Induction/consolidation is effective for patients with newly diagnosed multiple myeloma (NDMM) who are eligible for melphalan 200 mg/m2 + autologous stem-cell transplant (MEL200-ASCT), with high response rates seen with carfilzomib (K) + lenalidomide (R) + dexamethasone (KRd) or cyclophosphamide + dexamethasone (KCd). The primary aims of this analysis were to assess the progression-free survival (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 NDMM were randomized to KRd_ASCT for 4 28-day cycles with KRd induction (intravenous [IV] carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1-21; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, and 16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12; KCd_ASCT for 4 28-day induction cycles with KCd (IV carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; cyclophosphamide 300 mg/m2 on days 1, 8, and 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, and 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, and 16, subsequently amended to 70 mg/m2 on days 1 and 15 for up to 2 years; + lenalidomide 10 mg on days 1-21 every 28 days until progression) or lenalidomide alone (10 mg on days 1-21 every 28 days until progression) for maintenance. Minimal residual disease (MRD) analysis was conducted 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. Median PFS after a median follow-up of 45 months was significantly longer for KRd_ASCT versus KCd_ASCT (hazard ratio [HR], 0.53; P <.001), significantly longer for KRd_ASCT versus KRd12 (HR, 0.64; P = .023) and not significantly different for KRd12 versus KCd_ASCT (HR, 0.82; P =.262). Patients (n = 356) underwent a second randomization (R2) for maintenance, 178 to either KR or lenalidomide. Premaintenance responses were well matched, with ~60% of patients achieving complete response or better and ~65% being 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 (46% vs 32%; P = .04). The PFS was significantly longer after R2 in the KR arm versus the lenalidomide-alone arm (81% vs 68%; P = .026). The overall survival was 93% with KR and 90% with lenalidomide (P = .249).
A similar proportion of patients experienced ≥1 grade 3/4 hematologic adverse events (AEs)/serious AEs (SAEs) in both arms (22% [KR] vs 23% [lenalidomide]), with 18% and 21% of patients experiencing neutropenia with KR and lenalidomide, respectively, and 3% of patients in both arms experiencing thrombocytopenia. More patients experienced ≥1 grade 3/4 nonhematologic AEs/SAEs with KR (27%) versus lenalidomide (15%; P = .012), with infections being the most frequent (4% [KR] vs 7% [lenalidomide]). A second primary malignancy was observed in 4 patients receiving KR (n = 1 for the following: breast, thyroid, myelodysplastic syndrome, nonmelanoma skin cancer) versus 1 patient receiving lenalidomide (acute lymphoblastic leukemia). Dose reductions of lenalidomide occurred in 23% and 29% of patients in the KR and lenalidomide arms, respectively, and dose reductions of carfilzomib occurred in 20% of patients. The discontinuation rates resulting from toxicities were 10% versus 9% with KR and lenalidomide, respectively.
PFS was significantly longer with KRd_ASCT versus either KRd12 or KCd_ASCT in transplant-eligible patients with NDMM. A significant improvement in PFS was also observed upon maintenance with KR versus lenalidomide.
Abstract 141. ASH 2020. December 5, 2020. Survival Analysis of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients in the Randomized FORTE Trial.