Results of selected prospective clinical trials for newly diagnosed-transplant eligible patients carrying high-risk features
| Trial . | Regimen . | Study design (primary endpoint) . | Study definition of HR . | No. HR patients (%) . | Outcomes in HR vs SR . | PFS rates . | MRD− (%) . |
|---|---|---|---|---|---|---|---|
| CASSIOPEA53,115 | Dara-VTd vs VTd | Phase 3, transplant eligible (sCR at 100 d post-ASCT) | del(17p) ≥50% or t(4;14) ≥30% | 168 (15.5) | Prespecified subgroup analysis (sCR) showed consistent treatment benefit of D-VTd over VTd except for HR pts. However, ≥CR rates in HR pts favored D-VTd vs VTd (36.6% vs 32.6%; OR, 1.11; 95% CI, 0.58- 2.10). | D-VTd vs VTd reduced risk of progression/death (-53%) (median FU 18.8 mo): HzR 0.67; 95% CI, 0.35-1.30 (HR group) HzR 0.47; 95% CI, 0.33-0.67 (SR group) | 10−5 MRD post-cons (D-VTd vs VTd): 59.8% vs 44.2% (HR pts; OR, 1.88; 95% CI, 1.02-3.46) 63.7% vs 43.5% (all pts; OR, 2.27; 95% CI, 1.78-2.90; P < .0001) |
| GRIFFIN54 | Dara-VRd vs VRd | Phase 2, transplant eligible (sCR at the end of post-ASCT cons) | t(4;14), t(14;16), or del(17p) | 30 (15.4) | Subgroup analysis of sCR (end of post-ASCT at 13.5 mo): 18.8% (D-RVd) vs 30.8% (RVd), (OR, 0.52 95% CI, 0.09-2.90) | Median PFS not reached in either group. Insufficient power to analyze HR subgroup of pts | 10−5 MRD− at 22.1 mo FU (D-RVd vs RVd): 37.5 vs 28.6 (HR) 54.9 vs 20.5 (SR) 51.0 vs 20.4 (ITT) 47.1 vs 18.4 (ITT ≥CR) |
| STAMINA63,116 | ASCT + len maintenance (auto/len) vs ASCT + VRd consolidation + len maintenance (auto/VRd) vs tandem ASCT + len maintenance (auto/auto) | Phase 3, transplant eligible (38 mo PFS) | β2M > 5.5 mg/L, t(4;14), t(14;20), t(14;16), del (17p), del(13) detected by SC only, or aneuploidy | 223 (29) | 38-mo estimates PFS (95% CI): 57.6% (auto/len) vs 61.6% (auto/VRd) vs 62.9% (auto/auto) P value unavailable 6-y PFS in HR pts as treated analysis were 43.6% and 26% for auto/auto and auto/len, respectively (P = 0.03). | 38-mo estimates (95% CI): 57.6% (HR) vs 53.9% (SR) (auto/len) 61.6% (HR) vs 57.8% (SR) (auto/VRd) 62.9% (HR) vs 58.5% (SR) (auto/auto) PFS at 6 y (ITT population, P = 0.6): 40.9% (auto/len), 39.7% (auto/VRD), 43.9 (auto/auto), PFS at 6 y (as treated population, P = 0.03): 26% (HR) vs 38.6% (SR) (auto/len) NR (HR) vs 39.7% (SR) (auto/VRd) 43.6% (HR) vs 49.4% (SR) (auto/auto) | — |
| EMN02/HO9562 | VCD, followed by VMp or ASCT (single or tandem) | Phase 3, transplant eligible (PFS) | t(4;14) ≥10%, t(14;16) ≥10%, or del(17p) ≥20% | 225 (19) | Median PFS: 20.3 mo (VCD/VMp) vs 37.3 mo (VCD/ASCT), HzR 0.63 (95% CI, 0.46-0.88) | Median PFS: 20.3 mo (HR) vs 46.7 mo (SR) (VMp) 37.3 mo (HR) vs NR (SR) (ASCT) | — |
| GMMG-HD6 (NCT02495922) | VRD ± elo in induction and consolidation, followed by len-dex ± elo maintenance | Phase 3, transplant eligible (PFS) | — | — | Ongoing study | — | — |
| EMN18 (NCT03896737) | Dara-VCd vs VTd and ASCT, followed by Ixa ± Dara maintenance | Phase 3, transplant eligible (PFS, MRD neg) | del(17p) (≥ 10) or t(4;14) (≥ 15) or t(14;16) (≥ 15) | — | Ongoing study | — | — |
| GEM14 (NCT02253316) | Ongoing study | Phase II, transplant eligible (PFS) | — | — | Ongoing study | — | — |
| PERSEUS (NCT03710603) | VRd ± Dara followed by Len ± Dara maintenance | Phase III, transplant eligible (PFS) | del17p, t[4;14] and t[14;16], amp(1q21) | — | Ongoing study | — | — |
| Trial . | Regimen . | Study design (primary endpoint) . | Study definition of HR . | No. HR patients (%) . | Outcomes in HR vs SR . | PFS rates . | MRD− (%) . |
|---|---|---|---|---|---|---|---|
