Abstract
Objective
With the introduction of novel treatments for multiple myeloma, patients are now achieving deeper and sustainable clinical responses. Recent studies have demonstrated that achieving Minimal Residual Disease (MRD) negativity leads to better progression-free survival and overall survival outcomes (Lahuerta JJ, et al. J Clin Oncol 2017. 35[25]:2900-10; Munshi NC, et al. JAMA Oncol 2016. 3[1]:28-35; Landgren O, et al. Bone Marrow Transplant 2016. 51[12]:1565-1568). However, the relationship between MRD status and patient reported outcomes (PRO) has not been reported. The objective of this analysis is to evaluate whether PRO endpoints change by MRD status using data from two randomized clinical trials of daratumumab containing treatment regimens, POLLUX (Dimopoulos MA, et al. N Engl J Med 2016. 375[14]:1319-1331) and CASTOR (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766), for patients with relapsed or refractory multiple myeloma.
Methods
MRD status was assessed in POLLUX at the time of suspected CR, and at 3 and 6 months post-suspected CR for responders. Similarly, in CASTOR, MRD status was assessed for patients at the time of suspected CR and at 6 months and 12 months after first dose. MRD was assessed via next generation sequencing using the clonoSEQ® assay V2.0 (Adaptive Biotechnologies, Seattle, WA) at sensitivities of 0.001%. The PRO instruments (EORTC-QLQ-C30 and EQ-5D-5L) were collected in both POLLUX and CASTOR study prior to treatment, during the treatment phase, and post-progression. EQ-5D-5L assessed general health status and included an index value and visual analog scale (VAS) score. EORTC QLQ C30 assessed health related quality of life and included five functional scales (physical, role, emotional, social and cognitive), three symptom scales (fatigue, nausea & vomiting and pain) and a global health status (GHS) scale as well as six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Summary statistics (mean, standard deviation, median, min and max) by MRD status (baseline, prior to MRD negativity, MRD negativity prior to progression) were reported and for subjects who did not achieve MRD negativity (baseline, post baseline prior to progression) on a pooled sample of subjects from the two clinical trials. To interpret a meaningful change, a 5-point threshold was defined based on the EORTC guidelines for assessing quality of life in clinical trials.
Results
Overall 137 subjects in both CASTOR and POLLUX achieved MRD negativity and had PRO data available for analysis. At baseline, GHS, EQ-5D-5L VAS and index value were 62.1, 66.7, and 0.72 respectively (GHS and VAS scores closer to 100, and index value closer to 1.0 represent better health state). Mean values increased to 67.2, 70.9, and 0.75 after achieving MRD negativity. Pain scale (symptom scores closer to 0 represent less symptoms) reduced from 30.4 to 23.5 and fatigue was similar (33.8 at baseline to 31.2) when patients achieved MRD negativity. However, when we compared the five functional scales prior to and post MRD negativity, no evident differences were identified. The mean change from baseline to post-MRD-negativity in the EORTC QLQ-C30 GHS and Pain scores exceeded a 5-point threshold, reflecting a meaningful change in subject's health-related quality of life.
A total of 893 subjects in the pooled data set did not achieve MRD negativity and had PRO data available for analysis (EQ-5D-5L data were not available for 3 subjects). Baseline values for these MRD positive subjects were 60.0, 65.3, and 0.71 and the mean post-baseline (pre-progression) values remained similar at 61.1, 66.0, and 0.71 for GHS, VAS, and the index value, respectively. Pain reduced from mean 33.3 to 29.4 and fatigue was similar, changing from 36.2 to 37.6.
Conclusion
To our knowledge, this is the first analysis exploring the relationship between MRD status and PRO endpoints. Results from this analysis demonstrate that patients who achieve MRD negativity status show a trend in better health-related quality of life, with meaningful improvement in EORTC QLQ-C30 GHS and pain scores. These preliminary findings indicate that overall health-related quality of life and symptom domains of EORTC-QLQ-C30 and EQ-5D-5L might be sensitive to changes in MRD status, with changes in GHS and Pain exceeding meaningful threshold for subjects.
Disclosures
Avet-Loiseau: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. He:Janssen global services: Employment. Gries:Janssen Research & Development, LLC: Employment. Pei:Janssen Research & Development, LLC: Employment. Saha:Janssen Research & Development, LLC: Employment. Chiu:Janssen Research & Development, LLC: Employment. Cote:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment.
Establishing anchor-based minimally important differences for the EORTC QLQ-C30 in glioma patients
