Saad Usmani, M.D., MBA, FACP, Department of Hematologic Oncology and Blood Disorders of Atrium Health Levine Cancer Institute discusses Daratumumab‐lenalidomide‐dexamethasone vs standard‐of‐care regimens: Efficacy in transplant‐ineligible untreated myeloma.
Daratumumab has recently obtained FDA clearance for the treatment of transplant-negligible patients with newly diagnosed multiple myeloma (NDMM) in conjunction with lenalidomide-dexamethasone (D-Rd). The current PEGASUS study compared progression-free survival (PFS) in patients treated with D-Rd in the MAIA study and patients treated with common standard-of-care regimens from the de-identified database derived from the Flatiron Health electronic health record, which has data from patients treated predominantly in U.S. community-based oncology practices. In order to conduct an anchored indirect care comparison (ITC) of D-Rd to bortezomib-lenalidomide-dexamethasone (VRd) and bortezomib-dexamethasone (Vd), individual patient data from both data sources were used; lenalidomide-dexamethasone (Rd) was the common anchor for the ITC. To render ITCs for D-Rd vs VRd and Vd, respectively, hazard ratios (HRs) representing direct comparisons of PFS within MAIA (D-Rd vs Rd) and Flatiron Health (VRd vs Rd; Vd vs Rd) were used. The Flatiron Health patients resembled the MAIA trial population on calculated baseline characteristics after the implementation of MAIA inclusion/exclusion criteria and propensity-score weighting. D-Rd care was associated with a substantially lower risk of progression or death relative to Rd (HR 0.54; 95 % CI 0.42, 0.71) on the basis of a direct comparison within the MAIA. Compared to VRd (HR 0.68; 95 percent CI 0.48, 0.98) and Vd (HR 0.48; 95 percent CI 0.33, 0.69), D-Rd was associated with a substantially lower risk of progression or death based on the ITCs. The current ITC may help inform the choice of care in transplant-unqualifiable patients with NDMM in the absence of head-to-head studies comparing D-Rd to VRd or Vd.
In June 2019, daratumumab obtained approval from the US Food and Drug Administration (FDA) in conjunction with lenalidomide dexamethasone (D-Rd) for the treatment of patients with newly diagnosed multiple myeloma (NDMM) who were not suitable for autologous stem cell transplantation (ASCT).1 The FDA approval was based on findings from a recommended interim review of MAIA phase III clinical trial evidence.
Lenalidomide-dexamethasone (Rd), bortezomib-lenalidomide-dexamethasone (VRd), and bortezomib-dexamethasone (Vd), which together account for at least two-thirds of the treatment regimens used to treat patients with transplant-ineligible NDMM, are typical standard of care (SOC) regimens for the treatment of transplant-ineligible NDMM in the US.
2.1 Population and Architecture of Research
The present research (PEGASUS) used individual-level patient data from the phase III randomized controlled trial of the global MAIA and the de-identified database derived from the US Flatiron Health electronic health record ( EHR). To compare relative treatment effects between the two data sets, an anchored indirect treatment comparison (ITC) research design was used.
2.1.1 Trial with MAIA
Patients in MAIA were enrolled and randomized to obtain D-Rd or Rd between March 2015 and January 2017. Ineligibility for age-defined ASCT (⁇ 65 years) or existence of comorbidities outside high-dose therapy, performance status of the Eastern Cooperative Oncology Community (ECOG) ≤ 2, creatinine clearance ≥ 30 mL/min, and sufficient bone marrow reserve were the main eligibility criteria for MAIA.
