EFFICACY OF QUADRUPLET KCRD (CARFILZOMIB, CYCLOPHOSPHAMIDE, LENALIDOMIDE AND DEXAMETHASONE) INDUCTION FOR NEWLY DIAGNOSED MYELOMA PATIENTS: ANALYSIS OF THE MYELOMA XI STUDY BY MOLECULAR RISK
Author(s): ,
Charlotte Pawlyn
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Martin Kaiser
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Faith Davies
Affiliations:
Perlmutter Cancer Center,NYU Langone Health,New York,United States
,
David Cairns
Affiliations:
Clinical Trials Research Unit,Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Alina Striha
Affiliations:
Clinical Trials Research Unit,Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Anna Hockaday
Affiliations:
Clinical Trials Research Unit,Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Bhuvan Kishore
Affiliations:
Heart of England NHS Foundation Trust,Birmingham,United Kingdom
,
Mamta Garg
Affiliations:
Leicester Royal Infirmary,Leicester,United Kingdom
,
Cathy Williams
Affiliations:
Centre for Clinical Haematology,Nottingham University Hospital,Nottingham,United Kingdom
,
Kamaraj Karunanithi
Affiliations:
University Hospital of North Midlands,Stoke-on-Trent,United Kingdom
,
Jindriska Lindsay
Affiliations:
East Kent Hospitals University NHS Foundation Trust,Canterbury,United Kingdom
,
John Jones
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Matthew Jenner
Affiliations:
University Hospital Southampton NHS Foundation Trust,Southampton,United Kingdom
,
Nigel Russell
Affiliations:
Centre for Clinical Haematology,Nottingham University Hospital,Nottingham,United Kingdom
,
Gordon Cook
Affiliations:
Leeds Institute of Cancer and Pathology,University of Leeds,Leeds,United Kingdom
,
Mark Drayson
Affiliations:
Institute of Immunology and Immunotherapy,University of Birmingham,Birmingham,United Kingdom
,
Roger Owen
Affiliations:
St James’s University Hospital,Leeds,United Kingdom
,
Walter Gregory
Affiliations:
Clinical Trials Research Unit,Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Gareth Morgan
Affiliations:
Perlmutter Cancer Center,NYU Langone Health,New York,United States
Graham Jackson
Affiliations:
Department of Haematology,Newcastle University,Newcastle,United Kingdom
EHA Library. PAWLYN C. Jun 15, 2019; 267456; S873
Dr. Charlotte PAWLYN
Dr. Charlotte PAWLYN
Contributions
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Abstract

Abstract: S873

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 16:30 - 16:45

Location: Auditorium

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) 36mg/m2 IV d1-2, 8-9, 15-16 (20mg/m2 #1d1-2), cyclophosphamide (C) 500mg PO d1,8, lenalidomide (R) 25mg PO d1-21, dexamethasone (D) 40mg 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, phet=0.7841). For patients receiving KCRD there was no difference in response rate at the end of induction 1 by risk group (>=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.

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.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Immunomodulatory thalidomide analog, Myeloma, Proteasome inhibitor

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