Cardiovascular disease and amyloidosis in phase III multiple myeloma trials: a systematic review of eligibility, screening and event reporting

Background: Cardiovascular disease (CVD) and light chain (AL) amyloidosis are important causes of morbidity and mortality in patients with multiple myeloma (MM). Additionally, MM therapies can have cardiovascular effects. However, the extent to which phase III MM trials account for underlying CVD and amyloidosis through eligibility criteria, screening and reporting remains uncertain. These elements of trial design and reporting are essential for accurate interpretation of cardiovascular safety signals.

Objectives: To examine practice-changing MM trials with respect to amyloidosis and CVD eligibility criteria, assessment for cardiac amyloidosis, reporting of baseline cardiovascular characteristics and cardiovascular adverse events (CVAE).

Methods: Systematic review of phase III randomised controlled trials of MM drug therapies published in English between 2015 and 2025, identified by searching MEDLINE, Embase and Cochrane Library. Eligible trials enrolled adults aged ≥18 years with MM and included ≥100 patients per treatment group; non-randomised, subgroup and abstract-only reports were excluded.

Results: 41 trials enrolling 20 144 participants were included. Amyloidosis was an exclusion criterion in 30 trials typically using non-specific definitions. No trial reported active screening for amyloidosis or assessment of cardiac involvement. Baseline cardiovascular investigations were common but were not used to identify cardiac amyloidosis. At least one cardiovascular exclusion criterion was present in 98% of trials, most commonly heart failure and recent myocardial infarction. Baseline cardiovascular characteristics were reported in only one trial. CVAEs were investigator-reported, inconsistently defined and not centrally adjudicated.

Conclusions: Phase III MM trials frequently incorporate amyloidosis and CVD exclusion criteria. However, the prevalence of cardiac amyloidosis and other CVD 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.

PROSPERO registration number: CRD420251125097.