Refractoriness to last line of therapy: how often is it mandated and reported? A systematic review of randomized myeloma trials

dramatic advances in the treatment of multiple myeloma [1] have led to improved survival [2]. this is a result of numerous, successful drugs evaluated in randomized clinical trials. Varying proportions of patients with refractory disease may have important implications on the results of these clinical trials. the degree of refractoriness to previous therapies including the last line of therapy is an important consideration when trying to generalize results of the clinical trials [3]. Practice patterns in the treatment of MM are highly variable across the world. For instance, patients in the US are generally kept on lenalidomide maintenance until disease progression [4,5] as opposed to some patients in europe who are not kept on active maintenance therapy indefinitely [6]. these patients may progress while off treatment with their disease not truly refractory to their last line of therapy, e.g lenalidomide. in addition, there is no clear or consistent requirement in MM trials to only enroll patients with disease that is refractory to last line of treatment. this disparity in practices and inclusion criteria can thus impact the results of trials. in this systematic review of all MM randomized controlled trials from 2005 to 2020, we aimed to identify the frequency at which MM clinical trials mandated and/or reported disease refractoriness to last line of therapy for their enrolled participants. As no direct patient information was obtained and the information was gathered from publicly available and deidentified sources, this study was considered exempt from institutional review board approval. A previously published systematic review was utilized for this study [7]. We performed a search of three databases: (MedLiNe/PubMed, embase, and Cochrane registry of Controlled trials) [5]. An example search strategy using embase is highlighted in Supplementary table 1. two independent reviewers (GrM, KK) screened all studies, and any conflict was resolved through mutual discussion. this systematic review was performed according to the Preferred reporting items for Systematic reviews and Meta-Analyses (PriSMA) recommendations [8]. our search strategy was restricted to include trials of relapsed/refractory MM published as a manuscript or abstract from 2005 to 2020. the search was last updated in September 2021. All other studies including editorials, case reports, case series, review articles, case control, retrospective/prospective cohort, and single arm studies were excluded. the search strategy was not restricted to language. Abstracts from conference proceedings captured on these databases via our search strategy were also included. this study was not registered on ProSPero. two authors (PB and MG) performed and verified all data extraction. extracted data was tabulated using Microsoft excel (Microsoft, redmond, Washington, United States). We identified the following characteristics of studies: disease phase (relapsed/refractory), location of study (enrollment in one country versus multi-national) and study sponsor (pharmaceutical-funded study vs cooperative/single-center study). the most recent manuscript or abstract with updated data was used to collect data for each study. our primary outcome was to assess the proportion of randomized MM trials that mandated refractoriness to last line of therapy as an inclusion criterion. A key secondary outcome of this study was to assess the proportion of randomized MM trials that reported the percentage of enrolled patients with disease that was