SAN FRANCISCO—Trial results suggest a 3-drug regimen could represent a new standard of care for relapsed multiple myeloma (MM), according to a speaker at the 2014 ASH Annual Meeting.
In the phase 3 ASPIRE trial, patients who received combination carfilzomib, lenalidomide, and dexamethasone (KRd) had superior progression-free survival compared to patients who received only lenalidomide and dexamethasone (Rd).
There was a trend toward improved overall survival with KRd as well.
Patients who received KRd did experience more adverse events (AEs), but fewer patients discontinued treatment due to AEs in the KRd arm than in the Rd arm.
Keith Stewart, MBChB, of the Mayo Clinic in Arizona, presented these results at the meeting as abstract 79. The data were published in The New England Journal of Medicine as well. The trial was sponsored by Onyx Pharmaceuticals, Inc., the company developing carfilzomib.
ASPIRE included 792 patients with relapsed MM who had received 1 to 3 prior treatment regimens. Patients were randomized to treatment with KRd (n=396) or Rd (n=396), and baseline characteristics were similar between the arms.
“There was a slight preponderance of patients over the age of 65 in the Rd arm of the trial,” Dr Stewart noted. “Conversely, there were more patients on the Rd arm of the trial who had lower-risk cytogenetics.”
“Patients were also well-balanced for baseline exposure to prior therapies. Prior therapies included transplant in 55% of patients, bortezomib in two-thirds of patients, and lenalidomide in 20% of patients—again, equal in both arms of the trial.”
All patients received a standard dosing schedule of lenalidomide (25 mg on days 1-21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22).
Patients in the KRd arm also received carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1 and 27 mg/m2 thereafter). They received a 10-minute infusion of the drug on days 1, 2, 8, 9, 15, and 16. Carfilzomib was not given on days 8 and 9 in cycles 13 to 18 and not administered beyond 18 cycles.
‘Unprecedented’ results
The study’s primary endpoint was progression-free survival. And results showed progression-free survival was significantly longer in the KRd arm than in the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69; P<0.0001).
“Progression-free survival was significantly improved by 8.7 months with KRd,” Dr Stewart noted. “In a phase 3 clinical trial setting, this is unprecedented.”
“In all prespecified subgroups, the advantage of KRd in progression-free survival was maintained. That includes age, international staging system, and prior exposure to either bortezomib or lenalidomide, or both drugs.”
The secondary endpoints of the trial were overall survival, overall response rate, duration of response, health-related quality of life, and safety.
The data for median overall survival are not yet mature based on the prespecified statistical boundary at the interim analysis (P=0.005). However, there was a trend in favor of KRd (hazard ratio, 0.79; P=0.018).
The overall response rate was 87.1% with KRd and 66.7% with Rd (P<0.0001), and the complete response rates were 14.1% and 4.3%, respectively (P<0.001). The median duration of response was 28.6 months and 21.2 months, respectively.
In addition, KRd improved global health-related quality of life compared with Rd over 18 cycles of treatment (P=0.0001).
‘Reassuring’ toxicity data
“In the discussion of adverse events,” Dr Stewart said, “it’s important to note that the median treatment duration was 88 weeks with KRd and 57 weeks with Rd.”
Most patients in each arm experienced at least one AE—96.9% in the KRd arm and 97.2% in the RD arm.
In the KRd arm, 7.7% of patients died while still on treatment or within 30 days of receiving their last dose of treatment, as did 8.5% of patients in the Rd arm. The percentage of deaths attributable to AEs was 6.9% in both arms.
The rates of treatment discontinuation were 69.9% in the KRd arm and 77.9% in the Rd arm. More patients discontinued treatment due to disease progression—39.8% in the KRd arm and 50.1% in the Rd arm—than to AEs—15.3% in the KRd arm and 17.7% in the Rd arm.
The most common grade 3 or higher hematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).
The most common grade 3 or higher nonhematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were hypokalemia (9.4% vs 4.9%), fatigue (7.7% vs 6.4%), and diarrhea (3.8% vs 4.1%).
Other treatment-emergent AEs of any grade (in the KRd and Rd arms, respectively) included dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), ischemic heart disease (5.9% vs 4.6%), and peripheral neuropathy (17.1% vs 17.0%).
“The results [are] very reassuring with respect to cardiac and renal events, which were reported at rates consistent with, or even lower than, those reported in prior studies of single-agent carfilzomib or more heavily pretreated patients,” Dr Stewart said.
“Based on the results of this phase 3 trial, I think it’s fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.”
