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MRD testing: which platforms, which patients?
Roger Owen St James’s Institute of Oncology Leeds
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HR for PFS 0.41 HR for OS 0.57
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Multivariate analysis.
Rawstron et al, Blood 2015
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MRD: Transplant eligible, the story so far……………….
Predicts PFS and OS including CR pts Cytogenetic risk groups Independent of treatment
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Myeloma XI – transplant ineligible schema
Induction 1 Induction 2 Maintenance Max. response CTD PD SD CVD Lenalidomide R 1:1 MR PR R 1:1 R 1:1 CRD No CVD Observation VGPR CR Cochrane Armitage trend test N=297/1852 Median age 74.0 yrs (56-87) 62.8% male IgG 60.5% ISS III 34.2% MRD
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Overall 41/297 (13.8%) achieved MRD-negativity
Results Overall 41/297 (13.8%) achieved MRD-negativity CTDa CRDa MRD-negativity 16/143 (11.2%) 25/154 (16.2%) P=0.24 Cochran-Armitage Trend test P=0.22
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PFS according to MRD (qualitative)
Median PFS 18 month vs 34 month HR 0.44
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OS according to MRD Median PFS 18 month vs 34 month HR 0.44
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Impact of therapy.
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PFS according to MRD (quantitative)
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MRD and cytogenetic risk
Paiva et al. Blood 2016;127:
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Maintenance.
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Improvement in response during maintenance
Morgan et al, ASH 2016
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No change in conventional response with thalidomide maintenance but clear differences in neoplastic plasma cell levels “Using electrophoresis and immunofixation as a monitoring technique, there was no difference between the thalidomide maintenance and no maintenance arms in the percentage of patients that upgraded response status over time (P .19).” (1) 27.6 96 3.4 68.8 20 40 60 80 100 Become MRD negative Remain MRD negative Thalidomide maintenance No maintenance (2) Morgan et al, Blood 2012, 119(1): 7-15 Rawstron, JCO 2013; 31(20):2540-7
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297 pts 184 pts randomised Day 100 MRD 90 pts
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Myeloma X: TTP according to MRD
HR 0.39 Median TTP 8 v 20 months N=90
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Myeloma X: OS according to MRD
HR 0.52 Median OS 51 v 67 months N=90 Effect of Len salvage?
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PFS According to MRD Status at 10–5
POLLUX CASTOR 100 100 Vd MRD– Rd MRD– DVd MRD– DRd MRD– 80 80 DRd MRD+ 60 60 Patients progression free and alive (%) Patients progression free and alive (%) DVd MRD+ 40 40 Rd MRD+ 20 20 Vd MRD+ 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 Months Months Patients at risk Patients at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive 16 71 267 215 16 71 233 195 16 71 190 178 15 70 166 167 15 66 144 161 12 57 120 137 10 28 38 54 6 5 9 1 Vd MRD negative DVd MRD negative Vd MRD positive DVd MRD positive 6 26 241 225 6 26 176 189 6 26 123 172 5 26 68 134 3 15 20 76 2 7 26 1 4 1
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Proportion of MRD-negative Patients at 10–4, 10–5, and 10–6 Thresholds
POLLUX CASTOR *** 3.6X *** 4.4X *** 4.8X *** 5.1X ** 4.3X * 5.5X Sensitivity threshold 10–4 10–5 10–6 10–4 10–5 10–6 Daratumumab in combination with standard of care significantly improved MRD-negative rates at all thresholds *** P < ** P <0.005. * P <0.05. P values calculated using likelihood-ratio chi-square test. This slide contains information about an unlicensed indication or medicine
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Comparison of methods. Flow cytometry ASO-PCR NGS Applicability
>95% 60% ~90% Sensitivity 10-4/10-5 10-5 10-5/10-6 False positive No Potentially False negative Yes Baseline sample Desirable Essential Quality assessment Cost Low High Turnaround times Short ?Medium Quantitative Direct Yes, but……
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Flow v NGS Marinez-Lopez et al, Leukemia 2017 epub
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Post anti-CD38 therapy CD38 expression absent on all populations:
Plasma cells B-progenitors Monocytes impacts plasma cell identification CD319 CD229 Multi-epitope CD38
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Conclusions. Increasing applicability of MRD assessment
Trial and regulatory endpoint MFC and NGS both applicable Challenge in daratumumab treated patients
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