| CASSIOPEA53,115 | Dara-VTd vs VTd | Phase 3, transplant eligible (sCR at 100 d post-ASCT) | del(17p) ≥50% or t(4;14) ≥30% | 168 (15.5) | Prespecified subgroup analysis (sCR) showed consistent treatment benefit of D-VTd over VTd except for HR pts. However, ≥CR rates in HR pts favored D-VTd vs VTd (36.6% vs 32.6%; OR, 1.11; 95% CI, 0.58- 2.10). | D-VTd vs VTd reduced risk of progression/death (-53%) (median FU 18.8 mo): HzR 0.67; 95% CI, 0.35-1.30 (HR group) HzR 0.47; 95% CI, 0.33-0.67 (SR group) | 10−5 MRD post-cons (D-VTd vs VTd): 59.8% vs 44.2% (HR pts; OR, 1.88; 95% CI, 1.02-3.46) 63.7% vs 43.5% (all pts; OR, 2.27; 95% CI, 1.78-2.90; P < .0001) |
| GRIFFIN54 | Dara-VRd vs VRd | Phase 2, transplant eligible (sCR at the end of post-ASCT cons) | t(4;14), t(14;16), or del(17p) | 30 (15.4) | Subgroup analysis of sCR (end of post-ASCT at 13.5 mo): 18.8% (D-RVd) vs 30.8% (RVd), (OR, 0.52 95% CI, 0.09-2.90) | Median PFS not reached in either group. Insufficient power to analyze HR subgroup of pts | 10−5 MRD− at 22.1 mo FU (D-RVd vs RVd): 37.5 vs 28.6 (HR) 54.9 vs 20.5 (SR) 51.0 vs 20.4 (ITT) 47.1 vs 18.4 (ITT ≥CR) |
| STAMINA63,116 | ASCT + len maintenance (auto/len) vs ASCT + VRd consolidation + len maintenance (auto/VRd) vs tandem ASCT + len maintenance (auto/auto) | Phase 3, transplant eligible (38 mo PFS) | β2M > 5.5 mg/L, t(4;14), t(14;20), t(14;16), del (17p), del(13) detected by SC only, or aneuploidy | 223 (29) | 38-mo estimates PFS (95% CI): 57.6% (auto/len) vs 61.6% (auto/VRd) vs 62.9% (auto/auto) P value unavailable 6-y PFS in HR pts as treated analysis were 43.6% and 26% for auto/auto and auto/len, respectively (P = 0.03). | 38-mo estimates (95% CI): 57.6% (HR) vs 53.9% (SR) (auto/len) 61.6% (HR) vs 57.8% (SR) (auto/VRd) 62.9% (HR) vs 58.5% (SR) (auto/auto) PFS at 6 y (ITT population, P = 0.6): 40.9% (auto/len), 39.7% (auto/VRD), 43.9 (auto/auto), PFS at 6 y (as treated population, P = 0.03): 26% (HR) vs 38.6% (SR) (auto/len) NR (HR) vs 39.7% (SR) (auto/VRd) 43.6% (HR) vs 49.4% (SR) (auto/auto) | — |
| EMN02/HO9562 | VCD, followed by VMp or ASCT (single or tandem) | Phase 3, transplant eligible (PFS) | t(4;14) ≥10%, t(14;16) ≥10%, or del(17p) ≥20% | 225 (19) | Median PFS: 20.3 mo (VCD/VMp) vs 37.3 mo (VCD/ASCT), HzR 0.63 (95% CI, 0.46-0.88) | Median PFS: 20.3 mo (HR) vs 46.7 mo (SR) (VMp) 37.3 mo (HR) vs NR (SR) (ASCT) | — |
| GMMG-HD6 (NCT02495922) | VRD ± elo in induction and consolidation, followed by len-dex ± elo maintenance | Phase 3, transplant eligible (PFS) | — | — | Ongoing study | — | — |
| EMN18 (NCT03896737) | Dara-VCd vs VTd and ASCT, followed by Ixa ± Dara maintenance | Phase 3, transplant eligible (PFS, MRD neg) | del(17p) (≥ 10) or t(4;14) (≥ 15) or t(14;16) (≥ 15) | — | Ongoing study | — | — |
| GEM14 (NCT02253316) | Ongoing study | Phase II, transplant eligible (PFS) | — | — | Ongoing study | — | — |
| PERSEUS (NCT03710603) | VRd ± Dara followed by Len ± Dara maintenance | Phase III, transplant eligible (PFS) | del17p, t[4;14] and t[14;16], amp(1q21) | — | Ongoing study | — | — |
β2M, β2 microglobulin; cons, consolidation; CI, confidence interval; CR, complete response; FU, follow-up; HR, high-risk; HzR, hazard ratio; ITT, intention-to-treat population; Ixa, ixazomib; len, lenalidomide; NR, not reported; ns, not significant; OR, odds ratio; PFS, prgression-free survival; pts, patients; SC, standard cytogenetics; sCR, stringent complete response; SR, standard risk; VCd, bortezomib, cyclophosphamide and dexamethasone; VMp, bortezomib, melphalan, prednisone; VRd, bortezomib, lenalidomide, dexamethasone; VTd, bortezomib, thalidomide, dexamethasone.