1. MRD = Minimal Resistant Disease?
Roger Owen
St James’s Institute of Oncology Leeds

2. “Minimal Resistant Disease”: challenges to consider.
Genomic heterogeneity
Spatial heterogeneity

3. Lahuerta et al, J Clin Oncol 2017; 35: 2900-2910

4. Rawstron AC et al, Blood 2015, Mar 19; 125(12): 1932–1935

5. Measurable residual disease
Rawstron AC et al, Blood 2015, Mar 19; 125(12): 1932–1935

6. Perrot et al; Blood 2018;132(23):2456-2464.

8. Blood Dec 6;132(23):

9. Phenotype of MRD vs diagnostic plasma cells (n = 40).
Phenotypic difference between presentation and MRD – upregulation of intergrins, adhesion molecule and CXCR4 – chemoresistant population with stronger interaction with BM stroma – not clear whether this is a primary phenomenon or epiphenomenon merely reflecting availability of the niche in an MRD setting.
No change in markers used for MRD
Paiva et al. Blood 2016;127:

11. “Clonal evolution from diagnosis to MRD clonal PCs”
CNAs presentation v MRD
3/12 identical in both presentation and relapse
9/12 changes in CNAs – in 3 this is due to additional CNAs in MRD and in 6 this due to loss of presentation CNAs and acquisition of new ones in MRD state
GEP >1000 differentially expressed genes
Paiva et al. Blood 2016;127:

12. Impact of MRD at 6M post maintenance randomisation
PFS not reached versus 24 months for MRD-positive patients, HR 0.22
Median PFS
MRD neg
Not reached
MRD pos
24m
HR : 0.22, 95% CI [0.14, 0.34]
Log-Rank P <
de Tute et al, ASH 2017

13. Benefits of maintenance
PFS advantage demonstrated in both MRD-neg and MRD-pos patients
Benefit of lenolidamide can be demonstrated in both MRD-negative patients (yellow vs blue) and MRD-positive patients (green vs red).
de Tute et al, ASH 2017

14. Benefits of maintenance
Conversions to MRD-negativity were seen in 30% of MRD-positive patients on maintenance compared to 4% of patients randomised to no further therapy (p=0.0045).
Conversion noted in all induction therapy groups

15. Cohen et al, 2019
Gambella et al, 2019

16. Benefits of maintenance
Positive to negative conversion is associated with some benefit in PFS
Early achievement of MRD-negativity is associated with best outcome, supporting data previously published by ourselves and other European groups. Conversion from pos to neg confers some benefit in PFS (blue line), with patients who remain MRD-pos throughout and those who have a reemergance of disease having a similarly poor outcome.

19. De novo
Relapse / Refractory
MRD-ve / imaging-ve
30 (36.1%)
8 (24.2%)
MRD-ve / imaging+ve
4 (4.8%)
MRD+ve / imaging-ve
39 (47.0%)
10 (30.3%)
MRD+ve / imaging+ve
10 (8.4%)
7 (21.2%)
Total 83 33

20. Pt with high-risk disease at presentation
Pt with high-risk disease at presentation. Multiple and widespread focal lesions on PET.
4 different clones at presentation
Sampling at relapse showed clone 1 with additional changes as well as a new clone (5) which was not demonstrable at presentation
Combined spatial and genomic heterogeneity

21. Blood Adv Nov 13;2(21):

22. Conclusions. Minimal Resistant Disease is complex!
Outcomes currently determined by quantitative residual disease and tumour genomics
MRD remains treatment sensitive in some patients
MRD plasma cells differ from presentation plasma cells but biological significance remains unclear
MRD markers remains stable
Considerable genomic and spatial heterogeneity which increases with disease progression