Minimizing Terms for Toxicity Often Used in Multiple Myeloma Trials, Study Says

A study published in JAMA Network Open found that clinical trials in multiple myeloma regularly use minimizing language to describe adverse events (AEs). The use of such terminology may not reflect actual AE rates, and investigators should instead highlight AE rates and patient-reported outcomes (PROs) instead to allow clinicians and patients to evaluate tolerability, according to the authors.

While there has been significant progress in the treatment of multiple myeloma, relapse remains common, and patients usually require ongoing, long-term treatment to manage the disease. Multiple myeloma therapies can carry substantial toxicity profiles that can negatively impact quality of life, and these toxicities become increasingly important given the long-term maintenance therapy that is often needed in this patient population.

Patient in the hospital | Image credit: Tyler Olson -stock.adobe.com

The authors noted that efficacy and safety are usually reported in peer-reviewed articles and at scientific meetings, but that efficacy is often assessed preliminarily in single-group, phase 2 trials. The way these trials are reported is crucial, as is the ability to accurately compare and understand the safety profiles from the patient decision-making perspective as more therapies become available. Researchers added that PROs are the best gauge of whether a therapy’s AE profile is tolerable from the patient standpoint.

“Clinical trial investigators may increasingly use phrases that seek to minimize toxic effects, which we refer to as minimizing terms, when reporting clinical trial safety results. Terms such as tolerable, manageable, and safe may be used in a subjective fashion that may not reflect the actual toxic effects of these interventions,” the authors wrote. “In the absence of PROs, minimizing terms also may not reflect patient perceptions of whether these side effects are indeed tolerable or manageable.”

To the authors’ knowledge, their analysis is the first to assess the use of minimizing terms in a cohort or randomized clinical trials (RCTs). The study included 65 RCTs published from 2015 through early 2023 and aimed to determine the prevalence of minimizing terms as well as the characteristics of the trials that used them.

A total of 56 studies in the cohort (86%) used minimizing terms, with the most common being “well-tolerated” or “tolerable,” which were seen in 29 trials (45%). Further, trials often used “manageable” (28%), “acceptable” (25%), “expected” (23%), “safe” (23%), “favorable” (17%), and “convenient” (14%).

In terms of specific toxicities vs general safety profiles, 44 (78%) of the trials used at least 1 minimizing term to refer to the toxicity profile in general, 11 (20%) described both the general toxicity and a specific toxic effect with minimizing terms, and just 1 trial (2%) used minimizing language to describe a specific toxic effect alone.

The rate of serious adverse events (SAEs) among 38 trials that reported SAEs ranged from 19% to 66%, with a median of 48% (IQR, 35%-56%). In 33 of those trials, at least 1 minimizing term was used (median SAE rate, 48% [IQR, 34%-55%]). In 5 trials (13%), no minimizing terms were used (median SAE rate, 47% [IQR, 45%-63%]).

The rates of grade 3 or 4 AEs ranged from 23% to 94% in 37 trials that reported the overall frequency of grade 3 or 4 AEs. The median frequency of grade 3 or 4 AEs was 75% (IQR, 59%-82%), and 31 of these trials (84%) used at least 1 minimizing term (median grade 3 or 4 AE rate, 75% [IQR, 63%-82%]). Among the trials reporting grade 3 or 4 AEs, 6 (16%) did not use minimizing language (median grade 3 or 4 AE rate, 57% [IQR, 36%-78%]).

In a univariate analysis, there was no statistically significant association between the use of minimizing terminology and the rate of grade 3 or 4 AEs (OR, 1.35 per 10% AE rate increase; 95% CI, 0.88-2.10; P = .17). There was also no statistically significant association between the rate of grade 5, or fatal, AEs, and minimizing language use. An association was seen between the use of at least 1 minimizing term and whether a trial was industry sponsored, however (OR, 5.68; 95% CI, 1.05-41.0; P  = .03).

The study was limited in that it only analyzed RCTs, with authors noting that the use of minimizing terms may be more common in early-phase trials or conference presentations, which should also be evaluated. The statistical power of the analysis was also limited because many studies did not report SAE rates or total grade 3 or 4 AE rates.

“In this cohort study, we observed that trial investigators and sponsors regularly used minimizing terms to describe toxic effects in MM trials, especially in industry-sponsored studies, and this descriptive terminology did not reflect the actual rates of severe AEs or deaths in these trials,” the authors concluded. “Instead of using these terms, trial investigators should highlight event rates and PROs to allow clinicians and patients to better evaluate the true tolerability of AEs.”

Reference

Najjar M, McCarron J, Cliff ERS, et al. Adverse event reporting in randomized clinical trials for multiple myeloma. JAMA Netw Open. Published online November 10, 2023. doi:10.1001/jamanetworkopen.2023.42195