Step-up titration dosing (TD) of carfilzomib (K) is associated with prolonged duration of therapy and improved treatment outcomes compared to standard dosing (SD) in patients with multiple myeloma (MM).
Authors: Dvorak Kaitlyn , Funderburg Allesia , Zhao Qiuhong , Sharma Nidhi , Cottini Francesca , Bumma Naresh , Devarakonda Srinivas S. , Benson Don M. , Rosko Ashley Elizabeth , Khan Abdullah Mohammad 
Published: June 2022

e20016

Background: K is a 2nd-generation proteasome inhibitor (PI) approved for the treatment of multiple myeloma (MM). K-based regimens are associated with higher rates of CV toxicity compared with other PIs. We conducted a retrospective analysis to assess incidence of CV adverse events (AE) and outcomes of MM patients (pts) treated with K using a step-up TD schedule compared to SD protocol. Methods: A retrospective chart review was performed of MM pts treated with K at The Ohio State University Comprehensive Cancer Center (OSUCCC) from 1/1/13 to 9/1/19. Pt demographics, disease and K-related characteristics, CV AE, and follow-up information were collected. Pts were excluded if treated at both local center and at OSUCCC, not K-naïve when receiving treatment at OSUCCC, received a single dose of K while inpatient with no intent to continue treatment outpatient, or had a treatment plan entered but never received it. Results: Of the 166 pt charts analyzed, 36 were treated using a TD method (ex. step-wise C1D1 20mg/m2, C1D8 27mg/m2, C1D15 36mg/m2, for goal C2D1 56mg/m2 onwards) and 130 pts were treated using a standard dosing method (ex. C1D1 20mg/m2 and C1D8 56mg/m2 onwards). Pre-existing CV risk factors were similar between the two groups. There was a slight difference in baseline renal function (TD: median CrCl 94mL/min, SD: 76mL/min; p=0.01) and prior PI use (TD: 86.1%, SD: 95%; p=0.048) between the two groups. In pts treated with TD, hypertension (HTN) developed earlier compared with SD (p=0.02). There was a lower incidence of onset of dyspnea in the TD group compared to SD group (16.7% vs 36.2%, respectively; p=0.03). There were no differences in incidence of HTN, congestive heart failure, ischemic heart disease, arrythmias, or pulmonary HTN. The median number of cycles administered to titrated pts was 7 (range: 2-56) compared to 3 (range: 1-44) for standard pts (p<0.001). There was no statistical difference in CV AE being the cause for treatment discontinuation between the two groups. The overall response rate (ORR) was higher in the TD group compared to the SD group (63.9% vs 42.8%, respectively; p=0.04). Five-year overall survival (OS) was improved in patients treated with TD than with SD (43.8% vs 17.5%, respectively; p<0.001). By multivariable analysis, TD was associated with improved OS compared to SD (HR 0.47; 95% CI 0.29-0.77-3.58; P=0.003). Conclusions: A simple modification of K titration dosing improved the tolerability of MM therapy without compromising efficacy. Although there were no differences in AE being the cause of treatment discontinuation between the two groups, an improvement in duration of therapy, ORR, and OS was observed in the TD group. As a result, TD is the standard-of-care dosing for MM pts treated with K at the OSUCCC. Prospective trials are needed to confirm the safety and efficacy of this dosing regimen.