Minimal Residual Disease Testing Dr Christopher Venner Cross

Minimal Residual Disease Testing Dr Christopher Venner Cross Cancer Institute University of Alberta

What is “MRD”? • Minimal Residual Disease • Disease that is detected below the levels we can detect using “old school” tests like: - serum and urine protein electrophoresis (“m-protein” and “bence-jones proteins”) - Serum free light chain tests (“kappa and lambda light chains”) • Complete response criteria is met when: - M-protein and BJPs disappear - s. FLC ratio is normal - Clonal plasma cells in bone marrow <10% https: //www. af 3 m. org/2017/09/Seminaire-d-information-et-desoutien-aux-patients-et-leurs-familles-a-Paris-samedi-10 -juin. html

Importance of disease detection • We are entering an era where CR is becoming a more common event (>50%) • Further refinement needed to assess burden of disease when this endpoint achieved • Goal is to: 1. Identify those that are expected to do very well (i. e. lowest burden of MM) 2. Modify follow-up and even therapy in those that may have higher residual disease • Options: - Flow cytometry (FCM) - Next Generation Sequencing (NGS)

Schematic representation to illustrate the paradigm of the deeper the response, the longer the (progression-free) survival (filled lines). Bruno Paiva et al. Blood 2015; 125: 3059 -3068 © 2015 by American Society of Hematology

How can you detect MRD? • Flow cytometry from bone marrow aspirate (liquid) sample - Look for “funny” plasma cells (termed aberrant) - Based on abnormal surface protein expression - Need 8 -10 color flow cytometry and significant expertise - Need a good marrow sample - Can detect down to 10 -4 - 10 -6

Flow cytometry https: //www. dzu-doodles. com/ http: //www. bioinformin. net/cytometry. php

How can you detect MRD? • Next generation sequencing (NGS) - Look for the DNA blue print for the genes encoding “clonal” antibody sequence - Unique sequence representative of only the myeloma cells - Does not change - Also requires bone marrow biopsy and requires that “sequence” defining a given patients disease is established at baseline - Can detect down to 10 -5 - 10 -6

Are we winning?

Prognosis Greipp et al, JCO 2005 Palumbo et al, JCO 2015

Alberta Benchmarks Breckenridge et al, ASH 2017

The Survival Impact of Lenalidomide Maintenance Chemotherapy in Multiple Myeloma Patients Treated with Autologous Stem Cell Transplant and Bortezomib. Based Induction; An Analysis of Real World Data Local CCI-based outcomes Cherniawsky et al, ASH 2017

Can we find the winners?

MRD by flow cytometry Outcomes by MRD in MRC Myeloma IX Rawstron et al, JCO 2013

MRD by NGS Martinez-Lopez et al, Blood 2014

Prospective data – IFM 2009 Trial Design: Arm 1: RVDx 3 – ASCT – RVDx 2 – Len maintenance x 1 yr Arm 2: RVDx 8 – Len maintenance x 1 yr

Prospective data – IFM 2009

Prospective data – IFM 2009

Prospective data – POLLUX Trial Design: Arm 1: Daratumumab – Lenalidomide – Dex Arm 2: Lenalidomide – Dex MRD: DRd = 26% Rd = 6%

Prospective data – POLLUX

Where do we go from here?

Where do we go from here?

Where do we go from here? Questions for the Alberta MM program • What technique do we chose? • How best to justify the cost? - ~$1000/test - Expect 2 – 3 tests/patient • Who do we test? - All or just ones meeting criteria for CR? • Can we change therapy based on this? - Can we stop treatment if MRD negative? - If so how to define sustained MRD negativity? • Can we justify the adoption of new therapy simply based on the rate of MRD negativity? - More rapid adoption and funding of novel therapies