Defining the Standard in MRD Detection and Quantification
There have been tremendous advances in the treatment of blood cancers over the last sixty years. Take for example multiple myeloma (MM): In the 1950s the five-year survival rate was about 10%, and now it is more than 50%. Based on the recent trajectory of improvement gained from the rapid introduction of new treatments, some estimate that five-year survival could reach more than 65% for MM patients diagnosed in 2014.
Improved survival rates are a product of increased rates of response to treatment and increased depth of these responses. For many types of blood cancers, disease can now be reduced to levels undetectable by traditional techniques. However, many patients will still ultimately relapse due to the presence of minimal residual disease (MRD). Measuring MRD is thus gaining importance in the clinical, research, and regulatory settings.
For MRD quantification to be optimally used for prognostication in the clinical setting, or as a component of clinical trials, a technique that can be applied consistently and objectively is critical. A recent survey showed major heterogeneity in the practice of the MRD measurement method most commonly used currently, flow cytometry, which determines the percentage of cells in a sample that are cancerous based on analysis of combinations of cell surface markers.
Results from labs reporting on their methods for measuring MRD in MM patients showed considerable variation in the number of bone marrow cells analyzed for each patient, and number of abnormal plasma cells needed to define the presence of MRD, which together define the maximum achievable sensitivity. In fact, there was a 100-fold difference in sensitivity between the most and least sensitive labs (range: 0.0005% to 0.02%). There was also variation in the cell surface markers analyzed and the definitions of “abnormal” cells used in each lab.
Adaptive’s next-generation sequencing-based MRD detection and quantification method avoids the issues of standardization seen with flow cytometry. The clonoSEQ® Process uses a reproducible, universal assay to measure a stable DNA marker, and the assay’s digital readout is analyzed using automated algorithms that can account for the presence of multiple cancer clones and clonal evolution.
Sensitivity is also an important parameter for any MRD measurement method, especially in the era of novel therapies. The most sensitive flow cytometry protocols can reach a sensitivity of only about 0.001% (1 cancer cell per 100,000 white blood cells). The clonoSEQ MRD Test, however, has been shown to detect MRD at levels as low as 0.0001% (1 cancer cell per 1 million white blood cells). The clinical significance of this increased sensitivity was suggested in a recent study that showed that among patients who were all MRD negative as assessed by flow cytometry, there were actually some in whom MRD could be detected using our sequencing-based technology. Importantly, those patients in the flow cytometry-based MRD negative group who were MRD positive by sequencing progressed sooner than those who were MRD negative by sequencing.
Testing for MRD can help determine whether cancer treatment has been successful, provide important information about patient prognosis and help guide additional treatment decisions. MRD measurement can also be used to improve and accelerate the drug development process. Adaptive’s clonoSEQ Process is the only universal, standardized MRD assessment method, and it has repeatedly demonstrated superior sensitivity and specificity.