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Project Title: Health-related quality of life in Danish patients with multiple myeloma treated with Daratumumab, lenalidomide and dexamethasone in daily clinical practice
Scientific Abstract:
Background:
New treatments for multiple myeloma (MM) have improved survival. In particular, daratumumab-based therapies have improved prognosis, and the Daratumumab-Lenalidomide-Dexamethason combination (DRD) has become a new standard of care for treating patients with relapsed MM based on the results of the Pollux study. As survival improves expectation to live a good life with MM increases. In the Pollux study the combination of Daratumumab, Lenalidomide and Dexamethasone (DRD) treatment was described as well-tolerated with the greatest improvement and less worsening of health-related quality of life (HRQL) among the youngest patients. It is well known that populations in randomised clinical trials (RCTs) differ from the real-world (RW) setting. Only about 36% of the Danish patients with MM over 65 years fulfill standard inclusion criteria in RCTs. As the incidence of MM increases by age the gap between populations in RCTs and RW might expand. Several factors such as comorbidity, age, national policies and availability of drugs also affect this gap. Hence, information on how treatment is working and tolerated in RW populations is warranted.
We have established a database with a real-world population of 57 patients with MM, treated with DRD at first or later relapse and who are part of our prospective cohort study "Quality of life in Danish Multiple Myeloma patients" (QoL-MM) have reported patient-reported outcome (PRO) measures. To the best of our knowledge, HRQL in a DRD treated real-world population has not been compared to data from a clinical trial. We find it important to compare the data in these two populations over time, to give patients and physicians the best information on what to expect during DRD treatment.
Objective:
To compare patient characteristics and reported HRQL of a Danish real-world population treated for MM relapse with DRD during a 2 year period with the HRQL reported by the population treated with DRD in the Pollux study.
Study design:
Both the QOL-MM study and in the Pollux study assessed HRQL according to the European Organisation for Research and Treatment of Cancer Quality of life (EORTC) QLQ-C30. In QOL-MM, HRQL is measured at baseline, 4, 8, 12, 16 and 20 weeks and at 6, 9, 12, 15, 18, 21 and 24 months. In the Pollux study, HRQL is measured at start of specific cycles of therapy. We will compare data at comparable time points (e.g. cycle 2 will be compared to 8 weeks).
Participants:
Fifty-seven patients treated with DRD in our real world QOL-MM study (RW_DRD) and the cohort of patients treated with DRD in the Pollux study (Pol-DRD).
Primary and secondary outcome measures:
Primary outcome is HRQL measured by EORTC-QLQ-C30 at baseline, 4, 8, 12, 16 and 20 weeks and at 6, 9, 12, 15, 18, 21 and 24 months, comparing mean changes from baseline to the DRD treated population from the Pollux study at comparable time points.
Further, numbers reporting improvement/deterioration will be investigated at 4, 8 and 12 weeks and at 6, 9 and 12 months. To be categorized as reporting improvement/deterioration changes from baseline must exceed minimal important differences according to Cohens MID criterias.
Secondary outcomes are comparison of baseline characteristics (age, sex, ECOG performance status, cytogenetic profile, prior treatment and response to treatment) in RW-DRD to Pol-DRD.
Statistical analysis:
RW-DRD will be compared with Pol-DRD using a Matching-Adjusted Indirect Comparison analysis. A mixed-effect model for repeated measures will be applied to estimate the changes from baseline and least-squares mean changes is derived from the mixed-effect model. Results from the RW-DRD will be compared with Pol-DRD and differences reaching a statistical significant p-value of < 0.05 will be considered evident.
Brief Project Background and Statement of Project Significance:
The treatment of multiple myeloma (MM) has developed rapidly during the last decades. New immunomodulatory agents, proteasome inhibitors and monoclonal CD38 antibodies have improved survival (1,2,3) and now drug-antibody conjugates, bispecific antibodies and chimeric antigen receptor T cell therapy are bringing hope for even longer survival(4,5). Consequently, the side effects have changed as well as patients preferences(6) As survival improves, expectation to live a good life with MM increases. The primary goal for treatment is to obtain the most durable remission with the best health related quality of life (HRQL)(7,8). However, HRQL measurements are under-reported in many clinical trials and are not established as part of daily clinical care. Guidelines for the use of patients reported outcomes (PRO) are warranted(9).