2.1.2 Flatiron Health Database
Records were collected from the Flatiron Health (FH) EHR-derived de-identified database for patients with NDMM. The FH database is a national database derived from EHR data that is longitudinal, demographically, and geographically representative. The database contains detected data visited by more than 2.4 million US cancer patients from over 280 cancer clinics, mainly community-based oncology practices. The FH database, curated by technology-enabled abstraction, contains both structured data ( e.g. patient demographics, test findings, and coded diagnoses) and unstructured data ( e.g. free text from clinician notes and laboratory reports) from the EHR to identify clinical indicators that are frequently inaccessible in real-world data sources, like the International Staging System (ISS), ECOG performs FH patients were eligible for the present study if multiple myeloma (MM) was diagnosed between 1 January 2011 and 30 April 2019 and first-line therapy (LOT1) was started at an FH clinic.
2.1.3 Conditions of Eligibility
For the current research, the eligibility requirements (Figure S1 in Appendix S1) included NDMM, age > 65 years, and transplant ineligibility (MAIA) or no transplant as part of LOT1 (FH). There is no variable representing transplant eligibility status in the FH data; therefore, age ⁇ 65 years was used as a proxy for transplant ineligibility and no transplant as part of LOT1. Furthermore, the study was confined to patients who initiated their assigned study regimen (MAIA) or LOT1 (FH) and had ⁇ 1 disease response assessment after initiation of LOT1. All patients had to meet the inclusion criteria for the MAIA study, including ECOG output status ⁇ 2, creatinine clearance ⁇ 30 mL/min, an adequate reserve of bone marrow and hepatic function, and lack of selected comorbidities (see Appendix S1). Finally, the FH cohort was confined to LOT1 regimens used by around 10 percent of transplant-ineligible NDMM patients due to statistical power considerations; VRd, Rd, and Vd met this criterion.
2.1.4 Features of the Baseline
The baseline characteristics captured for both MAIA and FH patients included age at initiation of LOT1, sex, ethnicity, ISS level, stratification of cytogenetic risk, ECOG performance status, laboratory measurements (e.g., creatinine clearance, blood counts, liver function enzymes), MAIA-excluded comorbidities (e.g., serious cardiovascular disease, other primary malignancy) and MM diagnostic time interval. Appendix S1 offers info.
PFS, described as the time interval between LOT1 initiation and disease progression or death in months, was the primary outcome. The definition of disease progression in the MAIA cohort was based on criteria 2(8) and 9 of the International Myeloma Working Group (IMWG) for progressive diseases. A derived progression measure based on the application of IMWG parameters to the real-world data setting was used in the FH cohort to assess progression occurrences. Appendix S1 offers information about how disease progression and mortality are ascertained in FH. Patients were tracked or censored before their first PFS occurrence due to lack of follow-up or the maximum follow-up period of 48.5 months (the maximum available for participants in the MAIA). An additional 9 months of patient follow-up after the cut-off date for the first recommended MAIA interim review is included in this review; Appendix S1 offers 10 information.
PFS 's primary study was an on-treatment study in which patients were often censored for reasons other than disease deterioration or death if treatment was terminated. This method was chosen to decrease patient management variability across the clinical practice settings of the MAIA trial and FH routine. Patients were treated with MAIA before disease progression or unacceptable toxicity was detected. However, in regular clinical practice, this is not always the case when the care plan of the patient does not involve ongoing treatment for disease progression and where patients are more likely to discontinue treatment for a number of other reasons, including patient preference.11 The on-treatment review restricted qualified follow-up to patients with MAIA and FH who did not discontinue their ini As a sensitivity study, an intent-to-treat study of PFS was conducted without censoring at care discontinuation.
Because of the immaturity of the MAIA OS results, overall survival (OS), defined as the time interval in months between LOT1 initiation and death from any cause, was prespecified as an exploratory endpoint. For the first recommended interim review for MAIA PFS (41.4 months), follow-up for OS in this study was limited to the maximum follow-up period. In the next recommended interim review for OS, the next systematic analysis of OS in MAIA based on additional follow-up will take place. Since mortality sometimes occurs after LOT1 is discontinued and subsequent LOTs are initiated, only an intent-to-treat study for OS was conducted.