OPTIMISING TREATMENT FOR HIGH-RISK MYELOMA IN A STRATIFIED MULTI-CENTRE TRIAL: EXPERIENCE FROM MUKNINE OPTIMUM STUDY
Author(s): ,
Vallari Shah
Affiliations:
The Institute of Cancer Research,London,United Kingdom;The Royal Marsden Hospital,London,United Kingdom
,
Samantha Hinsley
Affiliations:
Leeds Institute of Clinical Trials Research, Leeds University,Leeds,United Kingdom
,
Amy Sherborne
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Sidra Ellis
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Amy Price
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Jack Kendall
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
David Johnson
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Roger Owen
Affiliations:
St James University Hospital,Leeds,United Kingdom
,
Mark Drayson
Affiliations:
University of Birmingham,Birmingham,United Kingdom
,
Louise Flanagan
Affiliations:
Leeds Institute of Clinical Trials Research, Leeds University,Leeds,United Kingdom
,
Debbie Sherratt
Affiliations:
Leeds Institute of Clinical Trials Research, Leeds University,Leeds,United Kingdom
,
Walter Gregory
Affiliations:
Leeds Institute of Clinical Trials Research, Leeds University,Leeds,United Kingdom
,
Graham Jackson
Affiliations:
Newcastle University,Newcastle,United Kingdom
,
Guy Pratt
Affiliations:
University Hospitals Birmingham NHS Foundation Trust,Birmingham,United Kingdom
,
Gordon Cook
Affiliations:
Leeds Institute of Cancer and Pathology, University of Leeds, Leeds,Leeds,United Kingdom
,
Sarah Brown
Affiliations:
Leeds Institute of Clinical Trials Research, Leeds University,Leeds,United Kingdom
,
Matthew Jenner
Affiliations:
University Hospital Southampton,Southampton,United Kingdom
Martin Kaiser
Affiliations:
The Institute of Cancer Research,London,United Kingdom;The Royal Marsden Hospital,London,United Kingdom
EHA Library. Kaiser M. Jun 16, 2018; 215634; PS1334
Dr. Martin Kaiser
Dr. Martin Kaiser
Contributions
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Abstract

Abstract: PS1334

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background
Outcomes for newly diagnosed myeloma (NDMM) patients with high risk molecular tumor features remain unsatisfactory. 

Aims
Insights from trials in relapsed myeloma and tumor evolutionary studies suggest that multi-targeted combination therapies could improve outcomes through eradication of rapidly evolving tumor sub-clones. We report here an update on one of the first multi-centre clinical trials for high risk NDMM, Myeloma UK (MUK) nine: OPTIMUM (NCT03188172).

Methods
MUKnine OPTIMUM investigates the five-drug combination Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, Dexamethasone (DCVRd) followed by high dose melphalan + ASCT augmented by Bortezomib, intensified consolidation (DVR) and maintenance (DR) in high risk NDMM. Challenges inherent to high risk sub-group trials were addressed in line with recommendations for trials in rare cancers (Bogaerts, Eur J Canc 2015). Outcomes for DCVRd are compared using a Bayesian strategy against molecularly matched near-concurrent high risk NDMM treated on the Myeloma XI trial. Precise molecular definition of high risk is key and based on evidence from independent Myeloma IX and Myeloma XI trials demonstrating the specific association of presence of 2 or more (‘double-hit’) high-risk genetic lesions (Adverse translocations; del(1p32); gain(1q21); del(17p)) AND/OR a SKY92 High Risk GEP Profile with adverse PFS and OS. Molecular risk screening is performed in a central laboratory using a combination of molecular genetic (MRC Holland) and gene expression (SkylineDx) assays. Primary endpoint of MUKnine is a 25% improvement in PFS over to the molecularly matched comparator high risk group from Myeloma XI. Central longitudinal flow-based MRD (10-5) is assessed for early surrogate PFS endpoint assessment and monitoring of disease dynamics. Up to 620 newly diagnosed patients will be molecularly screened and up to 105 patients with high risk status will receive OPTIMUM DCVRd therapy. Patient reported outcomes and clinical outcomes for non-high risk patients form part of the analysis.

Results
OPTIMUM opened to recruitment in October 2017 and at the time of abstract submission 41 patients have been registered for central molecular risk profiling. For 37 patients screening results were successfully generated, 4 samples failed due insufficient bone marrow myeloma cell content. Turnaround time for central screening results was on average 17 days (range 6-33 days), shorter than the protocol-defined maximum of 56 days. If clinically indicated, patients received up to two cycles of local standard induction therapy, e.g. VTD, whilst central screening was performed. Tumour cells from 18 patients were found to carry molecular high risk features as defined above, 7 were high risk by ‘double-hit’ genetics and SKY92, 3 by ‘double-hit’ only and 8 by SKY92 only. This overlapping but non-identical identification of high risk by genetic and GEP profiling prospectively confirms findings from MRC Myeloma IX and NCRI Myeloma XI and supports combined molecular testing, in particular for molecularly stratified trials. At the time of abstract submission, ten high risk patients had been registered for DCVRd therapy. Updated screening and recruitment results will be presented at the meeting.

Conclusion
We provide a first update on central molecular screening feasibility for stratification in the multi-centre UKMRA MUKnine OPTIMUM trial investigating five-drug combination therapy in high risk NDMM.

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

Keyword(s): Gene expression profile, Myeloma, Prediction, Risk factor

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