It is well documented, that populations in randomised clinical trials (RCTs) differ from the real-world (RW) setting(10,11). Only about 36% of the Danish patients with MM over 65 years fulfill standard inclusion criteria in RCTs(12). As the incidence of MM increases due to an aging population(2) the gap between populations in RCTs and RW might expand. Several factors such as comorbidity, age, national policies and availability of drugs affect this gap. Hence, information on how treatment is working and tolerated in RW populations is warranted.
In the Pollux study(13) the combination of Daratumumab, lenalidomide and dexamethasone (DRD) treatment was described as well-tolerated with the greatest improvement and less worsening of HRQL among the youngest patients. This indicates that the age influences reported HRQL. The same pattern was found in the CASTOR trial(14) comparing Daratumumab, Bortezomib and dexamethasone to bortezomib, dexamethasone treatment.
In our study we will present patient characteristics and reported HRQL of a Danish real-world population treated for MM relapse with DRD during a 2 year period. HRQL is assessed by European Organisation for Research and Treatment of Cancer Quality of life (EORTC) QLQ-C30 (EORTC QLQ-C30). The study employs real-time monitoring and data completeness is over 95%. We will compare this RW HRQL with the HRQL reported by the population treated with DRD in the Pollux study.
To the best of our knowledge, HRQL in a DRD treated real-world population, has not been compared to data from a clinical trial. We find it important to compare the data in these two populations over time, to give patients and physicians the best information on what to expect during DRD treatment.
Specific Aims of the Project:
The primary aim is described according to the estimated framework of PRO objectives in clinical trials15. We want to evaluate how HRQL, measured by EORTC-QLQ-C30, is affected during treatment with DRD in a Danish real-world population (RW-DRD) and compare the findings to HRQL reported by the population treated with DRD in the Pollux study13 (Pol-DRD), during the first 24 months on treatment. All domains of the EORTC-QLQ-C30 will be presented and the findings in RW-DRD will be compared to Pol-DRD at the following time points: baseline, after 4, 8, 12, 16 and 20 weeks and 6, 9, 12, 15, 18, 21 and 24 months, to explore whether HRQL is reported equally or differentially in the RW-DRD and POL-DRD cohorts.
We will compare baseline characteristic (age, sex, ECOG performance status, cytogenetic profile, prior treatment and response to treatment) in RW-DRD to POL-DRD.
We hypothesize that HRQL reported by a real-world population treated with DRD will be similar to the HRQL reported by the DRD treated population in the Pollux study13. Further we hypothesize that a Danish real-world population treated with DRD will be older, more frail and comorbid than the DRD treated population in the Pollux study13
Study Design:
Other
Explain:
Comparison of PRO measurements in a real world population with a clinical trial population
What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment safety Confirm or validate previously conducted research on treatment safety Other
Software Used: STATA
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
Our real-world population is constructed by combining data from the Danish Daratumumab real-world study16 with patient-reported outcome (PRO) measurements from the prospective cohort study, "Quality of life in Danish Multiple Myeloma patients" (QoL-MM)17.
The Daratumumab study combined real-world data from a complete Danish nationwide cohort of patients with multiple myeloma treated with a daratumumab-containing regimen until 31.12.201816,18. QoL-MM is a Danish prospective, nation-wide, observational survey, initiated in February 2017. Eligible participants are newly diagnosed or relapsed, symptomatic myeloma patients. All subjects are followed for 24 months.
Exclusion criteria: Not being able to understand Danish, a psychiatric diagnosis or mental difficulties that prevent participants from answering the questionnaires. All patients provided written consent before participation.
Fifty-seven patients started DRD treatment and answered the baseline questionnaire in QoL-MM within +/- 30 days and they constitute our real world study population named RW-DRD. If a patient stopped Daratumumab treatment within the first 30 days or dropped out of the QoL-MM study the patient leaves the RW-DRD study.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary outcome is HRQL measured by EORTC-QLQ-C30 at baseline, 4, 8, 12, 16 and 20 weeks and at 6, 9, 12, 15, 18, 21 and 24 months, comparing mean changes from baseline to the DRD treated population from the Pollux study at comparable time points (e.g. cycle 2 will be compared to 8 weeks). The data will be presented like figure 1 in Plesner et al13.
