The randomized FORTE trial showed that patients who were newly diagnosed with transplant-eligible multiple myeloma (MM) experienced significantly improved progression-free survival (PFS) with carfilzomib plus lenalidomide-dexamethasone (KRd) induction-ASCT-KRd consolidation versus either 12 KRd cycles or carfilzomib plus cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation.
Induction/consolidation is effective for patients with newly diagnosed MM who are eligible for melphalan 200 mg/m2 plus autologous stem-cell transplantation (MEL200-ASCT) with high response rates seen with KRd or KCd. Primary aims were to assess the PFS of KRd induction-ASCT-KRd consolidation (KRd_ASCT) versus 12 cycles of KRd (KRd12) versus KCd induction-ASCT-KCd consolidation (KCd_ASCT), and the PFS of KR versus lenalidomide monotherapy maintenance.
Patients aged ≤65 years with newly diagnosed MM were randomized to KRd_ASCT: four 28-day cycles with KRd induction (carfilzomib 20/36 mg/m2 intravenous [IV] on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg on days 1-21; dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd_ASCT: four 28-day induction cycles with KCd (carfilzomib 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, 16; cyclophosphamide 300 mg/m2 on days 1, 8, 15; dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Patients were then randomized to KR (carfilzomib 36 mg/m2 on days 1, 2, 15, 16, subsequently amended to 70 mg/m2 on days 1 and 15 for ≤2 years; plus lenalidomide 10 mg days 1-21 every 28 days until progression) or lenalidomide alone (10 mg on days 1-21 every 28 days until progression) for maintenance. Analysis of minimal residual disease (MRD) was assessed in patients with very good partial response or better before maintenance and then every 6 months.
Patients with NDMM were randomized 158, 157, and 159 to KRd_ASCT, KRd12, and KCd_ASCT, respectively. After a median follow-up of 45 months, median PFS was significantly longer for KRd_ASCT versus KCd_ASCT (not reached [NR] vs 57 months; hazard ratio [HR], 0.53; P <.001), significantly longer for KRd_ASCT versus KRd12 (NR vs 53 months; HR, 0.64; P = .023), and not significantly different for KRd12 versus KCd_ASCT (HR, 0.82; P = .262). Three-year overall survival for both KRd_ASCT and KRd12 was 90% versus 83% for KCd. Patients (N = 356) underwent a second randomization (R2) for maintenance: 178 to either KR or lenalidomide. Premaintenance responses were well-matched; approximately 60% of patients were in status of complete response or better; approximately 50% in stringent complete response; and approximately 65% were MRD-negative. Significantly more patients who were MRD-positive at randomization transitioned to MRD-negative with KR versus lenalidomide after a median follow-up of 31 months and a median duration of maintenance of 27 months (46% vs 32%; P = .04). Three-year PFS was significantly longer after R2 in the KR arm versus lenalidomide alone (75% vs 66%; P = .026). Three-year overall survival was 90% with both KR and lenalidomide.
There was a similar proportion of patients who experienced ≥1 grade 3/4 hematologic adverse events (AEs)/serious AEs in both arms (22% [KR] vs 23% [lenalidomide]); 18% and 21% of patients experienced neutropenia with KR and lenalidomide, respectively, and 3% of patients in both arms experienced thrombocytopenia. More patients experienced ≥1 grade 3/4 nonhematologic AEs/serious AEs with KR (27%) versus lenalidomide (15%), P = .012; infections were the most frequent (4% [KR] vs 7% [lenalidomide]). For 4 patients receiving KR, a second primary malignancy was observed (n = 1 for the following: breast, thyroid, myelodysplastic syndrome, nonmelanoma skin cancer) versus 1 patient receiving lenalidomide (acute lymphoblastic leukemia). In 23% and 29% of patients, dose reductions of lenalidomide occurred in the KR and lenalidomide arms, respectively, and in 20% of patients, dose reductions of carfilzomib occurred. Discontinuation rates due to AEs were 10% (KR) versus 9% (lenalidomide).
In patients who were newly diagnosed with transplant-eligible MM, PFS was significantly longer with KRd_ASCT versus either KRd12 or KCd_ASCT. A significant improvement in PFS was also observed on maintenance with KR versus lenalidomide.
Reference
Abstract 141. ASH 2020. December 5, 2020. Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized Forte trial.
