Could Patients with Multiple Myeloma (MM) Derive Additional Benefit from Their Treatments? Real-World Evidence for Carfilzomib Dosing Intensity on Survival and Treatment Progression
Authors: Medhekar Rohan , Hines Dionne , Panjabi Sumeet , Welliver Tim , Wang Xin , Wade Rolin L. 
Published: October 2019

Abstract
Introduction: Carfilzomib (K) was first approved in 2012 for the treatment of relapsed/refractory multiple myeloma (RRMM) at a dose of 27 mg/m2 twice weekly (27 BIW). The K dose has since been optimized; carfilzomib plus dexamethasone (Kd) is approved for patients with RRMM at a recommended K dose of 56 mg/m2 twice weekly (56 BIW) since 2016. Recently, the A.R.R.O.W trial showed that Kd 70mg/m2 once weekly (70 QW) significantly improved progression free survival compared to Kd 27 BIW. Considering the study time-period, however, patients are still treated with 27 BIW in the real-world leaving them possibly under-treated. The Kd 27 BIW, corresponds to a cumulative weekly dose (CWD) of K <120mg, while both Kd 56 BIW and Kd 70 QW (optimized dose-56 BIW/70 QW) correspond to a CWD of K >120mg. Therefore, in order to understand the relationship between dose and outcomes we examined the impact of K-dosing (CWD >120mg [optimized dose-56 BIW/70 QW] vs. CWD ≤120 mg [27 BIW]) on time to next treatment (TTNT) and overall survival (OS) among patients treated with Kd regimen.
Methods: IQVIA's Oncology Electronic Medical Records database was used to identify patients ≥18 years of age, with a diagnosis of MM between 1/1/2010 and 10/31/2017, receiving Kd regimen in any line of therapy, with ≥ 3 doses of K on or after their K-index date (first administration of K in the Kd regimen, between 1/1/2013 and 10/31/2017). Patients were required to have ≥ 3 doses of K in order to establish continuity and for calculating CWD. CWD was calculated as the cumulative sum of weekly dose of K received by the patient divided by the number of weeks with Kd administration. The first two K doses were excluded from the calculation of CWD as these represent the loading dose. OS and TTNT were compared between patients receiving optimized dose-56 BIW/70 QW vs. 27 BIW. OS was evaluated among the subset of patients with a recorded deceased or alive status and measured from the K-index date until death due to any cause or the end of the study period, where they were censored. TTNT was defined as the time from initiation of the Kd regimen until the start of a subsequent regimen that did not contain Kd (treatment progression). Additionally, a landmark analysis at 12 months from initiation of Kd regimen was conducted to measure the proportion of patients alive and the proportion of patients with treatment progression. Kaplan-Meier analysis was used to estimate OS and TTNT and the log-rank test was used to compare the groups. Adjusted hazard ratios for OS and TTNT were evaluated using Cox models.
Results : A total of 1,469 eligible MM patients with ≥3 Kd administrations were identified, of which 129 (8.8%; mean age: 63.5, SD: 9.8) received optimized dose-56 BIW/70 QW and 1,340 (91.2%; mean age: 67.0, SD: 10.4) received 27 BIW. The median follow-up time was slightly over a year for patients in both cohorts. The median K dose was 147.0 mg among patients in optimized dose-56 BIW/70 QW group and 88.1 mg among patients in 27 BIW group. Median OS was not estimable (NE), however, OS for the optimized dose-56 BIW/70 QW group (n=78) was significantly longer than that of the 27 BIW group (n=771; p=0.002) (Fig. 1). The proportion of patients in optimized dose-56 BIW/70 QW group alive at 12 months was 90.3% compared to 79.7% for patients in 27 BIW group respectively. Covariate-adjusted cox model showed that patients in optimized dose-56 BIW/70 QW group had a 64% lower risk of death than patients in 27 BIW group (adjusted HR: 0.364; 95% CI: 0.178-0.745; p = 0.0057, Table 1). TTNT was significantly longer for patients in optimized dose-56 BIW/70 QW group compared to patients in 27 BIW group (p=0.023; median TTNT: 17.5 [95% CI: 14.8-NE] and 13.2, [95% CI: 12.4-14.4], respectively) (Fig. 2). Covariate-adjusted cox model showed that patients in optimized dose-56 BIW/70 QW group had a 33% lower risk of treatment progression than patients in 27 BIW group (adjusted HR: 0.669; 95% CI: 0.483-0.927; p=0.0155, Table 1).
Conclusion: Among patients treated with Kd regimen, a smaller proportion were prescribed K at optimized dose-56 BIW/70 QW. Patients receiving the optimized dose-56 BIW/70 QW had significantly improved OS and TTNT compared to those receiving 27 BIW. Our findings suggest that these patient-relevant outcomes may be improved in a vast majority of RRMM patients currently under-treated with carfilzomib by optimizing the dose, taking into consideration patients' comorbidities and ability to tolerate therapy.

Disclosures
Medhekar: Amgen: Employment, Equity Ownership. Hines:Amgen: Consultancy. Panjabi:Amgen: Employment, Equity Ownership. Welliver:Amgen: Employment, Equity Ownership. Wang:Amgen: Consultancy. Wade:Amgen: Consultancy.