Efficacy and Safety of Salvage Therapy Using Carfilzomib for Relapsed or Refractory Multiple Myeloma Patients: A Multicentre Retrospective Observational Study
Authors: Muchtar Eli , Gatt Moshe , Rouvio Ory , Ganzel Chezi , Chubar Evgeni , Suriu Celia , Tadmor Tamar , Shevetz Olga , Lavi Noa , Shochat Tzippy , Cohen Yael C , Avivi Irit , Raanani Pia , Magen Hila 
Published: October 2019

Abstract
Introduction: Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group.
Methods: All consecutive patients with RR-MM who received carfilzomib-containing salvage therapy outside of a clinical trial between March 2013 and April 2015 were included in this study. For the response and survival analyses, patients were included only if they received at least one full cycle of carfilzomib and response evaluation was available. Carfilzomib was used either as a single agent or in combinations with other drugs, according to the treating physician's choice. Per manufacturer's recommendations, carfilzomib was given by intravenous infusion over 10-30 minutes on days 1, 2,8,9,15,16 of 28-days cycle. The recommended dose of carfilzomib was 20 mg/m2 on days 1 and 2 in cycle 1, which was increased on subsequent administrations to 27 mg/m2 (the 20/27 mg/m2 schedule), provided that the previous dose was well tolerated. Doses, however, were modified according to the treating physician's discretion.
Results: One-hundred and thirty-five patients were included. The median age at carfilzomib initiation was 67.9 years (range, 41-88). Male and female patients were equally balanced. Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 was evident in 14.8% of patients. All patients were previously exposed to bortezomib and 93% to lenalidomide as well. The median time from last treatment to carfilzomib was 5.5 months (range, 0.3-43). Patients had received a median of 3 lines of therapy prior to carfilzomib (range, 1-7). The median number of administrated cycles of carfilzomib was 4 (range, 0.3-22). The majority of patients (79.3%) received carfilzomib according to the 20/27 mg/m2 dose schedule. The remaining patients received carfilzomib either at a dose that did not exceed 20 mg/m2 (11.8%) or at maximal dose higher than 27 mg/m2 (8.9%, mostly as a 20/27/56 mg/m2 dose schedule). Carfilzomib was administrated as a single agent in 5.1% of patients or combined with a second agent in 43% of them. Additionally, 46.7% of patients received carfilzomib as part of a three-drug combination and 5.2% of patients as part of four-drug combination or more. In comparison to patients who received two-drug combination (or carfilzomib alone), patients who received three-drug (or more) combination were younger, with less prior treatment lines and higher baseline haemoglobin, albumin and eGFR (Table I). There was also pre-selection by lower frequency of ImIds resistance in the three-drug combination sub-group, but bortezomib resistance was similar between sub-groups. One hundred and twenty three patients (91.1% of patients) were evaluable for response and survival analysis. The overall response rate was 48.8%, with one patient (0.8%) achieving complete response (CR), 30 patients (24.4%) attaining very good partial response (VGPR) and 29 patients (23.6%) with partial response (PR). Additionally, 15 patients (12.2%) achieved minimal response (MR), reaching a clinical benefit response (CBR) rate of 61%. A multivariate analysis revealed three parameters negatively impact the likelihood of achieving response: bortezomib resistance (odds ratio 0.33, 95% CI 0.12-0.94, p=0.03); lenalidomide resistance (odds ratio 0.31, 95% CI 0.11-0.91, p=0.03), and albumin <3.5 g/dL (odds ratio 0.32, 95% CI 0.14-0.71 p=0.005). The median duration of response was 8.3 months, significantly higher in patients receiving three-drug combination and in patients presenting without extramedullary disease. The median progression free survival (PFS) and overall survival for the entire cohort were 4.9 months (95% CI 3.9-6.9) and 19.3 months (95% CI 9.4-not yet reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients.
Conclusion: In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields an effective results with a manageable toxicity. Drug resistance is an important factor in determining response quality to carfilzomib.

Disclosures
Raanani: Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board; BMS: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding.