S873 EFFICACY OF QUADRUPLET KCRD (CARFILZOMIB, CYCLOPHOSPHAMIDE, LENALIDOMIDE AND DEXAMETHASONE) INDUCTION FOR NEWLY DIAGNOSED MYELOMA PATIENTS: ANALYSIS OF THE MYELOMA XI STUDY BY MOLECULAR RISK
Authors: C. Pawlyn, M. Kaiser, F. Davies, D. Cairns, A. Striha, A. Hockaday, B. Kishore, M. Garg, C. Williams, K. Karunanithi, J. Lindsay, J. Jones, M. Jenner, N. Russell, G. Cook, M. Drayson, R. Owen, W. Gregory, G. Morgan, G. Jackson
Journal: HemaSphere (2019)

Background: Carfilzomib is a second‐generation irreversible proteasome inhibitor that has shown significant efficacy in phase III studies of relapsed myeloma patients. The UK NCRI Myeloma XI study is the first phase III randomised study that has reported outcomes for the use of carfilzomib as induction therapy in newly diagnosed myeloma patients prior to autologous stem cell transplant (ASCT). The KCRD combination deepened responses and prolonged progression‐free survival compared to response adapted immunomodulatory agent‐based triplet +/‐ proteasome inhibitor‐based triplet therapy (Jackson GH et al , ASH 2018). Aims: In this exploratory analysis we examine the efficacy of KCRD compared to triplet therapy across different molecular subgroups within the Myeloma XI trial. Methods: 1056 patients were randomised between KCRD (28 day cycles of carfilzomib (K) 36 mg/m2 IV d1‐2, 8–9, 15–16 (20 mg/m2 #1d1‐2), cyclophosphamide (C) 500 mg PO d1,8, lenalidomide (R) 25 mg PO d1‐21, dexamethasone (D) 40 mg PO d1‐4,8‐9,15‐16) and triplet CTD/CRD prior to ASCT. Patients who received CTD/CRD underwent response‐adapted intensification for suboptimal responders with a randomization to proteasome inhibitor (bortezomib, CVD) containing triplet or no further therapy. A maintenance randomisation at 3 months post ASCT compared lenalidomide to observation. Molecular analysis was available for a representative subset of patients (n = 339). High‐risk (HiR) was classified in the study as the presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra‐high risk (UHiR) the presence of two or more lesions. Exploratory analyses of outcome by individual molecular risk lesion and by HiR defined without the inclusion of gain(1q) and t(14;20) were also performed. Efficacy analyses included PFS and response. Results: KCRD was associated with a significantly longer PFS than triplet therapy for the whole population, with no significant heterogeneity between risk groups (standard risk (SR) hazard ratio (HR) 0.55, 95%CI 0.33, 0.92, median PFS KCRD NR vs CTD/CRD 36 months), HiR (HR 0.68, 95%CI 0.40, 1.19, median PFS KCRD NR vs CTD/CRD 37 months) and UHiR (HR 0.72, 95%CI 0.26, 2.02, median PFS KCRD 25 vs CTD/CRD 20 months, p het = 0.7841). For patients receiving KCRD there was no difference in response rate at the end of induction 1 by risk group (&gt; = VGPR: SR 86.0%, HiR 87.0% and UHiR 88.2%). However, UHiR disease was associated with significantly shorter PFS than both SR (p = 0.0073) and HiR (p = 0.0180) whilst there was no significant difference in outcome between patients with HiR (only one adverse lesion) and SR (p = 0.7213). Within groups of patients with each HiR lesion there was a benefit for KCRD over CTD/CRD. The lowest hazard ratio was observed in patients with a del(17p), (HR 0.12, 95%CI 0.03, 0.51, median PFS KCRD 38 vs CTD/CRD 17 months). When HiR was defined only by the presence of t(4;14), t(14;16) and/or del(17p) there remained a significant benefit for KCRD over CTD/CRD (HiR: HR 0.38, 95%CI 0.19, 0.77, median PFS KCRD 38 vs CTD/CRD 22 months, SR: HR 0.58, 95%CI 0.39, 0.88, median PFS KCRD NR vs CTD/CRD 38 months) with no heterogeneity of effect identified between risk groups. Summary/Conclusion: KCRD is associated with prolonged PFS compared with response‐adapted triplet therapy across all molecular risk subgroups, however these are defined. Even with the highly effective quadruplet combination KCRD, UHiR patients continue to have significantly worse outcomes than patients with standard risk disease and there remains an unmet need for novel therapeutic approaches for these patients.