Use of endpoints in multiple myeloma randomized controlled trials over the last 15 years: A systematic review

Abstract

Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event‐defined endpoints in 91 studies (60.3%) and response‐based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re‐analysis.

Characteristics of clinical trials for haematological malignancies from 2015 to 2020: A systematic review

“…Clinical end-points most relevant to patients include overall survival and quality of life [6], but these endpoints are often supplanted by surrogate end-points such as progression-free survival and response rate. Although surrogate end-points allow for earlier approval of drugs and availability to patients [7], these end-points do not consistently correlate with overall survival and quality of life [8e10].…”

Time‐to‐event surrogate end‐points in multiple myeloma randomised trials from 2005 to 2019: A surrogacy analysis

“…Furthermore, although the distinction between clinical and biochemical PFS is relevant from a prognostic and practical standpoint, the nature of disease progression is almost never reported in MM clinical trials. Although PFS is a frequently used approved end‐point for regulatory purposes, 19 and it is undeniable that outcomes in MM have improved dramatically for patients, the results of this analysis highlight the limitations of currently used surrogate outcomes.…”

“…and K.K.) performed and verified all data extraction as part of a previous research project that examined and characterised end‐points used in MM trials 19 . We identified the following characteristics of studies: phase of study (Phase II/III), line of therapy being treated (relapsed/refractory or front‐line) and location of study (enrolment limited to the United States vs. enrolment in multiple countries).…”

Response rates and minimal residual disease outcomes as potential surrogates for progression-free survival in newly diagnosed multiple myeloma

“…In an SLR of endpoints used in MM RCTs by Mohyuddin et al (2021), only 10 out of 76 (13.2%) phase 3 studies in the NDMM setting employed OS as a primary endpoint; PFS was the most common primary endpoint [ 38 ]. Response rate was the most commonly used primary endpoint in identified phase 2 studies [ 38 ].…”

“…In an SLR of endpoints used in MM RCTs by Mohyuddin et al (2021), only 10 out of 76 (13.2%) phase 3 studies in the NDMM setting employed OS as a primary endpoint; PFS was the most common primary endpoint [ 38 ]. Response rate was the most commonly used primary endpoint in identified phase 2 studies [ 38 ]. Because of the extended PFS observed in studies of patients with NDMM, a requirement for mature PFS data places a substantial burden on patients who are awaiting access to new therapies.…”