Updated Results from the FIRST Clinical Trial: Health-related quality of Life

In March 2015, Michel Delforge and colleagues published an updated analysis of the FIRST clinical trial, to compare lenalidomide plus low-dose dexamethasone (Rd) with the standard regimen of Melphalan, Prednisone, and Thalidomide (MPT). This updated analysis was presented in Haematologica, and assessed the health-related quality of life (HRQoL) of patients with newly diagnosed Multiple Myeloma (NDMM) who were aged over 65 years or transplant ineligible. Details of the study design and results from the interim analysis, in which continuous Rd showed improved progression-free survival (PFS) and overall survival (OS) compared with MPT, can be found in a previous MMHub article.

Key Findings:

• Patients (pts) were randomized into two groups: Rd (n=1,076) vs MPT (n=547)
• Surveys were completed at baseline (d1), at the end of Cycle 1 (4 wks of Rd; 6 wks of MPT), after 3, 6, 12, and 18 months of treatment, and at discontinuation 
• Analysis focused on EQ-5D utility value and six pre-selected HRQoL: Disease Symptoms and Side Effects of Treatment (from QLQ-MY20) and Global Health Status, Physical Functioning, Fatigue, and Pain (from QLQ-C30)
• Results from QLQ-MY20 and QLQ-C30 were scored from 0-100
• EQ-5D generated health utility values ranging from worst (−0.594) to best (1.000)
• The Minimal Important Difference (MID) for each domain allowed statistical differences to be translated into clinically meaningful differences or improvements
• The following maximum MIDs were applied: Global Health Status (MID=7); Physical Functioning (MID=9); Pain (MID=12); Fatigue (MID=10); Disease Symptoms (MID=10); and Side Effects of Treatment (MID=6); Walters and Brazier MID of 0.07 was applied to the EQ-5D utility

 Key Highlights:

• Analyses were performed on intention-to-treat (ITT) population
• Data cut off = May 24th 2013; Median follow up = 37 months
• Cross-sectional and longitudinal HRQoL analyses, and estimation of overall treatment effects were performed
• No statistically significant differences in HRQoL scores were observed at baseline 
• QLQ-C30 Pain and Fatigue domains and QLQ-MY20 Disease Symptoms domain indicated statistically significant symptom relief and reductions in Pain (P<0.05) in both groups at all post-baseline assessments
• Clinically meaningful improvement in Pain was observed for Rd (at 12 and 18 months); no improvement for MPT
• Significantly greater reduction in QLQ-MY20 Disease Symptoms (month 3) observed for Rd vs MPT (P=0.04), and an overall lower symptom score across all assessments
• Significant improvement in Fatigue (month 3, 6 and 12) observed for Rd vs MPT
• Worsening in Side Effects of Treatment domain for Rd and MPT, although Rd showed consistently lower scores (fewer/less severe side-effects) across all post-baseline assessments; Rd significantly lower than MPT at month 18 (P<0.05)
• Side Effects of Treatment MID of 6 not reached: Max score for Rd = 3.3 and MPT = 5.6
• Neutropenia grade 3–4 AE reported in ≥10% of pts in Rd group
• HRQoL improved (for Rd and MPT) from baseline across preselected domains of QLQ-C30 and EQ-5D, but dropped at disease progression
• Statistically significant improvement (Rd and MPT): Global Health Status, Physical Functioning, and EQ-5D Health Utility at all the time points after Cycle 1 (P<0.05)
• No significant differences: Global Health Status, Physical Functioning, EQ-5D Health Utility
• Clinically meaningful improvement in HRQoL (measured by EQ-5D) for Rd at all post-baseline assessments (except at month 1); improvement observed for MPT at month 3
• Linear mixed-model repeated-measures analyses confirmed cross-sectional analysis findings
• Significant within-treatment improvements observed for Rd and MPT in all domains (over time) except Fatigue and Side Effects of Treatment
• Significant difference in mean change from baseline for the Side Effects of Treatment domain in favor of Rd (P<0.0001)
• Mean change from baseline for pts aged ≤75 years: Rd, n=697; MPT, n=359 and ≥75 years: Rd, n=379; MPT, n=188 in a post hoc analysis
• Significant improvement in Fatigue from baseline in Rd (P=0.0002), but not MPT; all other within- and between- treatment changes consistent with overall population
• Significant benefit observed for Rd vs MPT in both age groups (P<0.05) for Changes in Side Effects of Treatment (QLQ-MY20)
• Pts ≥75 years: Significant improvement in Pain and Disease Symptoms; Rd significant improvement for Health Utility; Fatigue significantly declined for both Rd and MPT; Physical Functioning significantly declined for MPT but not Rd arm, and were significantly (P<0.05) better for Rd vs MPT

In conclusion, the improved PFS associated with continuous lenalidomide and low-dose dexamethasone (Rd) was also associated with an improved HRQoL for transplant ineligible NDMM patients. Importantly, the improvement in PFS does not come at the cost of increased side-effects and/or worsened symptoms, but actually leads to a significant improvement in the domain of Side Effects and Treatment, indicating good overall tolerability of this regimen. In addition, HRQoL measurements were consistent even in the higher age range (≥75 years) and in fact showed a statistically significant improvement in EQ5D Health Utility with Rd treatment compared with MPT for this age group. The study was limited by the fact that it did not observe HRQoL beyond 18 months.

Abstract

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients' health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.