S872 carfilzomib lenalidomide dexamethasone (krd) with or without transplantation in newly diagnosed myeloma (forte trial): efficacy according to risk status

Background: High and comparable rates of response and minimal residual disease (MRD) negativity were reported with four 28‐day induction cycles of KRd followed by autologous stem‐cell transplantation (ASCT) and 4 KRd consolidation (KRd_ASCT_KRd), and with 12 KRd cycles (KRd12) in newly diagnosed myeloma (NDMM) patients. Of note, both regimens were superior to carfilzomib‐cyclophosphamide‐dexamethasone (KCd) induction followed by ASCT and KCd consolidation (KCd‐ASCT‐KCd) (Gay F ASH 2018). Aims: We evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of patients according to their risk status. Methods: 474 NDMM patients ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10 −5 ) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with available Revised International Staging System (R‐ISS) 1 and R‐ISS 2/3. High‐risk patients may sometimes respond rapidly, but subsequently relapse early. Therefore, we also analyzed the rate of early relapse (<18 months from randomization) in the two arms. We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow‐up was 25 months. On intention‐to‐treat analysis, KRd_ASCT_KRd and KRd12 showed similar rates of ≥VGPR, ≥CR, sCR, MRD negativity in the overall population (Table 1A). Similarly, MRD negativity and response rates in the two treatment arms were comparable in the subgroups of patients with R‐ISS Stage 1 and with R‐ISS Stage 2/3 (Table 1B). Of note, rate of MRD negativity in high‐risk patients was around 50% (Table 1B). In the overall population, early relapses were significantly lower with KRd_ASCT_KRd vs KRd12 (12 patients [8%] vs 26 patients [17%]; P = 0.015), mainly related to a significantly lower rate of early relapse in patients with high risk status (R‐ISS Stage 2/3) (11 patients [12%] vs 22 patients [23%]; P = 0.05, respectively). Very few patients with R‐ISS Stage 1 relapsed, with no difference between KRd_ASCT_KRd and KRd12 (0 vs 2 patients). In multivariate regression analysis, patients receiving KRd_ASCT_KRd had a reduced risk of early relapse compared with those treated with KRd12 (OR 0.42; P = 0.021); R‐ISS Stage 2 (OR 3.6; P = 0.001) and R‐ISS Stage 3 (OR 4.85; P = 0.003) increased the risk of early relapse compared with R‐ISS 1. Summary/Conclusion: KRd‐ASCT‐KRd and KRd12 were equally effective in inducing high‐quality responses, and approximately 50% of high‐risk patients achieved MRD negativity. In addition, ASCT proved to be beneficial in high‐risk patients, reducing the risk of early relapse. image