What is the recommended management of heart failure in a patient receiving daratumumab?

Management of Heart Failure in Patients Receiving Daratumumab

Continue daratumumab while initiating standard guideline-directed medical therapy (GDMT) for heart failure, as daratumumab itself does not require discontinuation for cardiac dysfunction and may actually provide cardioprotective effects when combined with certain myeloma therapies.

Understanding Daratumumab's Cardiac Safety Profile

The FDA label for daratumumab does not list heart failure as a contraindication or require dose modification for cardiac dysfunction 1. While cardiac disorders including atrial fibrillation have been reported, heart failure is not specifically highlighted as a common adverse event in daratumumab monotherapy or combination regimens 1.

Importantly, emerging evidence suggests daratumumab may actually attenuate cardiac dysfunction when used with cardiotoxic agents like carfilzomib. A prospective study demonstrated that patients receiving daratumumab with carfilzomib and dexamethasone (DaraKd) maintained preserved cardiac systolic function, while those on carfilzomib-dexamethasone alone showed significant deterioration in left ventricular ejection fraction and strain parameters 2. Cardiovascular adverse events occurred less frequently with DaraKd (28.6%) versus carfilzomib alone (45%) 2.

Heart Failure Management Algorithm

Step 1: Initiate Standard GDMT Immediately

Regardless of daratumumab therapy, treat heart failure according to ejection fraction:

For HF with reduced ejection fraction (HFrEF, LVEF ≤40%):

• ACE inhibitors or ARBs (if ACE-I intolerant): Start low dose and titrate up every 1-2 weeks 3, 4
  • Examples: Enalapril 2.5 mg daily → 20 mg daily; Lisinopril 2.5 mg daily → 35 mg daily 5
• Beta-blockers: Initiate once patient is stable without IV inotropes or marked fluid retention 4
  • Start very low dose, double every 1-2 weeks as tolerated 4
• Mineralocorticoid receptor antagonists (spironolactone/eplerenone): For NYHA class II-IV with LVEF ≤35% 3
  • Start 25 mg daily, monitor potassium and creatinine after 4-6 days 4
• SGLT2 inhibitors: First-line therapy for all HFrEF patients 6, 7
• Diuretics: For fluid retention symptoms 3, 4

For HF with mildly reduced or preserved ejection fraction:

• SGLT2 inhibitors as first-line 6, 7
• Diuretics for congestion 3

Step 2: Monitor Cardiac Function During Daratumumab

• Baseline assessment: Obtain echocardiogram with LVEF and strain imaging before starting daratumumab if not already done 8, 9
• During therapy: Monitor for symptoms of worsening heart failure (dyspnea, edema, fatigue)
• Biomarkers: Consider BNP/NT-proBNP and troponin monitoring, particularly if using cardiotoxic combination agents like carfilzomib 8

Step 3: Address Myeloma Treatment-Specific Considerations

If patient is on carfilzomib + daratumumab:

• The combination appears safer than carfilzomib alone from a cardiac standpoint 2
• Continue both agents while optimizing GDMT
• Monitor closely for hypertension (4.3% grade ≥3) and cardiac failure (3.8% grade ≥3) 10

If considering switching from carfilzomib:

• Daratumumab-based regimens without carfilzomib (e.g., daratumumab/lenalidomide/dexamethasone or daratumumab/bortezomib/dexamethasone) are Category 1 preferred options for relapsed/refractory myeloma 10
• These alternatives have lower cardiac toxicity profiles

Step 4: Manage Complications and Comorbidities

Infection prophylaxis (critical with daratumumab):

• Herpes zoster prophylaxis: Mandatory for all patients on daratumumab 11
• Pneumocystis prophylaxis: If on high-dose dexamethasone 11
• Antiviral therapy: Recommended for all antibody-based therapies 11

Monitor for:

• Hepatitis B reactivation (test before starting) 11
• Hypogammaglobulinemia (may require IVIG for recurrent infections) 12

Key Clinical Pitfalls to Avoid

1. Do not discontinue daratumumab solely for heart failure - there is no evidence requiring this, and it may compromise myeloma control
2. Do not delay GDMT initiation - early optimization of heart failure therapy improves outcomes and reduces 30-day readmissions 13
3. Do not overlook infection risk - immunosuppression from both myeloma and therapy increases infection rates (Grade 3-4 infections in 21-37% depending on regimen) 1
4. Do not assume all cardiac symptoms are from daratumumab - evaluate for ischemia, arrhythmias, and other causes

Special Populations

For AL amyloidosis with cardiac involvement:

• Daratumumab has shown rapid responses with good tolerability even in patients with severe heart failure 14, 15
• The combination of daratumumab/pomalidomide/dexamethasone achieved complete hematologic response without paradoxical worsening of heart failure 15
• These ultra-fragile patients may particularly benefit from daratumumab's rapid action and favorable safety profile

Cardiology Referral Indications

Refer to cardiology (preferably cardio-oncology specialist) if 8:

• LVEF drops ≥10% from baseline or falls to <50%
• New or worsening NYHA class III-IV symptoms
• Elevated cardiac troponin without clear alternative cause
• Difficulty optimizing GDMT due to hypotension, renal dysfunction, or hyperkalemia