on standard deviation (SD), and the other based on standard error of the mean (SEM) (Online Resource: Table 2) [6,7]. The SEM method was not applied to Worst Pain as this is a single item and internal consistency cannot be tested. For Pain Severity and Pain Interference, the mean change from baseline for each treatment group at each cycle was compared with these two calculated MID thresholds; for Worst Pain, the comparison was with the SD-based method only.

EORTC QLQ-C30 and QLQ-MY20
For the purpose of interpreting changes in the EORTC QLQ-C30 scores from baseline, a mean change of at least 10 points on the standardized domain scores was required for the change to be considered meaningful (i.e., the MID), reflecting the lower benchmark for a moderate change [8]. Similarly, for the purpose of interpreting changes in EORTC QLQ-MY20 scores from baseline, a mean change from baseline of at least 10 points on the standardized domain scores was required for the change to be considered meaningful, reflecting the highest published MID for a QLQ-MY20 domain (Disease Symptoms), and to facilitate comparison with the QLQ-C30 [6].

Clinically relevant between-group differences
Threshold levels can be used to interpret the clinical relevance of treatment group differences in mean EORTC QLQ-C30 scores. Threshold values for trivial, small, medium, and large mean differences between treatment groups have been published for each domain (Online Resource: Table 3) [9]. These values are not specific to the MM population, but were used in the current study to indicate potential treatment group differences that may be clinically relevant. As there is no clear guidance on use of the actual thresholds, any value greater than the maximum rounded value of the trivial range was considered to indicate a clinically relevant difference between treatments.
The clinically relevant thresholds were not applied to subgroup analyses or to cycles in which there were fewer than 30 patients per treatment group. Additional post-hoc analyses with these models compared the treatment in terms of the change from baseline in the EORTC QLQ-C30 and QLQ-MY20 domains of interest. Covariates that were significant at the 5% level were considered to influence the outcome.

Response criteria
Pain response was assessed by the best treatment response defined according to the

European Society for Blood and Marrow Transplantation criteria and International
Myeloma Working Group Uniform Response Criteria [10][11][12]. The relevant levels of response are defined as follows:

Very good partial response (VGPR)
This requires two consecutive assessments made at any time before the institution of any new therapy: • Serum and urine M-component detectable by immunofixation but not on electrophoresis • Objective response (OR)

Progressive disease (PD)
Increase of ≥25% from the lowest response value in any one or more of the following: • Serum M-component (the absolute increase must be ≥0.5 g/dL) • Urine M-component (the absolute increase must be ≥200 mg/24 h) • Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (the absolute increase must be >10 mg/dL) • Bone marrow plasma cell percentage (the absolute percentage must be ≥10%) •