Further, numbers reporting improvement/deterioration will be investigated at 4, 8 and 12 weeks and at 6, 9 and 12 months. To be categorized as reporting improvement/deterioration changes from baseline must exceeds minimal important differences according to Cohens MID criterias19.
HRQL data from the Pollux study has been published, but incompletely (Plesner et al13). We apply for access to the HRQL data and clinical data in the Pollux study for comparative analyses as described.
Secondary outcome will be a presentation and comparison of the baseline clinical characteristics.
Main Predictor/Independent Variable and how it will be categorized/defined for your study: The main independent variable is HRQL measured by the EORTC-QLQ-C30 questionnaire during a two-year period on DRD treatment.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
The following variables registered in the combined database of the Danish Daratumumab real-world study16 and the "Quality of life in Danish Multiple Myeloma patients" (QoL-MM)17 will be included in data presentation and analyses: Age, sex, CRAB criteria, ISS, R-ISS, renal function, liver function, hematology parameters (hemoglobin, leucocytes, lymphocytes, neutrophils, thrombocytes), cytogenetics, comorbidity (CCI), former lines of treatment, treatment response.
Statistical Analysis Plan:
Patient baseline characteristics of the RW-DRD population will be summarized using descriptive statistics, including numbers, means with standard deviation, median and minimum and maximum value. The mean HRQL score at baseline will be calculated based on scoring manuals 20,21. These data will be compared to Pol-DRD and P-values below 0.05 was considered statistically significant.
Compliance rates will be calculated as a proportion of patients completing the physical functioning domain of the EORTC QLQ-C30 instrument at each follow-up time point. These data will be compared to the Pol-DRD.
A mixed-effect model for repeated measures will be applied to estimate the changes from baseline and least-squares mean changes is derived from the mixed-effect model. Results from the RW-DRD will be compared with Pol-DRD and differences reaching a statistical significant p-value of 10 point23 from baseline at 3, 6 and 9 months in RW-DRD population was compared to cycle 3, 6 and 12 in Pol-DRD population.
For assessing median time to meaningful improvement/deterioration, the Kaplan-Meier method and half standard deviation of the baseline value from the Pol-DRD population as threshold for improvement/deterioration will be used. Cox proportional hazards model will be used to calculate Hazard ratio (HR) and 95% confidence intervals (CIs) and the model will be adjusted with stratification factors (international stating system (I, II or III), numbers of prior lines of therapy (1 vs 2 or 3 vs >3), and prior Lenalidomide treatment (yes vs no)). Comparing the HRQL findings from the RW-DRD with Pol-DRD the Cochran-Mantel-Haenszel chi-squared test will be used to compare the median time to improvement and deterioration.
No imputation of missing data or adjustments for multiplicity will be made.
Narrative Summary:
New treatments for multiple myeloma have improved survival. In particular, daratumumab-based therapies have improved prognosis, and the Daratumumab-Lenalidomide-Dexamethason combination (DRD) has become a new standard of care for treating patients with relapsed MM based on the results of the Pollux study. As survival improves expectation to live a good life with MM increases.
We have established a database with a real-world population of 57 patients with MM, treated with DRD at first or later relapse. These patients are part of our prospective cohort study "Quality of life in Danish Multiple Myeloma patients" (QoL-MM) where participants have reported patient-reported outcome (PRO) measures. To the best of our knowledge, HRQL in a DRD treated real-world population has not been compared to data from a clinical trial. We find it important to compare the PRO data from our real world population with PRO data from the Pollux trial. This will give patients and physicians the best information on what to expect during DRD treatment.
Project Timeline:
If the data we request can be delivered, we will be ready to make the analyses within three months, to have a draft manuscript within 5 months that will be reported to the YODA Project. A final manuscript ready for submission will be expected within 6 months.
Dissemination Plan: We aim to submit the manuscript to Hemasphere or British Journal of Haematology.
Bibliography:
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4 Wang BY, Zhao WH, Chen YX, Cao XM, Yang Y, Zhang YL et al. Five-year remission without disease progression in a patient with relapsed/refractory multiple myeloma with extramedullary disease treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study: a case report. J Med Case Rep 2022; 16: 1--8.
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