1. MRD testing: which platforms, which patients?
Roger Owen St James’s Institute of Oncology Leeds

2. HR for PFS 0.41
HR for OS 0.57

4. Multivariate analysis.
Rawstron et al, Blood 2015

5. MRD: Transplant eligible, the story so far……………….
Predicts PFS and OS including CR pts
Cytogenetic risk groups
Independent of treatment

6. 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

7. 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

8. PFS according to MRD (qualitative)
Median PFS 18 month vs 34 month
HR 0.44

9. OS according to MRD
Median PFS 18 month vs 34 month
HR 0.44

10. Impact of therapy.

11. PFS according to MRD (quantitative)

12. MRD and cytogenetic risk
Paiva et al. Blood 2016;127:

13. Maintenance.

14. Improvement in response during maintenance
Morgan et al, ASH 2016

15. 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

16. 297 pts
184 pts randomised
Day 100 MRD 90 pts

17. Myeloma X: TTP according to MRD
HR 0.39
Median TTP 8 v 20 months
N=90

18. Myeloma X: OS according to MRD
HR 0.52
Median OS 51 v 67 months
N=90
Effect of Len salvage?

20. 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

21. 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.
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22. 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……

23. Flow v NGS
Marinez-Lopez et al, Leukemia 2017 epub

24. Post anti-CD38 therapy CD38 expression absent on all populations:
Plasma cells
B-progenitors
Monocytes
impacts plasma cell identification
CD319
CD229
Multi-epitope CD38

25. Conclusions. Increasing applicability of MRD assessment
Trial and regulatory endpoint
MFC and NGS both applicable
Challenge in daratumumab treated patients