Flow cytometry detection of minimal residual disease in multiple myeloma: Lessons learned at FDA-NCI roundtable symposium.

Abstract

To the Editor: The qualification process for a surrogate endpoint biomarker as a development tool is a formalized process based on evidentiary standards and FDA requirements exist regarding the use of minimal residual disease (MRD) as an endpoint for drug approval. For regulatory approval, a surrogate must be shown to be reasonably likely to predict clinical benefit but this must be coupled with a clear understanding of the disease process, and the effect of the intervention on both the clinical benefit endpoint and the biomarker. It is also important to recognize the relationship between the biomarker and different interventions and to identify confounding factors that may diminish the correlation of the biomarker and the clinical benefit endpoint 1-3. Finally, standardization of the definition and assessment methods for MRD is necessary for wider implementation, generalizability, and interpretation of results. Recently, an FDA-NCI Roundtable Symposium on the flow cytometric detection of MRD in multiple myeloma was held at the FDA in Silver Spring, Maryland 4 with the goals to: (a) examine the evidence on the clinical utility of MRD in multiple myeloma as a surrogate biomarker for drug response; and to (b) ascertain the status of consensus concerning the standardization of a flow cytometric device (assay) (and its relationship to molecular tests) for the detection of MRD in multiple myeloma. Over the past decade, the proportion of patients with multiple myeloma achieving a complete response (CR) has risen to 50–75% of patients with many reaching stringent CR (sCR) 5. As expected, clinical studies show that patients with multiple myeloma reaching a deeper response to therapy have a better progression-free survival (PFS) and overall survival (OS). Interestingly, recent studies focusing on patients achieving CR after high-dose therapy show up to about 30% have detectable MRD by former (standard-sensitivity) flow cytometry assessment of bone marrow aspirates (i.e., flow cytometry MRD positive) 2, 6. Furthermore, within the group of patients with multiple myeloma who achieve a CR, those that are flow cytometry MRD negative have significantly better PFS and OS compared to those patients with multiple myeloma who reach CR but are MRD positive 7. Based on a smaller number of patients with multiple myeloma, molecular assays (e.g., sequencing of IgH locus and PCR based assays) have been reported to correlate with flow cytometry MRD testing 7. Additionally, molecular imaging has been reported to play a role in the determination of MRD status 8. Virtually every study focusing on MRD testing in myeloma has reported that being MRD negative is associated with better PFS and some studies have found MRD negativity to be associated with better OS 1, 2, 6, 7. Therefore, as proposed, MRD testing needs to be accurately defined in the uniform response criteria for multiple myeloma and consequently, MRD should be considered for regulatory purposes including drug approval in the field of multiple myeloma 4. To facilitate this process, preliminary strategies for flow cytometry MRD testing have been developed 4. Indeed, efforts are ongoing with stakeholders to develop new International Myeloma Working Group (IMWG) “response criteria” for use in clinical trials and to agree upon development and implementation details. Importantly, as proposed, future studies are needed to further expand our knowledge regarding optimal antigen panels as well the role of molecular assays (e.g., sequencing of IgH locus and PCR based assays) 4. Given the consistent body of data showing that flow cytometric MRD detection is associated with better PFS, and some studies showing an association with better OS 1, 2, 6, 7, we conclude that the introduction of well-validated protocols for flow cytometric MRD testing in multiple myeloma has the potential to pave the way for cell-based and molecular-based surrogate biomarkers 7 as endpoints in clinical trials for multiple myeloma within the near future. Ola Landgren,1* Nicole Gormley,2 Danielle Turley,2 Roger G. Owen,3Andy Rawstron,3 Bruno Paiva,4 David Barnett,5 Maria Arroz,6 Paul Wallace,7Brian Durie,8 Constance Yuan,1 Ahmet Dogan,9Maryalice Stetler-Stevenson,1 and Gerald E. Marti2 1National Cancer Institute (NCI), Bethesda, Maryland; 2U.S. Food and Drug Administration (FDA), Silver Spring, Maryland; 3HMDS Laboratory, St James's Institute of Oncology, Leeds, United Kingdom; 4Clínica Universidad de Navarra; Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain; 5UK NEQAS for Leucocyte Immunophenotyping, Royal Hallamshire Hospital, Shefield, England; 6Centro Hospitalar de Lisboa Ocidental (CHLO), HSFX, Clinical Pathology Department, Lisbon, Portugal; 7Roswell Park Cancer Institute, Department of Flow and Image Cytometry, Buffalo, New York; 8Cedars-Sinai Comprehensive Cancer Center, Los Angeles, California; 9Hematopathology Service, Memorial Sloan-Kettering Cancer Center, New York, New York