Cardiovascular Toxicity after Carfilzomib, Lenalidomide, and Dexamethasone Combination Chemotherapy in the Real-World 364 Asian Multiple Myeloma Patients on Behalf of the Korean Multiple Myeloma Working Party (KMM2201 study)
Authors: Lee Ji Hyun , Min Chang-Ki , Jo Jae-Cheol , Lee Yoo Jin , Kim Jin Seok , Uhm Hyun-Seok , Jung Jong Heon , Moon Joon Ho , Cho Hee Jeong , Lee Myung-won , Yoon Sung-Soo , Byun Ja Min , Lee Jae Hoon , Lee Je-Jung , Jung Sung-Hoon , Shin Ho-Jin , Kim Do Young , Yi Jun Ho , Lee Seung-Shin , Do Young Rok , Yoon Dok Hyun , Cho Hyungwoo , Lee Won-Sik , Lee Ho Sup , Uhm Jieun , Kim Hyo Jung , Jang Hee Ryeong , Kim Sung-Hyun , Kim Kihyun 
Published: December 2023

Background: Carfilzomib, a selective and irreversible epoxyketone proteasome inhibitor (PI), in combination with lenalidomide and dexamethasone (KRd) significantly improved the survival of relapsed and/or refractory multiple myeloma (RRMM) patients as well as newly diagnosed MM patients.
The major dose-limiting toxicity of carfilzomib, cardiovascular adverse events (CVAE), have been reported in a variety of studies, which necessitates cautious risk management for patients who are treated with carfilzomib-based combination regimen. By far, the incidence and risk factors, as well as the outcome of CVAE in a large cohort of Asian patients after KRd regimen is lacking.
Patient and method: Retrospective data of 364 RRMM patients who have received KRd regimen for RRMM in 21 centers participating in the Korean multiple myeloma working party (KMMWP) between February, 2018 and October, 2020, was analyzed. 41% of the patient was trial-ineligible, which was defined by patient-, disease-, and treatment-related features that were insufficient to meet the eligibility criteria for ASPIRE trial. CVAE was defined by dyspnea, hypertension (HTN), congestive heart failure (CHF), ischemic heart disease (IHD), arrhythmias, and venous thromboembolism (VTE). Time to onset of CVAE was defined by the first date of KRd therapy to the onset date of first CVAE.
Results: The median age was 63 years (range, 28-85). CVAEs were observed in 16% of total analyzed patients after a median 9 months (range, 0-36 months) of KRd treatment, among which 3 patients (1%) showed fatal CVAEs. More specifically, dyspnea, HTN, CHF, IHD, arrhythmias, and VTE occurred in 11%, 3%, 3%, 1%, 2%, and 3% of the patients after a median of 9, 21, 16, 31, 8, and 16 months after KRd therapy. CVAE resulted in dose reduction and discontinuation of carfilzomib in 13 (4%) and 14 patients (4%), respectively. 5 patients (1%) discontinued KRd treatment due to any CVAE. By univariate analysis, among the factors affecting the cardiovascular events, such as age ≥75 years, ECOG performance status ≥ 3, creatinine clearance &lt; 30 ml/min, Hb &lt; 8g/dL, diabetes mellitus, HTN, underlying heart disease, cerebrovascular disease, prior bortezomib, thalidomide, doxorubicin, and cyclophosphamide therapy, and autologous stem cell transplantation, HTN was the only factor that significantly affected the occurrence of CVAEs after KRd therapy (odds ratio 1.877, 95% confidence interval, 1.025-3.440, P=0.041). CVAEs after KRd regimen did not affect progression-free or overall survival in the study cohort (Figure1A, and 1B).
Conclusion: The incidence of CVAE after KRd therapy in this large cohort of real-world Asian RRMM patients was comparable with previous prospective and retrospective studies. Cardiovascular event after carfilzomib-based regimen did not affect progression-free or overall survival in RRMM patients. The recognition and management of underlying HTN has the utmost importance amongst the CV risk factors to mitigate CVAE in the Asian RRMM patients treated with KRd regimen.
Acknowledgement
This study would not have been possible without the collaboration of the Korean multiple myeloma working party. We especially thank the patients, families, caregivers who participated in this study. This work was supported by Amgen.