Reporting of Postprotocol Therapies and Attrition in Multiple Myeloma Randomized Clinical Trials

Abstract

Key Points Question What proportion of multiple myeloma randomized clinical trials report postprotocol therapies, and when reported, how do these therapies compare with existing standard of care? Findings In this systematic review of 103 randomized clinical trials including 47 251 patients, only 43.7% of the trials reported postprotocol therapies. When described, the proportion of patients receiving postprotocol therapies was low, and often not at par with standard of care therapy. Meaning These findings suggest that reporting of postprotocol therapies is poor in multiple myeloma trials, necessitating reporting guidelines on postprotocol therapies for ongoing and future trials.

Ivosidenib and Azacitidine in IDH1 -Mutated AML

“…This lack of adequate postprotocol therapy (that has previously proved to be effective) is also common among contemporary randomized trials in oncology. 4 Third, the trial switched end points and was halted early -tactics that can exaggerate the effect size. 5 Given these limitations, we do not believe this trial to be a practice-changing trial.…”

“…Subgroup analyses have an increased probability of alpha and beta errors. 2 Thus, we conducted adjusted indirect comparisons (Bucher's method 3 ) with pooled data 4 and subgroup trial results 5 for venetoclax-azacitidine as compared with ivosidenib-azacitidine in patients with previously untreated IDH1-mutated AML. We found no significant differences between treatments in adjusted indirect comparisons of overall survival, either in pooled data (hazard ratio for death, 0.43; 95% confidence interval [CI], 0.16 to 1.16) or subgroup trial results (hazard ratio, 0.64; 95% CI, 0.24 to 1.70).…”

The AGILE trial of ivosidenib plus azacitidine versus azacitidine alone: How many limitations is too many?

“…Post-protocol therapy influences all endpoints that occur after the initial EFS or progression free survival (PFS) event, including overall survival. Inappropriate post-protocol care may result from imbalance across study arms, or, in the case of the AGILE trial, if both arms receive post-protocol therapy that falls short of the current standard of care [6] . Just four months into the study, ivosidenib was FDA approved for use in IDH1-mutant AML and rapidly gained uptake among leukemia physicians, and yet, only two patients on the control arm of AGILE received post-protocol ivosidenib when their AML progressed [7] .…”

“…AGILE cannot answer the question of whether ivosidenib and azacitidine is superior to the current standard of care: venetoclax and azacitidine. This is particularly salient as venetoclax and azacitidine appear to work particularly well in IDH-mutant AML, with a median OS of 17.5 months [ 1 , 6 ].…”

Hard-wired biases in trials: maintenance azacitidine in patients with acute myeloid leukemia and framework for future trials

“…Substandard postprogression therapy has been described in multiple myeloma and renal cell carcinoma trials. 8,9 Here, in a trial run globally, we hypothesize that postprogression treatment may have been beneath the standard of care. In the placebo arm, 47% of patients received “low intensity” therapy.…”