Commentary on “Is posttransplant lenalidomide the standard-of-care after an autotransplant for plasma cell myeloma” by Giovanni Barosi and Robert Peter Gale

Abstract

Barosi and Gale [1] judge the quality of evidence which supports the current guidelines that lenalidomide maintenance following autologous stem cell transplant (ASCT) for multiple myeloma (MM) is a standard-of-care. In 2017, the United States Food Drug Administration (FDA) and the European Medicines Agency (EMA) added to the label of lenalidomide the indication of maintenance treatment following ASCT for MM. This approval was based on the findings of three phase 3 randomized clinical trials (RCTs): CALGB 100104 [2], IFM 2005-02 [3] and RV-MM-PI-209 [4], which were designed with time to progression (TTP)/progression free survival (PFS) as the primary endpoint. All three studies met their primary endpoint with hazard ratios (HR) of 0.37, 0.50 and 0.47, respectively [2–4]. With additional follow-up, CALGB 100104 demonstrated a statistically significant overall survival (OS) benefit (HR 0.61, p= 0.0004) [5]. As none of these studies were powered to evaluate OS as the primary endpoint, a meta-analysis of the three studies using patient-level data was conducted, revealing a survival advantage with lenalidomide relative to placebo/observation (HR 0.75, 95% CI 0.63–0.90, p= 0.001; median OS: lenalidomide: not reached; placebo/observation: 86 months) [6]. Myeloma XI, a fourth RCT, reported increases in both PFS (HR 0.48, p < 0.0001) and OS (HR 0.69, p= 0.013) with lenalidomide maintenance relative to observation [7]. A meta-analysis incorporating all four of these RCTs revealed an overall hazard ratio for OS of 0.72 [7]. The National Cancer Comprehensive Network (NCCN) guidelines has included single-agent lenalidomide maintenance as the preferred maintenance regimen, listing it as category 1 (based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate) [8]. Barosi and Gale [1] utilize the GRADE [9] (Grading of Evidence, Assessment, Development and Evaluation) approach to evaluate the quality of evidence for the use of lenalidomide maintenance post-ASCT. They conclude that the IFM, CALGB and GIMEMA trials present a risk of bias from selective reporting, because the three studies did not report quality of life (QoL) or second PFS data. However, the CALGB and IFM studies were not designed to evaluate QoL and none of them included second PFS as a secondary endpoint. The presence of selective reporting biases should be based on whether or not the investigators report out their planned analyses, as reporting of unplanned analyses are fraught with dangers from lack of adequate power and unrecognized confounders. The authors note that there are no widely-accepted guidelines in cancer that define the magnitude of benefit needed to recommend an intervention. They reference the work of Sobrero et al., who define levels of benefit (high, medium and low) in the setting of palliative treatment for solid tumors based on the HR for OS, gains in median OS, and absolute or proportional gains in OS at a ‘late’ time point [10]. It is unclear how their model can be applied in the post-ASCT MM setting, where the median OS and gain in median OS are in years. Having referenced this work, Barosi and Gale then go on to arbitrarily define a survival HR of 0.70 as the threshold for meaningful clinical benefit and conclude based on this threshold that a survival HR of 0.75 [6] is of moderate quality evidence. Recognizing that the threshold is arbitrary, they go on to conclude that it is * Sarah A. Holstein [email protected]