The Utility Of Minimal Residual Disease (MRD) Assessment At First Relapse: Results From The BSBMT/Ukmf Myeloma X (Intensive) Trial
Authors: Ashcroft John , de Tute Ruth M , Cairns David A , Fletcher Marie , Owen Roger G , Rawstron Andy , O'Connor Sheila J.M. , Williams Cathy D. , Snowden John A , Cavenagh J. D. , Parrish Christopher , Morris Treen , MB Brown Julia , Cook Gordon 
Published: October 2019

Abstract

Introduction
Minimal residual disease (MRD) assessment by multicolour flow cytometry (MFC) following upfront therapy is a powerful prognostic tool in multiple myeloma (MM) and there is growing evidence supporting its role as an outcome measure in clinical trials. There is however no published data assessing its utility in the relapse setting. Our aim was to test the utility of MFC at first relapse following a second autologous transplant (ASCT2) or weekly cyclophosphamide (C-weekly) consolidation following re induction chemotherapy in patients entered into the BSBMT/UKMF Myeloma X trial.

Patients and Methods
Eligible MM patients relapsing after a prior ASCT were enrolled and received a bortezomib-containing re-induction regimen (PAD, Bortezomib, Doxorubicin and Dexamethasone) before being randomized to either ASCT2 or C-weekly. The primary endpoint was time-to-progression (TTP) with secondary endpoints of overall survival and overall response rate (to PAD and randomized intervention). Bone marrow aspirate samples were analyzed by MFC at trial entry to establish neoplastic phenotype and then at specified time-points following treatment. After red cell lysis and washing, samples were labelled with CD27-FITC, CD56-PE, CD19-PerpCPCy5.5, CD38-PE-Cy7, CD138-APC and CD45-APC-Cy7. A minimum of 500,000 events were acquired on a FacsCanto II cytometer and data was analyzed using a standardized gating strategy. Sensitivity of the assay is 0.01% of leucocytes. Response assessment (after re-induction, 100 days post-ASCT2 or 30 days post C-weekly) and disease progression were determined using IMWG criteria. Unfavourable genetic abnormalities were defined as FGFR3/IGH, IGH/MAF and TP53 deletion by interphase FISH.

Results
297 patients with a median age of 61 (range 38 -75) were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n=89, C-weekly n=85. Of the whole trial cohort, MFC analysis was available in 224 at presentation, 162 at completion of re-induction therapy, 46/89 at D100 post ASCT2 and 50/85 at D30 post C-weekly.
In an intention to treat analysis of all available randomized patients, achieving MRD negativity was highly predictive for improved TTP: All patients (MRD+ 12mns 95%CI 10-13 vs. MRD- 24mns 95CI NR; logrank P=0.0003), ASCT arm (MRD+ 15mns 95%CI 11-19 vs. MRD- 24mns 95%CI 16-42; logrank P=0.0227) & C-weekly arm (MRD+ 11mns 95%CI 8-12 vs. MRD- 15mns 95%CI 9-NR) logrank P=0.0107).
MRD status was also assessed in conjunction with IMWG conventional categorical response assessment. CR was demonstrable in 39% of patients post ASCT2 and 22% of patients following C-weekly. The presence of MRD predicted outcome in those patients achieving a CR and the most favourable outcome was seen in CR/MRD- patients (<CR/MRD+ 11 mns (95%CI 9-12 mns), <CR/MRD- 16 mns (95%CI 4-29 mns), CR/MRD+ 10 mns (95%CI 7-24 mns) and CR/MRD- 25 mns (95%CI 15-41 mns); logrank p<0.0001).
MRD status was also assessed according to cytogenetic risk group as defined by interphase FISH. Adverse cytogenetics were present in 19% of patients. Achieving MRD negativity was associated with an improved outcome in patients with both favourable and adverse cytogenetic profiles: Adverse; MRD+ 10 mns (95%CI 8-11 mns), MRD- 23 mns (95%CI 16-25 mns), Favourable; MRD+ 11 mns (95%CI 9-13 mns), MRD- 16mns (95%CI 10-NR mns); logrank p= 0.0058.

Conclusion
These data clearly demonstrate that MRD assessment by MFC is a sensitive predictor of outcome in the first relapse setting, irrespective of the consolidation therapy given. MRD assessment predicts outcome in patients achieving CR and is applicable to patients with both favourable and adverse cytogenetics. This data is comparable to that published by us and others in the context of primary therapy and suggests that MRD assessment is an appropriate outcome measure in relapsed MM.

Disclosures:
Williams: Janssen: Honoraria, Speakers Bureau. Snowden:Janssen: Honoraria, Research Funding, Speakers Bureau.