What are the cardiovascular manifestations and complications associated with multiple myeloma, including disease‑related, treatment‑related, and metabolic effects?

Cardiovascular Manifestations and Complications of Multiple Myeloma

Multiple myeloma causes cardiovascular complications in approximately 7.5% of patients through three primary mechanisms: direct disease effects (cardiac amyloidosis), treatment-related toxicity (particularly from proteasome inhibitors and immunomodulatory drugs), and exacerbation of pre-existing cardiovascular risk factors in this predominantly elderly population. 1, 2

Disease-Related Cardiovascular Manifestations

Cardiac Amyloidosis

• Up to 15% of multiple myeloma patients develop systemic amyloidosis with cardiac involvement, where prognosis is directly determined by the extent of cardiac deposition 2
• Direct amyloid protein deposition in the heart causes restrictive cardiomyopathy and conduction abnormalities 3

Metabolic and Hematologic Effects

• Renal impairment, anemia, and hyperviscosity from the disease itself exacerbate underlying cardiovascular risk factors 2
• These disease-related factors compound cardiovascular stress, particularly in elderly patients who already have baseline cardiovascular disease 3

Treatment-Related Cardiovascular Toxicity

Proteasome Inhibitors (Particularly Carfilzomib)

Carfilzomib carries the highest cardiovascular risk among proteasome inhibitors, with an odds ratio of 2.68 for high-grade cardiac toxicity and a relative risk of 2.2 for grade ≥3 cardiovascular adverse events compared to controls. 4, 1

Specific Carfilzomib-Related Events:

• Hypertension: all grades 12.2–16%, grade ≥3: 4.3–9% 4
• Heart failure: all grades 3–6.4%, grade ≥3: 2.5–4.8% 4
• Ischemic heart disease: all grades 0.9–5.9%, grade ≥3: 0.8–3.3% 4
• Dyspnea: 23.9% all grades 4

Carfilzomib Monitoring Requirements:

• Pre-treatment: Comprehensive cardiovascular evaluation including ECG and echocardiography to identify patients at high risk for cardiovascular adverse events 4, 2
• During treatment: Accurate blood pressure monitoring and surveillance for early signs of cardiac dysfunction to prevent treatment interruptions 4
• High-risk features: Age >65 years, prior atrial fibrillation, antiplatelet use, and higher-grade cytokine release syndrome predict in-hospital cardiovascular events 5

Immunomodulatory Drugs (Lenalidomide, Thalidomide, Pomalidomide)

Immunomodulatory drugs carry an odds ratio of approximately 2.0 for high-grade cardiac toxicity, with thromboembolism being the predominant concern. 1

Thromboembolic Complications:

• Both venous and arterial thromboembolism occur at high rates with immunomodulatory agents 6
• Mandatory thromboprophylaxis is now a standard recommendation for all patients receiving immunomodulatory drugs 2
• Peripheral neuropathy from these agents (stocking-glove distribution) does not represent CNS involvement and should be distinguished from central complications 7

Other Novel Therapies

CAR-T Cell Therapy:

• In-hospital cardiovascular events occur in 11.7% of multiple myeloma patients receiving CAR-T therapy, with median onset at 8 days post-infusion 5
• Most common in-hospital events: atrial arrhythmias (5.5%) and new left ventricular dysfunction (3.9%), with 90% of LV dysfunction cases showing functional recovery 5
• Critical distinction: In-hospital cardiovascular events are relatively uncommon, reversible, and not linked to mortality, whereas post-discharge cardiovascular events (7.8%, median 13 months) predict worse survival 5

Comprehensive Cardiovascular Management Algorithm

Baseline Risk Stratification (Before Treatment Initiation)

• Mandatory baseline assessment: ECG and echocardiography for all patients 2
• Identify high-risk patients: Pre-existing cardiovascular disease, age >65 years, hypertension, prior atrial fibrillation, renal impairment 4, 5
• Cardiac amyloidosis screening: Consider advanced imaging (cardiac MRI) if clinical suspicion exists 3

During Active Treatment

• Blood pressure monitoring: Frequent and accurate monitoring, particularly with carfilzomib 4
• Surveillance for heart failure: Serial assessment for dyspnea, edema, and early signs of cardiac dysfunction to detect changes before overt heart failure develops 6
• Arrhythmia monitoring: Drug interactions play a significant role; review QT-prolonging medications 1
• Thromboprophylaxis: Administer to all patients on immunomodulatory drugs 2

Post-Treatment Surveillance

• Long-term monitoring: Post-discharge cardiovascular events, though rare, are associated with higher mortality and warrant continued surveillance 5
• Multidisciplinary collaboration: Close coordination between hematology and cardiology is critical for optimal outcomes 8, 2

Common Pitfalls and Caveats

• Do not delay cardiovascular evaluation: Comprehensive cardiac assessment before starting carfilzomib is essential, as early detection allows for treatment modifications without compromising anti-myeloma efficacy 4
• Distinguish peripheral from central neuropathy: Proteasome inhibitor-induced peripheral neuropathy (length-dependent, stocking-glove pattern) is not CNS involvement 7
• Treatment discontinuation decisions: These should occur in a multidisciplinary setting, weighing complication severity, prognosis, expected benefits, and availability of effective alternatives 2
• Recovery potential: Most carfilzomib-related cardiac dysfunction and CAR-T-related LV dysfunction are reversible with prompt intervention 4, 5