Previous results from the phase III ENDEAVOR study showed that treatment with the proteasome inhibitor carfilzomib plus dexamethasone extended progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), compared with bortezomib plus dexamethasone (18.7 months vs. 9.4 months; hazard ratio [HR] = 0.53; 95% CI 0.44-0.65; p<0.0001). According to the results of a second interim analysis published in Lancet Oncology, treatment with the carfilzomib combination also improved overall survival (OS), compared with the bortezomib combination in this patient population.
“On the basis of these results, carfilzomib combined with dexamethasone should be considered a standard of care for patients with relapsed or refractory MM,” reported the authors, led by Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece.
The open-label, randomized, controlled, head-to-head comparison of carfilzomib and bortezomib included 929 adult patients enrolled between June 2012 and June 2014 from 198 hospital or outpatient oncology centers in 27 countries. Eligible patients had received one to three prior lines of therapy and had achieved at least partial response to at least one line of therapy.
Patients were randomized 1:1 based on International Staging System (I vs. II-III) score, previous lines of therapy (1 vs. 2-3), previous proteasome inhibitor therapy (yes vs. no), and planned route of bortezomib administration for that cohort (intravenous vs. subcutaneous) to receive either:
- carfilzomib (20 mg/m2 administered via a 30-minute intravenous infusion on days 1-2; escalated to 56 mg/m2 thereafter, if tolerated, on days 1, 2, 8, 9, 15, and 16) and dexamethasone (20 mg administered orally or via intravenous infusion on days 1, 2, 8, 9, 15, 16, 22, and 23) in 28-day cycles (n=464; median age = 65 years; interquartile range [IQR] = 58-72 years)
- bortezomib (1.3 mg/m2 administered as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11) and dexamethasone (20 mg administered orally or via intravenous infusion on days 1, 2, 4, 5, 8, 9, 11, and 12) in 21-day cycles (n=465; median age = 65 years; IQR=60-71 years)
At data cutoff (January 3, 2017), 398 patients had died: 189 in the carfilzomib cohort and 209 in the bortezomib group. The most common cause of death was progressive disease (n=118 [25%] and n=130 [28%], respectively), followed by adverse events (AEs; n=30 [7%] and n=19 [5%]) and unknown causes (n=41 [9%] and n=60 [13%]).
Treatment-related deaths were reported in five patients receiving carfilzomib (related to pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown cause [n=1]) and two patients receiving bortezomib (related to cardiac arrest [n=1] and pneumonia [n=1]).
After a median follow-up of 37.5 months (range = 34.4-41.9 months), OS was longer in patients receiving carfilzomib (47.6 months; 95% CI 42.5 to not reached), compared with those receiving bortezomib (40.0 months; 95% CI 32.6-42.3; HR=0.791; 95% CI 0.648-0.964; p=0.01). “OS was similar between treatment groups for about the first 15 months, after which the curves started to separate,” the authors reported.
However, in a post-hoc landmark analysis that measured OS from time of disease progression, the median OS did not differ between groups: 21.5 months (95% CI 16.3-25.1) in the carfilzomib group and 21.5 months (95% CI 18.3-26.2) in the bortezomib group (HR=1.032; 95% CI 0.822-1.297; p=0.61).
The median treatment exposure was 48.0 weeks (IQR=24.1-88.7 weeks) in the carfilzomib group, which was “nearly twice as long” as in the bortezomib group (27.0 weeks; IQR=15-50 weeks), the authors noted.
Incidences of grade ≥3 AEs, serious AEs, and fatal AEs were slightly higher in the carfilzomib cohort. Grade ≥3 AEs occurred in 81 percent (n=377) of carfilzomib-treated patients and 71 percent (n=324) of bortezomib-treated patients (p value not reported), the most common of which were anemia (16% vs. 10%, respectively), hypertension (15% vs. 3%), pneumonia (9% vs. 9%), and thrombocytopenia (9% vs. 9%). Serious AEs occurred in 59 percent (n=273) of carfilzomib-treated patients and 40 percent (n=182) of bortezomib-treated patients, the most common of which were pneumonia (8% vs. 9%, respectively), pyrexia (4% vs. 1%), dyspnea (4% vs. 1%), and acute renal failure (2% vs. 2%).
Dose reductions were required in 32 percent (n=146) of the carfilzomib-treated patients and 50 percent (n=230) of the bortezomib-treated patients. In the carfilzomib group, 415 patients (89.6%) discontinued treatment, mostly related to disease progression (n=183) and AEs (n=96); in the bortezomib group, 429 (94.1%) discontinued treatment, also mostly related to disease progression (n=208) and AEs (n=94).
The median time to next treatment (starting from randomization) was 26.3 months (95% CI 24.2-30.6) in the carfilzomib group and 14.4 months (95% CI 12.6-16.6) in the bortezomib group (p value not reported). A potential limitation of the study is that subsequent therapies received during follow-up could have confounded interpretation of the OS analysis, the researchers noted.
“Given the relapsing nature of MM, it would be of interest to know if the administration of one proteasome inhibitor in an early line of therapy affects the efficacy of another proteasome inhibitor given in a later line of therapy,” the researchers wrote. However, this study could not provide a “robust analysis” on the topic because of heterogeneity in the subpopulations of patients, which is a limitation of the study.
Onyx Pharmaceuticals, Inc. – a subsidiary of Amgen Inc., the manufacturer of carfilzomib – supported the study.
The authors report financial support from Amgen, Celgene, Janssen, Novartis, Takeda, Bristol-Myers Squibb, and Chugai.
Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 August 23. [Epub ahead of print]