In the treatment of relapsed multiple myeloma, another therapy combining carfilzomib has shown significantly better benefit than standard therapy (bortezomib plus dexamethasone). In a recent phase 3 trial, carfilzomib combined with dexamethasone was associated with a two-fold better risk of progression or death than standard therapy. ”The ENDEAVOR trial is the first head-to-head study comparing proteasome inhibitors,” said Dr. Meletios Dimopoulos. He presented the latest study results at the 20th European Hematology Association (EHA). An early phase 3 trial-ASPIRE-showed that carfilzomib (an irreversible ketone oxide proteasome inhibitor) combined with lenalidomide and dexamethasone significantly improved progression-free survival compared with bortezomib combined with dexamethasone, a study published in the New England Journal of Medicine.The ASPIRE results were unprecedented, but then Carfilzomib combined with dexamethasone for relapsed patients also showed favorable results. Dr. Dimopoulos reported results from the novel ENDEAVOR trial, with a median progression-free survival of 18.7 months for patients in the carfilzomib combined with dexamethasone group compared with 9.4 months in the bortezomib/dexamethasone group (HR,0.53; P < 0.0001). The primary endpoint was progression-free survival with a median follow-up of 11.2 months. Dr. Dimopoulos said, "If age or prior bortezomib therapy is not considered, carfilzomib combined with dexamethasone is superior to bortezomib combined with dexamethasone and represents a new standard of care." Dr. Kostas Stamatopoulos said that carfilzomib is significantly better than bortezomib in the fight against myeloma. He told Medscape Medical News, "These results confirm the authors' conclusion-this may represent the best drug for the treatment of relapsed multiple myeloma." In this trial, 929 patients with relapsed multiple myeloma were randomized 1:1 to receive two therapies. The treatment regimen consisted of carfilzomib 56 mg/m2 (given intravenously over 30 minutes) on days 1,2, 8, 9, 15 and 16 (20 mg/m2 on days 1,2 and 56 mg/m2 thereafter) and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 in a 28-day course. The other group received bortezomib 1.3 mg/m2 (intravenous or subcutaneous) on days 1, 4, 8 and 11 and dexamethasone 20 mg for 21 days on days 1, 2, 4, 5, 8, 9, 11 and 12. 83.6% of patients received bortezomib subcutaneously. Treatment was continued until progression or intolerable toxicity occurred. The median age of patients in both groups was 65 years; 17% were ≥75 years in the carfilzomib group compared with 14% in the bortezomib group. Approximately 50% of patients had an ISS score of II or III. The median number of prior therapies received was 1. Disease progression or death occurred in 37% of patients in the carfilzomib group (n= 464) compared with 52% in the bortezomib group (n= 465), and progression-free survival showed benefit from carfilzomib in all subgroups, including those based on age, renal function, and number of prior therapies. The median time to remission was 21.3 months and 10.4 months in the two groups, respectively. With regard to the secondary endpoint-remission rates, complete remission rates were 13% (n= 58) and 6% (n= 29) in the carfilzomib and bortezomib groups, respectively; good partial remission rates were 54% (n= 252) and 29% (n= 133), respectively; and overall remission rates were 77% and 63% in the carfilzomib and bortezomib groups, respectively (P< 0.0001 ). Although overall survival data showed 75 and 88 patient deaths in the carfilzomib and bortezomib groups, respectively, the authors write that these data are inconclusive and that patients will continue to be followed up. Although patients were treated with carfilzomib for a longer period of time - 40 weeks vs. 27 weeks - the rate of patients discontinuing treatment due to adverse effects was similar, 14% and 16% in the carfilzomib and bortezomib groups, respectively. Grade 3 or higher adverse reactions occurred in 73% of patients in the carfilzomib group compared to 67% in the bortezomib group, with serious adverse reaction rates of 48% and 36%, respectively. The incidence of grade 3 or higher hypertension (9% vs 3%), dyspnea (5% vs 2.2%) and heart failure (5% vs 1.8%) was higher in the carfilzomib group. Dose reductions due to adverse reactions were 23% and 48% in the carfilzomib and bortezomib groups, respectively. The incidence of peripheral neuropathy was higher in the grade 2 or higher bortezomib group-32% vs 6% (P < 0.0001); bortezomib dose reduction (61.9%) was associated with neuropathy-related events compared with 6.6% for carfilzomib. Four and three patients died in the carfilzomib and bortezomib groups, respectively, due to adverse effects. Further evaluation of progression-free survival according to age showed that carfilzomib was superior to bortezomib in all subgroups, including patients <65 years of age, patients 65-74 years of age, and patients >75 years of age (HR 0.58,0.53, and 0.38, respectively). Although these data are still being evaluated, Dr. Dimopoulos said serial assessments to date have shown no difference in increased ventricular ejection fraction between the two groups. We found a significantly higher overall remission rate in the carfilzomib group than in the bortezomib group,” he said. The complete remission rate (13% vs. 6%) or good partial remission rate (54% vs. 29%) was twice as high as in the bortezomib group.” New drugs – including carfilzomib, next-generation immunomodulatory drugs such as pomalidomide, and monoclonal antibodies such as elotuzumab – will increase the number of effective treatment options for relapsed multiple myeloma. That said, the optimal combination therapy and combination therapy to improve quality of life, chemotherapy-free intervals and overall survival still need to be determined. Equally important and not sufficiently elucidated are the safety and cost issues.