Sub-group analysis of the ASPIRE clinical trial: carfilzomib significantly improves PFS of high-risk patients with MM

The ASPIRE clinical trial was conducted in 2015 to assess the efficacy of carfilzomib, in addition to lenalidomide and dexamethasone, in patients with relapsed Multiple Myeloma (MM). The addition of carfilzomib resulted in a significant improvement in progression free survival (PFS). A subset of Multiple Myeloma (MM) patients with cytogenetic abnormalities, such as translocations (4;14), (14;16) and deletion (17p) are considered high-risk, as they are associated with a poor prognosis. In order to assess the benefit of this triple-drug regimen specifically on this high-risk subset, a pre-planned sub-group analysis was conducted by Herve Avet-Loiseau and colleagues at the Centre de Recherche en Cancérologie de Toulouse INSERM, and the results were published in the September 2016 edition of Blood.

Key Findings:

• Details of the ASPIRE study design can be found in a previous MM Hub article
• Patients were treated with either carfilzomib, lenalidomide and dexamethasone (KRd), or lenalidomide plus dexamethasone alone (Rd); all data is given as KRd vs Rd
• FISH was performed on sorted CD138+ cells from BM with specific probes to detect t(4;14) and t(14;16) and del(17p)
• Cytogenetic risk status - 417 pts classified as:
  • High-risk = t(4;14), t(14;16) and del(17p); standard risk = known baseline cytogenetic status; unknown = pts with a FISH assessment but the result of one or more genetic subtypes was not available
• Median PFS:
  • High-risk (n = 100) = 23.1 months (95%CI, 12.5-24.2) vs 13.9 months (95% CI, 9.5-16.7) (HR, 0.70; 95% CI, 0.43-1.16)
  • Standard-risk (n = 317) = 29.6 months (95% CI, 24.1 to not estimable (NE)) vs 19.5 months (95% CI, 14.8-26.0); (HR, 0.66; 95% CI, 0.48-0.90)
  • Unknown cytogenetic risk = 28.4 months (95% CI, 22.1-32.3) vs 17.6 months (95% CI, 14.0-22.2); (HR, 0.74; 95% CI, 0.56-0.98)
• ORR:
  • High-risk = 79.2% vs. 59.6%; odds ratio = 2.919 (95% CI, 1.140-7.470)
  • Standard-risk = 91.2% vs. 73.5%; odds ratio = 3.805 (95% CI, 1.945-7.443)
• CR:
  • High-risk = 29.2% vs 5.8%; sCR = 16.7% vs 3.8%
  • Standard-risk = 38.1% vs 6.5%; sCR = 15.0% vs 3.5%
• Median DoR:
  • High-risk = 22.2 vs 14.9 months
  • Standard-risk = 30.4 vs 20.4 months
• Analysis within the high-risk subgroup according to individual genetic abnormality yielded comparable results
• Safety: AEs and overall safety was comparable to the overall population; no new safety signals identified

Abstract

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.