Updated results from the ENDEAVOR study by cytogenetic risk status

The ENDEAVOR phase III trial compared the efficacy of carfilzomib and dexamethasone (Kd) plus bortezomib and dexamethasone (Vd) in relapsed and refractory Multiple Myeloma (MM) patients, and showed a significant benefit in progression free survival (PFS) for the use of Kd. A subset of MM patients has a high-risk cytogenetic status, based on the presence of the following genetic abnormalities: translocations: t(4;14) or t(14;16), and the deletion: del(17p). In a pre-planned sub-group analysis, the PFS benefit of Kd versus Vd was assessed for high-risk cytogenetic status versus standard risk status, and the findings published in Leukemia in June 2017, by W-J. Chng and colleagues from the National University Cancer Institute, Singapore. For details of the clinical trial set-up, see previous MM Hub article.

Key Findings:

• Known cytogenetic risk status = 785 patients (pts) (84.5%); (n=381 for Kd; n=404 for Vd)
• High-risk cytogenetics = 210 pts (27%); (n=97 for Kd; n=113 for Vd)
• Standard-risk cytogenetics = 575 pts (73%)
• Data by cytogenetic subgroup given as Kd vs. Vd:
• High-risk: median PFS = 8.8 vs. 6.0 months (HR = 0.646; 95% CI, 0.453–0.921; P=0.0075)
• Standard-risk: median PFS = not estimable vs. 10.2 months (HR = 0.439; 95% CI, 0.333–0.578; P<0.0001)
• Pts with unknown cytogenetics (15.5% of pts): 15.4 vs. 12.2 months (HR = 0.673; 95% CI, 0.410–1.106; P=0.058)
• ORR:
  • High-risk = 72.2% vs. 58.4% (OR = 1.85, 95% CI, 1.03–3.30; P=0.019); CR or better = 15.5% vs. 4.4%
  • Standard-risk = 79.2% vs. 66.0% (OR = 1.97; 95% CI, 1.35–2.86; P=0.0002); CR or better = 13.0% vs. 7.9%
• Median DOR:
  • High-risk = 10.2 vs. 8.3 months; Standard-risk = not estimable vs. 11.7 months
• Median PFS:
  • del(17p) = 7.6 vs. 4.9 months; HR = 0.73; 95% CI, 0.42–1.27; P=0.13
  • t(4;14) = 10.1 vs. 6.8 months; HR = 0.63; 95% CI, 0.38–1.02; P=0.03
  • t(14;16) = too few pts
• Median PFS benefit was observed for Kd vs. Vd regardless of the number of prior treatment regimens, or the prior treatment exposure for both standard and high-risk pts

Safety:

• Safety of both Kd and Vd in all subgroups was consistent with data previously published for the overall population
• Treatment-emergent adverse events (TEAEs) = 70–75% vs. 63–68%
• TEAE-related treatment discontinuations = 19–22% with both Kd and Vd
• Grade ≥2 peripheral neuropathies: high-risk = 3.1% vs. 35.1%; OR = 0.059 (95% CI, 0.018–0.198); standard-risk group = 6.4% vs. 33.4%; OR = 0.135 (95% CI, 0.079–0.231)

In conclusion, the PFS benefit and superiority of carfilzomib and dexamethasone compared to bortezomib and dexamethasone, carries through into MM patients with high-risk genetic abnormalities, regardless of the number and type of prior treatment regimens. This finding is consistent with the sub-group analysis of the ASPIRE clinical trial, which assessed carfilzomib in combination with lenalidomide and dexamethasone, suggesting that the addition of carfilzomib offers a distinct advantage for patients with high-risk MM.

Abstract

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma(MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.