# APBA Kısa Özet

This systematic review examined 41 phase III randomized controlled trials of multiple myeloma (MM) published between 2015 and 2025, encompassing a total of 20,144 participants. The study evaluated the role of cardiovascular disease (CVD) and light chain (AL) amyloidosis in trial eligibility criteria, screening practices, and event reporting. The findings reveal a significant gap in the systematic assessment of these conditions, which are important causes of morbidity and mortality in MM patients and may be affected by MM therapies. The review highlights that while exclusion criteria for CVD and amyloidosis are prevalent, the methods for identifying these conditions are largely absent, limiting the ability to interpret cardiovascular safety signals from trial data.

# Çalışma neyi araştırdı?

The primary objective of this systematic review was to examine phase III multiple myeloma trials with respect to: (i) the presence and nature of cardiovascular disease and amyloidosis eligibility criteria; (ii) whether active screening for amyloidosis or assessment of cardiac involvement was performed; (iii) the reporting of baseline cardiovascular characteristics; and (iv) the methods used for reporting cardiovascular adverse events (CVAEs). The impetus for this review was the recognition that MM therapies can have cardiovascular effects, and that both CVD and AL amyloidosis are significant contributors to patient outcomes, yet their representation in trial design and reporting remains uncertain.

# Yöntem

  • Arama stratejisi: A comprehensive search was conducted across MEDLINE, Embase, and the Cochrane Library for publications from 2015 to 2025. The search strategy was designed to identify phase III randomized controlled trials of multiple myeloma drug therapies.
  • Seçim kriterleri: Eligible studies were required to be published in English, involve adults aged ≥18 years with multiple myeloma, and include ≥100 patients per treatment group. Non-randomised, subgroup analyses, and abstract-only reports were excluded to ensure a focus on robust phase III evidence.
  • Veri toplama ve analiz: Data extraction focused on eligibility criteria related to CVD and amyloidosis, screening practices, baseline cardiovascular characteristics, and the reporting of cardiovascular adverse events. The review adhered to PRISMA guidelines for systematic reviews, ensuring transparency and methodological rigor in the selection and synthesis of evidence.

# Temel bulgular

The synthesis of data from 41 included trials revealed several consistent patterns:

  • Trial volume: A total of 41 phase III MM trials were included, enrolling a combined total of 20,144 participants.
  • Cardiovascular exclusion criteria: At least one cardiovascular exclusion criterion was present in 98% of the included trials (40/41). The most frequently encountered criteria were heart failure and recent myocardial infarction.
  • Amyloidosis exclusion criteria: Amyloidosis was listed as an exclusion criterion in 30 of the 41 trials (approximately 73%). However, the definitions used for amyloidosis exclusion were predominantly non-specific, often lacking the rigor required to accurately identify cardiac amyloidosis.
  • Screening and assessment: A critical finding was that no trial reported active screening for amyloidosis or systematic assessment of cardiac involvement. This means that the true prevalence of cardiac amyloidosis within these trial populations could not be determined.
  • Baseline cardiovascular data: Baseline cardiovascular characteristics were reported in only a single one of the 41 included trials. This paucity of baseline data limits the ability to characterize the cardiovascular risk profile of the trial populations.
  • Cardiovascular adverse event reporting: Cardiovascular adverse events were almost universally investigator-reported. Crucially, these events were inconsistently defined across trials and were not centrally adjudicated by an independent committee. This lack of standardization and independent verification limits the comparability of safety data across different trials.

# Bulgular ne anlama geliyor?

The collective findings of this review paint a picture of trial designs that include broad exclusion criteria for cardiovascular disease and amyloidosis, yet fail to implement the necessary screening and reporting mechanisms to accurately capture these conditions. The implications are significant:

  • Underestimation of prevalence: Because there was no active screening, the true prevalence of cardiac amyloidosis and other cardiovascular diseases within the trial populations remains unknown and likely underestimated.
  • Challenges in safety interpretation: The inconsistent definition and lack of central adjudication of cardiovascular adverse events make it difficult to compare cardiovascular safety signals across different MM therapies.
  • Impact on clinical generalizability: The lack of baseline cardiovascular data and screening means that the results of these pivotal phase III trials may not fully reflect the cardiovascular risk profile of the broader multiple myeloma patient population seen in clinical practice.
  • Regulatory and clinical implications: The current trial design limitations hinder the ability to make definitive statements about the cardiovascular safety of specific MM agents and complicate the development of risk-stratified treatment approaches.

# Klinik önem

The clinical implications of these findings are profound and warrant attention from clinicians, researchers, and regulators alike:

  • Patient risk assessment: Clinicians treating multiple myeloma patients should have a high index of suspicion for underlying cardiovascular disease and amyloidosis. Given that trial exclusion criteria are common but screening is absent, real-world patients may possess risk factors that were systematically excluded from or not captured by pivotal trials.
  • Trial design recommendations: Future phase III multiple myeloma studies should incorporate routine baseline cardiovascular screening into their protocols. This could include electrocardiograms (ECGs), echocardiograms, cardiac magnetic resonance imaging (MRI) where appropriate, and serum free light chain measurements to aid in the detection of amyloidosis. Furthermore, these baseline characteristics should be systematically reported.
  • Standardized adverse event reporting: There is an urgent need for standardized definitions of cardiovascular adverse events and the establishment of independent adjudication committees. Central adjudication would provide a more reliable and comparable dataset on cardiovascular safety, enabling meaningful meta-analyses across trials.
  • Regulatory guidance: Regulatory bodies could consider issuing guidance on the recommended inclusion of cardiovascular screening and standardized adverse event reporting in phase III oncology trials, particularly for therapies with known cardiovascular effects.

# Sınırlılıklar

The authors acknowledge several limitations inherent to this systematic review that affect the generalizability and precision of the conclusions:

  • Dil ve yayın seçimi: The review was restricted to publications in English. This language restriction introduces a potential selection bias, as it excludes trials published in other languages that may have different eligibility criteria or reporting practices.
  • Tanım farklılıkları: The variability in how amyloidosis exclusion criteria were defined across the included trials means that the actual rate of exclusion may differ from the reported 73%. Non-specific definitions likely resulted in some patients with cardiac amyloidosis being included, while others may have been excluded based on imprecise criteria.
  • Veri eksikliği: The absence of active screening procedures and the paucity of reported baseline cardiovascular data mean that the review could not determine the actual prevalence of cardiac amyloidosis or other cardiovascular diseases within the included trials. This is a major limitation for drawing firm conclusions about the true burden of these conditions in the trial populations.
  • Raporlama tutarsızlığı: The reliance on investigator-reported cardiovascular adverse events without central adjudication introduces the risk of inconsistency. Different investigators may apply different thresholds or definitions for what constitutes a cardiovascular adverse event, potentially leading to under-reporting or over-reporting across trials.
  • Zaman aralığı: The study period of 2015 to 2025, while comprehensive, may not capture the most recent evolutions in trial design, cardiovascular screening technologies, or updated regulatory guidance that has emerged towards the end of the period.

APBA’s commentary on these findings: The current evidence base indicates that phase III multiple myeloma trials systematically overlook the systematic screening and assessment of cardiovascular disease and amyloidosis. This gap creates a blind spot in our understanding of cardiovascular safety signals for emerging MM therapies. However, it is important to note that this review is based solely on reported exclusion criteria and existing data presentation; it does not necessarily reflect all screening practices occurring in clinical trial sites. Future research protocols that integrate active cardiac screening and central event adjudication will be essential for improving the quality of clinical evidence and supporting more informed clinical decision-making in the management of multiple myeloma.