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

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

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

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

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

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

Blood. 2018 Dec 6;132(23):2456-2464

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;127:1896-1906

“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;127:1896-1906

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 < 0.0001 de Tute et al, ASH 2017

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

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

Cohen et al, 2019 Gambella et al, 2019

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.

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

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

Blood Adv. 2018 Nov 13;2(21):2811-2813

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