ASPIRE Trial Confirms Survival Benefit in Myeloma for Carfilzomib Plus Lenalidomide/Dexamethasone

Keith Stewart, MB ChB

In the final analysis of the phase III ASPIRE trial, an improvement in survival was confirmed with the combination of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone for patients with relapsed/refractory multiple myeloma, according to findings presented at the 2017 ASH Annual Meeting.¹

Patients assigned to the carfilzomib-containing regimen (n = 396; Krd) had a median overall survival (OS) of 48.3 months versus 40.4 months for patients who received lenalidomide and dexamethasone (n = 396; Rd). The hazard ratio (HR) for Krd versus Rd was 0.79 (95% CI, 0.67-0.95;P= .0045).

The updated analysis confirms data showing that carfilzomib was associated with a median PFS of 26.1 months compared with 16.6 months among patients who received lenalidomide alone (HR, 0.66; 95% CI, 0.55-0.78;P<.0001).

&ldquo;The addition of carfilzomib resulted in a higher objective response rate, a tripling of the complete response rate, significant and clinically relevant prolongation of both progression-free and overall survival, and improved health-related quality of life (HRQOL),&rdquo; said A. Keith Stewart, MB ChB, director of the Center for Individualized Medicine at the Mayo Clinic in Rochester, Minnesota. &ldquo;The combination of carfilzomib, lenalidomide, and dexamethasone is an excellent treatment option, proven to extend survival in relapsed/refractory multiple myeloma, particularly at first relapse.&rdquo;

As previously reported, the trial met the primary endpoint of PFS, as the carfilzomib regimen resulted in a median PFS of 26.3 months versus 17.6 months for patients treated with Rd.²

The ASPIRE patient population (n = 792) had a median age of about 65, and about 90% of the participants had ECOG performance status of 0-1. More than 40% of the patients had stage III disease at diagnosis, three-fourths had standard cytogenetic risk, and a majority of patients had received 2 or 3 prior regimens for myeloma.

At the time of the primary analysis, median OS had yet to be reached. Estimated 2-year survival was 73.3% with carfilzomib and 65.0% for Rd. The ASPIRE protocol specified a final survival analysis after 510 deaths. The trial reached that landmark on April 28, after a median follow-up of 67 months, said Stewart.

A difference began to emerge in a preliminary survival analysis performed after 18 months, showing event rates of 17.9% with carfilzomib and 24.5% with Rd (HR, 95% CI, 0.69; 95% CI, 0.51-0.93). The survival advantage persisted across all prespecified subgroups.

Investigators also revisited and updated previously reported findings for PFS, response, and safety. Reanalysis of investigator-assessed PFS yielded a 9.5-month difference in median values in favor of the carfilzomib arm, almost identical to the difference seen in the primary analysis. The updated analysis demonstrated a 34% reduction in the risk for progression or death.

Investigators defined high-risk cytogenetics as t(4;14), t(14;16), or deletion 17p in &ge;60% of plasma cells. Stewart said 48 patients in the carfilzomib arm and 52 in the control group met that definition. In that subgroup, the carfilzomib regimen resulted in an objective response rate (ORR) of 79.2% compared with 59.6% in the Rd arm and a 30% reduction in the PFS hazard. Substantially fewer high-risk patients in the carfilzomib arm received subsequent therapy (39.6% vs 57.7%).

OS for selected subgroups was consistently superior with carfilzomib including patients in first relapse (47.3 vs 35.9 months) and patients who received transplant prior to first relapse (57.2 vs 38.6 months).

Median duration of therapy in the experimental arm was 72.0 weeks for carfilzomib, 85.0 weeks for lenalidomide, and 80.2 weeks for dexamethasone. In the control arm, patients received lenalidomide for a median duration of 56.7 weeks and dexamethasone for a median of 48.7.

Adverse event (AE) rates were similar between the treatment groups including all-grade AEs (98.0% in both groups), grade &ge;3 AEs (87.0% with carfilzomib vs 83.0% for the control group), serious adverse events (65.6% vs 56.8%), discontinuation due to AEs (33.4% vs 30.1%), and grade 5 AEs (11.5% vs 10.5%).

Updated safety data showed that all-grade nonhematologic events were generally more common in the experimental arm for diarrhea (44.4% vs 37.3%), fatigue (33.4% vs 31.9%), cough (29.6% vs 18.0%), pyrexia (29.8% vs 21.6%), upper respiratory infections (30.1% vs 20.8%), hypokalemia (29.6% vs 14.9%), and muscle spasms (27.0% vs 21.1%). With respect to grade &ge;3 adverse events, only hypokalemia in the carfilzomib arm (10.5%) affected as many as 10% of patients in either group.

Hypertension (17.1% vs 8.7%) and venous thrombotic events (10.2% vs 6.2%) occurred more often with carfilzomib. Otherwise, the incidence of acute renal failure, cardiac failure, ischemic heart disease, and peripheral neuropathy occurred in a similar proportion of patients in both groups. The most common grade &ge;3 special interest AE was hypertension (6.4% with carfilzomib). No other grade &ge;3 special-interest event occurred in as many as 5% of patients.

&ldquo;The safety is consistent with previous findings, and no new safety signals were observed for carfilzomib, lenalidomide, and dexamethasone after extended follow-up,&rdquo; said Stewart.

References

1. Stewart AK, Siegel D, Ludwig H, et al. Overall survival (OS) of patients with relapsed/refractory multiple myeloma (RRMM) treated with carfilzomib, lenalidomide, and dexamethasone (Krd) versus lenalidomide and dexamethasone (Rd): Final analysis from the randomized phase 3 ASPIRE trial. Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 743.
2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.N Engl J Med.2015; 372:142-152.