VIENNA – In the treatment of relapsed multiple myeloma, yet another treatment regimen with carfilzomib (Kyprolis, Onyx Pharmaceuticals, Inc) has shown significant superiority over the standard of care, bortezomib (Velcade, Millennium Pharmaceuticals, Inc) plus dexamethasone (multiple brands).
In the latest phase 3 trial, carfilzomib combined with dexamethasone resulted in a twofold improvement in risk for progression or death over the standard combination.
"The ENDEAVOR trial is the first head-to-head study comparing two proteasome inhibitors," said first author Meletios Dimopoulos, MD, of the National and Kapodistrian University Athens, in Greece.
He presented late-breaking research here at the 20th Congress of the European Hematology Association (EHA).
An earlier phase 3 trial, known as ASPIRE, showed that carfilzomib, an irreversible epoxyketone proteasome inhibitor, in combination with lenalidomide (Revlimid, Celgene Corporation) and dexamethasone, significantly improved progression-free survival compared with the combination of bortezomib and dexamethasone, as reported by Medscape Medical News and published in the New England Journal of Medicine.
The results from ASPIRE were called "unprecedented," but subsequent research combining carfilzomib with dexamethasone also showed great promise in these relapsed patients.
Dr Dimopoulos now reports that in the new ENDEAVOR trial, patients in the carfilzomib and dexamethasone arm had a median progression-free survival of 18.7 months compared with 9.4 months in the bortezomib/dexamethasone arm (hazard ratio [HR], 0.53; P < .0001).
Progression-free survival was the study's primary endpoint. Median follow-up was 11.2 months.
"(Carfilzomib combined with dexamethasone) was superior to bortezomib and dexamethasone regardless of age or prior bortezomib exposure and represents a new standard of care," said Dr Dimopoulos.
The hierarchy in this class of drugs in terms of relapsed disease has changed, said an expert not involved with the study.
"Carfilzomib emerges as clearly superior to bortezomib in terms of antimyeloma effect," said Kostas Stamatopoulos, MD, PhD, of the G. Papanicolaou Hospital, in Thessaloniki, Greece, who was comoderator of the scientific session with the ENDEAVOR presentation.
"These results justify the authors' conclusion that it may represent the 'best in class' agent for relapsed multiple myeloma," he told Medscape Medical News.
In the trial, 929 patients with relapsed multiple myeloma were randomly assinged in a 1:1 ratio to the two regimens.
Treatment regimens consisted of carfilzomib 56 mg/m2 (30-min IV infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1 and 2, and 56 mg/m2 thereafter) and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.
The other arm received bortezomib (1.3 mg/m2, IV or subcutaneous) on days 1, 4, 8, and 11 and dexamethasone (20 mg) on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Bortezomib treatment was subcutaneous in 83.6% of patients.
The treatment cycles were repeated until disease progression or toxicity levels became unacceptable.
The median age of the patients was 65 years in both groups; 17% were aged 75 years or older in the carfilzomib group and 14% in the bortezomib group. About 50% of patients had ISS stage II or III. The median number of prior treatments was one.
Although 37% of patients in the carfilzomib/dexamethasone arm (n = 464) had disease progression or death, the rate was 52% in the bortezomib/dexamethasone arm (n = 465), and progression-free survival was in favor of carfilzomib in all subgroupings, including those based on age, renal function, and number of prior regimens.
The median duration of response was 21.3 months vs 10.4 months in the two groups, respectively.
In terms of the secondary endpoint of response rates, a total of 13% (n = 58) of the carfilzomib group had a complete response vs 6% (n = 29) in the bortezomib group; 54% (n = 252) had a very good partial response vs 29% (n = 133) in the bortezomib group; and the overall response rate in the carfilzomib group was 77% vs 63% in the bortezomib group (P < .0001 for all three measures).
Although overall survival data showed 75 deaths in the carfilzomib/dexamethasone group and 88 deaths in the bortezomib/dexamethasone group, the authors noted that the data were inconclusive, and the patients continue to be followed.
The median duration of response was 21.3 months in the carfilzomib group and 10.4 months in the bortezomib group.
Although patients receiving carfilzomib remained on treatment much longer ― 40 weeks vs 27 weeks of treatment ― the rates of discontinuation as a result of adverse events were similar, at 14% in the carfilzomib group vs 16% in the bortezomib group.
In the carfilzomib group, 73% experienced adverse events of grade 3 or higher compared with 67% in the bortezomib group, and 48% in the carfilzomib group had serious adverse events compared with 36% in the bortezomib group.
Rates of grade 3 or higher hypertension were higher in the carfilzomib group (9% vs 3%), as were rates of dyspnea (5% vs 2.2%) and cardiac failure (5% vs 1.8%).
Adverse events led to dose reductions in 23% of carfilzomib patients and 48% of bortezomib patients.
Peripheral neuropathy of grade 2 or higher was more common in the bortezomib arm, occurring in 32% of patients and 6% in the carfilzomib arm (P < .0001); 61.9% of dose reductions with bortezomib were related to neuropathy-related events, compared with 6.6% in carfilzomib patients.
Four deaths in the carfilzomib arm and three in the bortezomib arm were attributed to adverse events.
A further evaluation of progression-free survival according to age showed that carfilzomib outperformed bortezomib in all subsets, including patients younger than 65 years, those aged 65 to 74 years, and even in those older than 75 years (HR, .58, .53, and .38, respectively).
Although the data are still being evaluated, Dr Dimopoulos said serial evaluation has so far shown no evidence of difference in an increase in the ventricular ejection fraction in the two groups.
"We found the overall response rate was significantly higher with carfilzomib combined with dexamethasone compared with bortezomib and dexamethasone," Dr Dimopoulos said.
"Twice as many patients achieved a complete response (13% vs 6%) or a very good partial response or better (54% vs 29%)."
"(Carfilzomib combined with dexamethasone) was superior to bortezomib and dexamethasone regardless of age or prior bortezomib exposure and represents a new standard of care."
The findings bode well for the advancements being made on a broader level in the development of powerful agents to combat multiple myeloma, Dr Stamatopoulos added.
"It becomes increasingly clear that novel agents, including carfilzomib, but also next-generation immunomodulatory drugs, such as pomalidomide [Pomalyst, Celgene Corporation] as well as monoclonal antibodies, such as elotuzumab, will increase the meaningful therapeutic options for relapsed multiple myeloma," Dr Stamatopoulos said.
"That said, the optimal combinations and sequence of combination therapies for improving quality of life, the treatment-free interval, and overall survival remain to be decided."
"Equally important, and still not fully elucidated, are safety and cost issues," he said.
The study received funding from Onyx Pharmaceuticals, Inc. Dr Dimopoulos has served as an advisor or consultant for Celgene Corporation Centocor, Ortho Biotech Inc, and Onyx Pharmaceuticals, Inc. Dr Stamatopoulos has disclosed no relevant financial relationships.
20th Congress of the European Hematology Association (EHA). Abstract LB2071. Presented June 14, 2015.
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου