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.
- 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)
- 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 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.
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.