Carfilzomib has shown encouraging activity in high-risk subset of patients with relapsed and refractory multiple myeloma (MM) with cytogenetic abnormalities.1 The phase 3 ASPIRE study demonstrated that carfilzomib/lenalidomide/dexamethasone (KRd) therapy resulted in significant prolongation of progression-free survival (PFS) compared with standard lenalidomide/dexamethasone (Rd) in patients with relapsed MM (RMM).2 Avet-Loiseau and colleagues presented results of a preplanned subgroup analysis of the ASPIRE study based on baseline cytogenetic risk status.3 In the ASPIRE trial, a total of 792 patients with RMM (1-3 prior lines of therapy) were randomized to KRd (n = 396) or Rd (n = 396); standard doses and schedules of all 3 drugs were applied. Cytogenetic risk status was assessed using fluorescence in situ hybridization. Based on central review of bone marrow samples obtained at study entry, the high-risk patient group was defined by the presence of t(4;14) or t(14;16) or deletion 17p in ?60% of plasma cells. Both high-risk and standard-risk cytogenetic groups derived improved PFS benefit with KRd therapy versus Rd therapy. Patients with high-risk cytogenetics achieved a 9-month improvement in median PFS with KRd treatment compared with those treated with Rd (23.1 months vs 13.9 months; hazard ratio [HR], 0.70). The standard-risk cytogenetic subgroup also achieved a similar 10-month improvement in median PFS with KRd therapy compared with Rd therapy (29.6 months vs 19.5 months; HR, 0.66). In comparison to Rd therapy, treatment with KRd resulted in higher overall response rates in both the high-risk (79.2% vs 59.6%) and standard-risk (91.2% vs 73.5%) groups as well as longer duration of response (high risk: 22.2 months vs 14.9 months; standard risk: 30.4 months vs 20.4 months). Grade ?3 adverse events were higher with KRd treatment (89.1% vs 78.4%) in the high-risk group, but similar in the standard-risk group. Grade 3/4 adverse events included dyspnea, hypertension, acute renal failure, cardiac failure, ischemic heart disease, and peripheral neuropathy. The authors concluded that KRd had a favorable benefit–risk profile and provided a clinical benefit compared with Rd in patients with RMM, irrespective of baseline cytogenetic risk status, and resulted in improved outcomes in patients with high-risk disease. KRd therefore improves and partially overcomes the poor prognosis associated with high-risk cytogenetics.
