The ASPIRE study compares the use of lenalidomide and dexamethasone with or without the second-generation proteasome inhibitor carfilzomib in relapsed or refractory multiple myeloma patients. In an interim report, the progression-free survival (PFS) data for this study showed a clear advantage for the carfilzomib group (carfilzomib plus lenelidomide/dexamethasone). Those patients had a median PFS of 26.3 months, as compared to the control (lenalidomide/dexamethasone) group's median value of 17.6 months, which afforded a hazard ratio (HR) for death or disease progression of 0.69 (95% CI: 0.57-0.83; two-sided p<.001) (N Engl J Med 2015;372:142-152).
Final overall survival (OS) data for this pivotal trial were presented by researchers, including David Siegel, MD, PhD, of the John Theurer Cancer Center, Hackensack University Medical Center (J Clin Oncol 2018; doi:10.1200/JCO.2017.76.5032). These data also displayed a clear advantage for patients taking the triplet therapy including carfilzomib. When asked about the significance of the OS data, Siegel noted, “These results, along with the OS data from the ENDEAVOR trial, provide further confirmation for the PFS data-based approval of carfilzomib to treat relapsed or refractory multiple myeloma patients.”
The ASPIRE trial was a phase III, multicenter, open-label study that compared the treatment of adults having relapsed or refractory multiple myeloma with carfilzomib plus lenalidomide/dexamethasone or lenalidomide/dexamethasone.
Participation in this trial was limited to patients having 1-3 prior lines of therapy. Prior therapy with the first-in-class proteasome inhibitor bortezomib was permitted if the patient did not have disease progression while being treated. Patients with previous lenalidomide/dexamethasone treatment were eligible if they did not have therapy discontinuation as a result of adverse events, disease progression within the first 3 months of treatment, or progression at any time during treatment if lenalidomide/dexamethasone was the last therapy. Additionally, proper renal, hepatic, and hematological functioning was necessary for eligibility. Patients were deemed ineligible if they had grade 3 or 4 peripheral neuropathy (or grade 2 with pain) within 2 weeks prior to randomization or class III or IV heart failure (New York Heart Association).
Patients were randomized in a 1:1 fashion to either the carfilzomib plus lenalidomide/dexamethasone regimen (carfilzomib group) or the lenalidomide/dexamethasone regimen (control group), receiving their experimental medications in 28-day treatment cycles. Carfilzomib was delivered via a 10-minute infusion on days 1, 2, 8, 9, 15, and 16 of each therapy cycle for cycles 1-12. For cycles 13-18 (carfilzomib dosing was ceased after 18 cycles), patients were infused on days 1, 2, 15, and 16. On days 1 and 2 of the first dosing cycle, the carfilzomib patients received 20 mg/m2 carfilzomib, while all subsequent infusions were at the 27 mg/m2 level. During each 28-day therapy cycle, patients (both carfilzomib and control groups) received 25 mg lenalidomide on days 1-21 and 40 mg dexamethasone on days 1, 8, 15, and 22.
The primary endpoint for this study was independent, review committee-assessed PFS. An important secondary endpoint was OS. At the time of the interim analysis, the OS data did show an advantage for the carfilzomib group, however, the pre-specified stopping point for analysis had not been crossed, thus patient monitoring for OS was continued. If the OS results were deemed to be significant at final analysis, test results obtained at the interim analysis for objective response rate (ORR), disease control rate, and health-related quality of life (HRQoL) would be used to determine statistical significance.
From July 2010 to March 2012, 792 patients were enrolled for participation in ASPIRE, with patients being randomized to either the control (n=396) or the carfilzomib (n=396) group. This trial was international in scope, with patients being included from Europe, North America, and the Middle East. The baseline characteristics (e.g., age, ECOG performance status, number, and types of prior therapies, etc.) for both treatment groups were well-balanced.
The cutoff date for the interim analysis was June 16, 2014. At that time, 29.8 percent of patients in the carfilzomib group and 21.7 percent of participants in the control group were still taking their investigational treatments. By that date, 305 deaths had occurred, which was 60 percent of the pre-specified 510 that were required for final analysis.
As previously mentioned, the median PFS values for the carfilzomib and control groups were 26.3 months (95% CI: 23.3-30.5 months) and 17.6 months (95% CI: 15.0-20.6 months), respectively. Regarding these data, Siegel commented, “Most significantly, a clear advantage for the carfilzomib group with regards to PFS was noted across all predefined subgroups.”
