New data from the 56th Annual Meeting of the American Society of Hematology (ASH) show that the addition of carfilzomib to lenalidomide and dexamethasone combination therapy achieved “unprecedented efficacy” in the treatment of relapsed multiple myeloma.
Progression-free survival was 26.3 months for patients receiving carfilzomib and 17.6 months for patients receiving only lenalidomide and dexamethasone (P= .0001).
Dr. A. Keith Stewart from the Mayo Clinic in Arizona, the study’s principal investigator, said in a news release, “The progression-free survival benefit in the combination therapy group was very impressive. Progression-free survival of more than 2 years can be considered an unprecedented outcome for patients with first-time relapsed myeloma.”
Although neither group reached median overall survival in this interim analysis, overall survival tended to be longer in the carfilzomib group (73.3% vs 65%; HR = 0.79; P = .018). The trial results did not exceed the statistical range set by statisticians at the start of the trial.
Importantly, the addition of the third drug did not significantly increase toxicity, and in fact, patients in the carfilzomib group had higher quality-of-life scores than patients in the control group, the authors wrote.
The second key message of the study, Dr. Stewart said, was that the overall response rate was significantly higher for the three-drug combination than for the two-drug combination, and even more impressive was that the rate of complete remission was more than three times higher in patients who received all three drugs than in those who received two.
The overall remission rates in the carfilzomib and control groups were 87.4 percent and 66.9 percent, respectively, and the percentage of patients achieving complete remission or better was 31.8 percent and 9.4 percent, respectively.
By adding carfilzomib to the gold standard of treatment for multiple myeloma, we can observe an unprecedented duration of remission without additional toxicity, which is a very promising outcome for patients who have relapsed and undergone extensive pretreatment, the authors write.
The results of this interim analysis were published concurrently in the New England Journal of Medicine.
Dr. Brad Kahl, director of the University of Washington Lymphoma Service and conference chair, commented on the potential for these results to lead to changes in clinical practice, saying, “I think this will establish a new standard of care for the treatment of this patient population.”
1. study details
Carfilzomib, a second-generation proteasome inhibitor, was approved by the FDA 2 years ago for the treatment of patients with multiple myeloma who have received at least two treatments, including bortezomib and immunomodulatory therapy.
The combination of lenalidomide and dexamethasone is the current standard of care for the treatment of patients with relapsed multiple myeloma. In this randomized, multicenter phase 3 study (the ASPIRE study), Stewart and his colleagues compared the efficacy of a three-drug combination of lenalidomide, dexamethasone and carfilzomib with standard combination therapy.
The primary endpoint was progression-free survival, and secondary endpoints included overall survival, overall remission rate, duration of remission, health-related quality of life and safety.
The trial included 792 patients from 20 countries, randomly assigned 1:1, stratified by β2-microglobulin level (<2.5 vs ≥2.5 mg/L), prior bortezomib therapy (whether or not they received this therapy), and prior lenalidomide therapy (whether or not they received this therapy). Each patient received lenalidomide (25 mg) on days 1-21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 in a 28-day course.
Patients in the trial group received carfilzomib injections (20 mg/m2 [day 1,2 of the first course] on days 1-12 of the course; thereafter the dose was 27 mg/m2). Infusions were not administered on days 8,9 of cycles 13-18 and were not received for more than 18 cycles.
The study met the primary end point of progression-free survival at the prespecified interim analysis time (HR = 0.69; P < .0001).
Overall event-free survival at 24 months was 73.3% and 65.0%, respectively. The median duration of remission was better in the carfilzomib group than in the control group (28.6 months vs 21.2 months).
2. Adverse effects
The proportion of patients who discontinued treatment due to adverse reactions was similar in both groups (15.2% in the carfilzomib group vs. 17.4% in the control group). Deaths during study treatment or within 30 days of receiving the final dose were 7.7% and 8.5% in the two groups, respectively.
The most common hematologic treatment emergencies (≥ grade 3) included neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).
The most common non-hematologic events (all grades) included diarrhea (16.6% vs. 12.3%), fatigue (32.9% vs. 30.6%) and cough (28.8% vs. 17.2%); Grade 3 or higher adverse reactions included pneumonia (12.5% vs. 10.5%), hypokalemia (9.4% vs. 4.9%) and hypophosphatemia (8.4% vs. 4.6%) .