Despite the recent approval of several new drugs in multiple myeloma (MM), including proteasome inhibitors and immunomodulatory agents, the treatment of patients with relapsed and/or refractory disease is still challenging. The proteasome inhibitor carfilzomib was approved by the U.S. FDA in July 2012 based on data from a phase II trial showing an overall response rate (ORR) of 23.4 percent and a median response duration of 7.8 months. These outcomes though, may differ in a non–clinical trial, real-world setting.
In a retrospective, multicenter study recently published in Blood, Eli Muchtar, MD, from the Institute of Hematology at the Rabin Medical Center in Petah Tikva, Israel, and colleagues examined the safety and efficacy of carfilzomib in patients with relapsed/refractory MM in 10 medical centers across Israel.
“Carfilzomib, especially in combination with other drugs, such as dexamethasone and/or cyclophosphamide, is active in almost half of patients with relapsed and/or refractory MM,” Dr. Muchtar told ASH Clinical News. “This study provides important data on predictors of response to carfilzomib and supports combination treatment to improve response, although the optimal combination has yet to be determined.”
Dr. Muchtar and co-authors wrote, “Also, as drug resistance is an important factor in determining response quality to carfilzomib in this study, a better understanding of the resistance mechanisms can help in both treatment selection as well as in creating ways to overcome it.”
The study included 135 patients (median age = 67.9 years; range = 41-88 years), who had been treated with a median of three prior lines of therapy (range = 1-7).
Details about prior treatments included:
- All patients had bortezomib exposure, and 80.7 percent of patients were refractory to this drug.
- 93 percent had been treated with lenalidomide, and 50 percent of patients had received a lenalidomide-containing regimen as their last treatment line before carfilzomib initiation.
- 62.2 percent had been treated with thalidomide.
- 4.4 percent were exposed to pomalidomide.
Most of the patients in the study received carfilzomib as part of a two- or three-drug combination regimen.
The ORR was 47.2 percent (among 127 patients who were evaluable for response) among patients treated with carfilzomib:
- 1 patient (0.8%) achieved complete response (CR)
- 30 patients (23.6%) achieved very good partial response (VGPR)
- 29 patients (22.8%) achieved partial response (PR)
- 15 patients (11.8%) achieved minimal response (MR)
Among those who did not achieve a response, 15.8 percent had stable disease and 25.2 percent had disease progression while on carfilzomib treatment.
“There was a strong trend toward an improved ORR in patients who received a three-drug (or more) combination compared to patients receiving a two-drug combination or carfilzomib alone (54.4% vs. 38.9%; p=0.1),” Dr. Muchtar and co-authors wrote; they noted, however, that this group of patients had more favorable parameters, including younger age, fewer lines of prior treatment, and less sensitivity to immunomodulatory drugs.
Response rates also varied based on carfilzomib dosage, with the recommended dose (20/27 mg/m2) yielding the best ORR. Patients who received the standard dose of 20/27 mg/m2 had an ORR of 56.9 percent. In contrast, patients who received doses lower than 20/27 mg/m2 had an ORR of 15.4 percent and those who received doses higher than 20/27 mg/m2 failed to respond (p<0.0001).
“Drug resistance is a major determinant of response to carfilzomib, and although bortezomib resistance negatively impacted response probability to carfilzomib, lenalidomide resistance had a similar negative effect,” Dr. Muchtar said, noting that “carfilzomib resistance could not be overcome with dose intensification.”
Multivariate analysis revealed three negative predictors of response, the researchers noted: bortezomib resistance (ORR=42.2% for bortezomib-resistance vs. 68% for bortezomib-sensitivity; p=0.02), lenalidomide resistance (ORR=40.8% for lenalidomide-resistance vs. 75% for lenalidomide-sensitivity; p=0.03), and extramedullary plasmacytoma (EMP; ORR=40% with presence of EMP vs. 49% for no EMP; p=0.39). Though this last finding did not reach statistical significance, presence of EMP was also associated with higher rates of stable and progressive disease (56.7% and 36.5%, respectively).
The median duration of response among carfilzomib-treated patients was 8.4 months (95% CI 5.1-14.5); as with ORR, duration of response was significantly higher in patients receiving the three-drug (or more) combination than in those receiving a two-drug regimen or carfilzomib alone (14.5 months vs. 7.1 months; p=0.04).
Median progression-free survival (PFS) for the entire patient population was 4.9 months (95% CI 3.8-6.4), and the overall survival was 12.2 months (95% CI 9–not reached). Again, the use of three or more drugs in combination was associated with better outcomes than a two-or-fewer drug regimen (PFS=6 months vs. 3.9 months [p=0.01]; OS=not reached vs. 9.4 months [p=0.01]).
The toxicity was determined to be “manageable,” though treatment-related mortality occurred in 5 percent of patients – a number that was higher than seen in previous carfilzomib clinical trials. “This relatively high treatment-related death rate may be a result of new drug implantation or the unselected nature of the patients included in this study, and requires further focus in future clinical trials,” the authors wrote. Dr. Muchtar and co-authors did note some limitations of the study, including its retrospective nature, which “limits the quality of the safety data.”
Muchtar E, Gatt ME, Rouvio O, et al. Efficacy and safety of salvage therapy using carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study. Br J Haematol. 2015 November 16. [Epub ahead of print]