Suzuki, Kenshi

AbstractDeeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression‐free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0–4 months; n = 424) versus late responders (best confirmed response >4 months; n = 281). Newly diagnosed patients enrolled in TOURMALINE‐MM2 receiving ixazomib‐lenalidomide‐dexamethasone (IRd) (n = 351) or placebo‐Rd (n = 354) were evaluated post hoc. Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS (n = 511) or DOR (n = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo‐Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo‐Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor‐immunomodulatory drug‐steroid combination is not a negative predictor of outcome.

Abstract Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.