The 24-month OS rates were 73.3 percent (95% CI: 68.6-77.5%) and 65.0 percent (95% CI: 59.9-69.5%) for the carfilzomib and control groups, respectively. These figures gave a HR for death of 0.79 (95% CI: 0.63-0.99, p=0.04).
The ORR values for the carfilzomib and control groups were 87.1 percent (95% CI: 83.4-90.3%) and 66.7 percent (95% CI: 61.8-71.3%), respectively. These results were considered statistically significant (p< 0.001). Among the patients showing a response to their treatments, 31.8 percent of those in the carfilzomib group and 9.3 percent of the control group displayed a complete response or better.
Final OS Analysis
April 28, 2017, was the cutoff date for the final OS analysis, at which time 32.6 percent (129) of the carfilzomib patients and 24.7 percent (98) of the patients in the control group were still alive.
The median OS for the carfilzomib group was 48.3 months (95% CI: 42.4-52.8 months) and 40.4 months (95% CI: 33.6-44.4 months), providing a HR of 0.79 (95% CI: 0.67-0.95; one sided p=.0045) “This result crossed the pre-specified stopping boundary (one-sided p=.023) and was thus statistically significant,” Siegel noted.
Since the OS data were statistically significant at the final analysis, the test results obtained at interim analysis for ORR (carfilzomib group—87.1% vs. control group—66.7%; two-sided p<001) and HRQoL (overall treatment effect, 4.2; 95% CI, 2.1-6.4; two-sided p<001) were also deemed statistically significant.
For patients having received only one prior line of therapy, the carfilzomib participants (n=184) had a median OS of 47.3 months, while similar patients in the control group (n=157) had a median OS of 35.9 months to give a HR of 0.81 (95% CI: 0.62-1.06). Among these patients whose single line of therapy was bortezomib, those in the carfilzomib group (n=93) had a median OS of 45.9 months, while those in the control group (n=73) had a median OS of 33.9 months, for a HR of 0.82 (95% CI: 0.56-1.19). For those patients whose single therapy line did not include bortezomib, the carfilzomib participants (n=91) had a median OS of 48.3 months, while those in the control group (n=84) had a median OS of 40.4 months, providing a HR of 0.80 (95% CI: 0.55-1.17).
Trial participants receiving two or more prior lines of therapy still had an advantage in median OS for the carfilzomib group (n=212, 48.8 months) over the control group (n=239, 42.3 months), with a HR of 0.79 (95% CI: 0.62-0.99).
“The largest median OS difference with treatment-based stratification was noted in those patients having prior transplantation at first relapse,” Siegel explained. “For the 88 carfilzomib participants in this analysis subgroup, the median OS was 57.2 months, whereas similar patients in the control group had a median OS of 38.6 months for an HR of 0.71 (95% CI: 0.48-1.05),” he added.
While all patients in the intent-to-treat population (i.e., 396 each in the carfilzomib and control groups) were included in the OS analysis, safety analysis was performed using patients that actually received at least one dose of experimental treatment (carfilzomib group—392; control group—389). The most common treatment-emergent adverse events (TEAEs) of grade 3 or higher in the safety population were:
- carfilzomib group—neutropenia (31.1%), anemia (18.6%), and thrombocytopenia (16.8%);
- control group—neutropenia (27.5%), anemia (17.5%), and thrombocytopenia (13.1%).
“The safety data showed that carfilzomib was generally well-tolerated and, when AEs did arise, they were generally manageable,” Siegel stated.
One potential area of concern for carfilzomib-based therapies is cardiopulmonary issues. “In a number of animal models, proteasome inhibitors were shown to cause cardiac injuries,” he noted.
“In this trial, as in the ENDEAVOR study, there were clear advantages in both the PFS and OS analyses for those therapies which included carfilzomib,” Siegel stated.
“The results from this trial provide documentation that this triple regimen of carfilzomib plus lenalidomide and dexamethasone should be a standard of care for relapsed or refractory multiple myeloma patients,” he said. “The strength of the benefit for the carfilzomib-based therapy in the OS analysis is especially compelling when one considers the length of time over which the data were obtained and the myriad of confounding factors which can present over that time.
“Carfilzomib is an extremely effective drug that has a reasonable safety profile with manageable toxicities, yet this compound is often under-utilized in the treatment of relapsed or refractory multiple myeloma patients,” Siegel stated.
“Ultimately, I would hope that with this trial, clinicians will develop higher levels of comfort in dealing with any potential TEAEs that might arise in their patients. Close patient monitoring is required with this, however, a clear benefit with regards to OS has been shown for this drug in the treatment of relapsed or refractory multiple myeloma patients.”
Richard Simoneaux is a contributing writer.