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Carfilzomib combination extends PFS in high-risk multiple myeloma regardless of cytogenetic status
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The addition of carfilzomib to lenalidomide and dexamethasone prolonged PFS in patients with relapsed and refractory multiple myeloma regardless of cytogenetic risk status, according to the results of a preplanned subgroup analysis of the ASPIRE trial.
High-risk cytogenetics are common in patients with multiple myeloma and can lead to poorer outcomes. Approximately 11% of patients have deletion 17p and 14% have translocation 4;14.
Carfilzomib (Kyprolis, Onyx) was approved for multiple myeloma based on an interim analysis from the phase 3 ASPIRE trial, which showed the addition of carfilzomib to lenalidomide (Revlimid, Celgene) and dexamethasone significantly reduced the risk for progression or death (HR = 0.69; 95% CI, 0.57-0.83). Median PFS was 26.3 months in the carfilzomib arm and 17.6 months in the control arm.
Herv é Avet-Loiseau, MD, head of the laboratory for genomics in myeloma at University Cancer Center of Toulouse, in Toulouse, France, and colleagues conducted a preplanned subgroup analysis to determine whether this benefit persisted in patients with high-risk cytogenetics.
All patients received 25 mg oral lenalidomide (days 1-21) and 40 mg oral/IV dexamethasone (days 1, 8, 15 and 22) in 28-day cycles with IV carfilzomib (n = 396) or without (n = 396).
One hundred patients (median age, 60.5 years) — 48 of whom received carfilzomib and 52 of whom received lenalidomide and dexamethasone alone — had high-risk cytogenetics due to the presence of translocation 4;14 or 14;16 or deletion 17p in bone marrow samples.
The standard-risk cytogenetic subgroup comprised 317 patients (carfilzomib, n = 147; median age, 65 years; control, n = 170; median age, 67 years). Cytogenetics risk was unknown in the remaining 375 patients.
The addition of carfilzomib to lenalidomide and dexamethasone conferred a 9.2-month improvement in median PFS in the high-risk group (23.1 months vs. 13.9 months; HR = 0.7; 95% CI, 0.43-1.16) and a 10.1-month improvement in the standard-risk group (29.6 months vs. 19.5 months; HR = 0.66; 95% CI, 0.48-0.9).
Among patients with unknown cytogenetics, median PFS was 28.4 months in the carfilzomib arm and 17.6 months in the control arm (HR = 0.74; 95% CI, 0.56-0.98).
The overall response rate was greater with the addition of carfilzomib in the high-risk group (79.2% vs. 59.6%) and the standard-risk group (91.2% vs. 73.5%). Many of these were complete responses or better (high risk, 29.2% vs. 5.8%; standard risk, 38.1% vs. 6.5%).
Grade 3 or worse treatment-related adverse events occurred in a similar proportion of patients treated with carfilzomib or the control regimen among standard-risk patients (86.5% vs. 84.5%) and high-risk patients (89.1% vs. 78.4%).
Despite that carfilzomib improved outcomes in both cohorts, researchers noted the benefit still was greater in the standard-risk group.
“Although [carfilzomib] treatment resulted in a 9- to 10-month improvement in PFS compared with [the control], for patients with high-risk or standard-risk cytogenetics, the absolute median PFS was approximately 6 months shorter for both arms in the high-risk cytogenetic subgroup,” Avet-Loiseau and colleagues wrote. “Carfilzomib improves, but does not abrogate, the poor prognosis associated with high-risk cytogenetics in patients with relapsed multiple myeloma and should be considered a standard of care in these patients, irrespective of baseline cytogenetic status.” – by Nick Andrews
Disclosure: Onyx provided funding for this research. Avet-Loiseau reports no relevant financial disclosures. Other researchers report consultant/advisory and speakers bureau roles and employment with, honoraria from and equity ownership in Amgen, Onyx and other pharmaceutical companies. Please see the full study for a list of all other researchers' relevant financial disclosures.
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