Representation, characterisation and reporting of amyloidosis and cardiovascular disease in phase III multiple myeloma trials
O Henriques Peck, A Mccoubrey, J Travers, J Lees, M Petrie, N LangAbstract
Background
Cardiovascular disease and AL amyloidosis are major drivers of morbidity and mortality in multiple myeloma (MM), with cardiac AL amyloidosis a key determinant of prognosis. Furthermore, MM therapies can cause cardiovascular toxicity. Trials often aim to exclude patients with amyloidosis but specific screening for this may be sub-optimal. Heterogeneity in representation, characterisation and reporting of cardiac amyloidosis and cardiovascular disease may mask cardiovascular safety and efficacy signals in MM trials.
Purpose
To examine phase III MM trials with respect to: (1) eligibility criteria relating to cardiac amyloidosis and non-amyloid cardiovascular disease; (2) presence or absence of active screening for cardiac amyloidosis; (3) reporting of participant baseline cardiovascular characteristics; and (4) cardiovascular adverse events (CVAE) reporting.
Methods
We conducted a systematic review of phase III randomised MM drug trials published between 2015 and 2025, evaluating eligibility criteria related to amyloidosis and cardiovascular disease, screening methods for cardiac amyloidosis, reporting of baseline cardiovascular characteristics and CVAEs.
Results
Forty-one trials enrolling 20,144 participants were included. Amyloidosis was an exclusion criterion in thirty trials (14818 participants, 74%) but usually using non-specific definitions. No trials reported active screening for amyloidosis and none specified how cardiac involvement was assessed. Protocol-mandated screening or baseline cardiovascular investigations that might identify markers of cardiac amyloidosis were frequent (30 trials; 14941 participants; 74%). However, these were not specifically used for the purpose of amyloidosis identification. Electrocardiography was used in 74% of trials, echocardiography in 24%, cardiac magnetic resonance imaging in 2% and cardiac biomarkers in 5%. At least one cardiovascular disease exclusion criterion featured in 92% of trials, most commonly ‘heart failure’ (89%; defined as NYHA ≥III or LVEF <40%) and ‘recent myocardial infarction or unstable angina’ (87%). Baseline cardiovascular characteristics were reported in only one trial. Cardiovascular adverse events were investigator-reported using inconsistent methods and with no central adjudication.
Conclusions
Phase III MM trials frequently incorporate amyloidosis and cardiovascular disease exclusion criteria. However, the prevalence of participants with cardiac amyloidosis and other cardiovascular disease within these practice-changing MM trials remains poorly defined and CVAE reporting remains suboptimal. These limitations may bias safety and efficacy outcomes and reduce trial generalisability.Central Illustration Amyloidosis Exclusion from MM Trials