Case study | Practical management of cardiovascular events in carfilzomib therapy in RRMM

Patients with Multiple Myeloma (MM) have a higher incidence of cardiovascular comorbidities due to treatment- and disease- related side effects and complications. Proteasome inhibitors, such as bortezomib and carfilzomib, that are commonly used to treat MM have a documented association with cardiovascular-specific toxicity. 

Results from a recent head-to-head ENDEAVOR study showed superiority of carfilzomib with dexamethasone (Kd) versus bortezomib with dexamethasone in overall survival in patients with RRMM, which was reported in a previous MM Hub article. The use of proteasome inhibitors (PI) in MM is considered to be effective and tolerable, so it is necessary to assess the management of cardiovascular events that arise from therapy.

Two MM case studies were published in Hematology by Ajdrzej Jakubowiak from The University of Chicago Medicine, USA, and colleagues. The case studies assessed patients with cardiovascular events during carfilzomib therapy, with recommendations based on the outcomes.

 Key Highlights Case Study 1:

• An African-American female (68-years old) was diagnosed with immunoglobulin G kappa MM, Durie-Salmon stage IIA, in 2012
• The patient had a history of hypertension and stage II chronic kidney disease (creatine 1.1 mg/dL)
• At second relapse, the patient was treated with Kd: 20 mg/m² carfilzomib intravenously (IV) titrated to 56 mg/m² IV twice-weekly with dexamethasone 20 mg orally
• A baseline cardiovascular evaluation was taken and shown to be normal
• Twelve hours after receiving an initial dose on day 2 of cycle 2, the patient was sent to the ER with acute onset dyspnea, orthopnea and hypoxemia
• She was consequently diagnosed with acute congestive cardiac failure
• The next carfilzomib dose was held and the patient was diuresed with IV Lasix^® (40 mg twice-daily) and administered IV nitroglycerin (5 mcg/min initially before being up-titrated to 10 mcg/min)
• Following this she was given oral Lasix (40 mg daily) and an angiotensin converting enzyme inhibitor (enalapril 2.5 mg twice daily; up-titrated to 5 mg twice-daily) along with a beta-blocker (carvedilol 3.125 mg twice-daily, up-titrated to 6.25 mg twice-daily).
• After successful intervention and left heart catheterization and a coronary angiography, her symptoms improved
• Carfilzomib was restarted at a reduce dose of 45 mg/m² twice-weekly and she continued therapy for 16 months until discontinuation due to disease progression

Key Highlights Case Study 2:

• 70-year-old white male diagnosed with IgA kappa MM, Internal Staging System stage III, 2013
• The patient had a history of peripheral neuropathy, stage III chronic renal insufficiency and hypertension
• He began Kd treatment as second-line therapy: 20 mg/m² IV and oral dexamethasone 20 mg which was increased to 56 mg/m² on day 8 of cycle 1 on a twice-weekly schedule
• On day 9 of cycle 1, after infusion, patient had raised creatinine (2.48 mg/dL) and BUN to 69 mg/dL
• On day 12 of cycle 1, the patient was admitted to hospital with acute renal failure, nausea, vomiting and dizziness and increased blood pressure
• The patient was given hydrated with normal saline, followed by a single dose of IV furosemide 40 mg; carfilzomib doses on days 15 and 16 of cycle 1 were stopped
• Amlodipine dose was increased to 10 mg daily, losartan was discontinued, metoprolol succinate was administered at 25 mg daily and increased to 50 mg daily
• Symptoms improved and creatinine levels dropped to 1.68 mg/dL and blood pressure to140/84 mmHg
• on day 1 of cycle 2mHg
•   mg/dL.s  drugs seem to pose.he question is whether the value added not beneficial in MMsk too great to
• Treatment was restarted with carfilzomib 45 mg/m² twice-weekly on day 1 of cycle 2
• The patient continues to receive treatment with stable hemodynamics and is currently in complete remission after 11 cycles

Conclusion

Since cardiovascular events are associated with carfilzomib treatment, a baseline cardiovascular risk assessment should be performed before starting therapy. If the patient has a history of hypertension, this should be controlled prior to therapy initiation. Patients with a history of major cardiovascular events have a higher risk of complications and should be more closely monitored during treatment. Hydration is a standard requirement prior to treatment and this should be re-evaluated and determined based on the needs of the patient. Generally, monitoring and early intervention with any arising cardiovascular events should prevent complications escalating unnecessarily. Finally, the authors noted that patient education was key - increasing patient awareness of signs and symptoms of cardiovascular events would lead to quicker intervention times. 

Abstract

Objectives and importance: Patients with multiple myeloma (MM) have an increased risk of cardiovascular comorbidities due to disease burden and treatment-related risk factors. Proteasome inhibitors, including bortezomib and carfilzomib, are effective and generally well tolerated anti-MM agents. However, cardiovascular-related toxicities have been reported with this class of agents, the mechanisms of which are not fully understood. We discuss the practical management of cardiovascular events during carfilzomib therapy for relapsed MM.

Clinical presentation: We present two adapted cases of treatment-emergent cardiovascular events in patients receiving an approved regimen of carfilzomib for the treatment of relapsed MM. These cases are reflective of clinical practice at the University of Chicago Medicine.

Intervention: Using the two adapted cases, we discuss and illustrate practical approaches for management of cardiovascular events during carfilzomib therapy, including baseline cardiac risk assessment, hydration, cardiovascular monitoring, and interventions for patients with suspected cardiovascular signs or symptoms, and patient education.

Conclusion: Carfilzomib has favorable benefit-risk profile in MM; adopting proactive practices can assist in the prevention, early detection, and management of carfilzomib-associated cardiovascular events, which may allow for continuation of therapy with this effective agent.