A non-interventional observational post authorization safety study of subjects treated with lenalidomide

Study Design The study included a lenalidomide cohort and a background cohort. Patients in both cohorts had received ≥ 1 prior antimyeloma therapy and were required to have never received lenalidomide. Enrolled patients who were treated on the study with lenalidomide for off-label indications were kept in the study. To achieve a patient population reflective of those treated in real-world clinical practice, there were few restrictions on eligibility. Exclusion criteria were refusal to participate in the study, concurrent participation in an interventional clinical trial, and previous exposure to lenalidomide. Patients in the lenalidomide cohort commenced lenalidomide treatment, whereas those in the background cohort commenced a therapy other than lenalidomide. Patients previously enrolled in the background cohort who were subsequently prescribed lenalidomide as a new line of treatment could re-enter the study as new patients in the lenalidomide cohort. Recruitment began in August 2008 and ended once 1500 patients in the lenalidomide cohort began the third treatment cycle; up to 1500 patients could be enrolled in the background cohort. The sample size was determined based on incidences of AEs of special interest reported in the MM-009 and MM-010 RRMM clinical trials.18,19 Data from these trials indicated that 83% of patients completed ≥ 3 months of study intervention. Thus, it was estimated that enrolling approximately 1800 patients would provide for 1500 patients at 3 months. Treatment was per the routine practice of the investigator, and all participating patients provided written informed consent. The study protocol was approved by the Committee for Medicinal Products for Human Use and each center’s institutional review board or independent ethics committee, as applicable. The final data cutoff was August 31, 2017.

Study Objectives The primary objectives of the study were to characterize and assess the incidence of AEs of special interest in patients with RRMM treated with lenalidomide in a real-world setting and compare this with the incidence of these AEs in a non-lenalidomide background cohort. The AEs of special interest represent those reported with lenalidomide treatment (and listed in the summary of product characteristics), including neutropenia, thrombocytopenia, infections, bleeding events, venous thromboembolism (VTE), cardiac failure, cardiac arrhythmias, QT prolongation, neuropathy, rash, hypersensitivity, hypothyroidism, and renal failure. Secondary objectives included monitoring neuropathy in patients with baseline neuropathy taking lenalidomide, compliance with pregnancy testing requirements in women of childbearing potential taking lenalidomide, and identification of new safety signals with lenalidomide treatment.

Assessments Assessments were conducted per routine clinical practice. AEs were coded per Medical Dictionary for Regulatory Activities, version 18.0. AE severity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 whenever possible. Treatment-emergent AEs (TEAEs) were defined as AEs occurring on or after the first treatment and within 30 days after the last dose. Patients were followed for up to 36 months for second primary malignancy (SPM) assessments per a protocol amendment modifying the design of the study 3 years after trial start. Follow-up occurred 30 days after ending active treatment and was subsequently scheduled for every 6 months. SPMs were identified using the Medical Dictionary for Regulatory Activities terms under the “Neoplasms benign, malignant, and unspecified” System Organ Class. SPMs were assessed as medically important events and reported as serious AEs.

Analyses Analyses were performed using the safety population (patients who received ≥ 1 dose of treatment). The sample size of 1500 in the lenalidomide cohort would permit evaluation of AEs with an incidence of 1/500 to be detected with a 95% CI.