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Editorial Multiple Myeloma Measurable (Minimal) Residual Disease—A Meaningful Biomarker in Multiple Myeloma Manisha Bhutani and Saad Z Usmani Plasma Cell Disorders Program, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, US I ndividual studies and meta-analyses highlight superior survival outcomes among those multiple myeloma patients achieving measurable residual disease (MRD) negative status. With the availability of next-generation flow cytomery and sequencing technologies, it is realistically possible to track MRD response in every patient. As the scientific evidence mounts, MRD is being established as a desired end-point for clinical trials. Future efforts should be directed at validating MRD as a surrogate biomarker for developing curative strategies and determining how MRD can be used to guide therapeutic decisions. Keywords MRD, myeloma, biomarker, imaging, flow cytometry, ASO-qPCR, NGS, surrogate Disclosure: Manisha Bhutani and Saad Z Usmani have nothing to disclose in relation to this article. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received in the publication of this article. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: October 21, 2016 Published Online: November 2, 2016 Citation: Oncology & Hematology Review, 2016;12(2):75–6 Corresponding Author: Saad Z Usmani, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, US. E: saad.usmani@carolinashealthcare.org Treatment paradigms in multiple myeloma are undergoing rapid transformation. Deep remissions are possible in a large number of patients with new effective therapies with or without autologous stem cell transplantation (ASCT), and this improvement is seen among all categories including newly diagnosed, relapsed refractory, elderly, as well as high-risk patients. Despite an increasingly improving proportion of complete response (CR), relapse remains an inevitable occurrence. While poor disease biology is always to be blamed, persistence of measurable residual disease (MRD) at the time of conventionally defined CR is, arguably, one of the major reasons for relapse. Conventional methods for defining CR lack the sensitivity to detect clinically relevant burden of malignant plasma cells. The measurement of MRD using sensitive assays, including multiparameter flow cytometry (MFC), 1 allele- specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR), 2 and next-generation sequencing (NGS) techniques, 3 has unequivocally identified patients at high risk of disease recurrence and short survival. Consequently, more rigorous definitions of response have been developed by the International Myeloma Working Group (IMWG), with recent revisions that include the MRD-negative category as the deepest level of treatment response. 4 Based on several small- to medium-sized studies, two recent meta-analyses have confirmed the prognostic impact of MRD. 5,6 Munshi and colleagues conducted a meta-analysis of published studies from 1990–2016, including 14 studies for a pooled analysis of progression-free survival (PFS) and 12 for overall survival (OS). 6 In their meta-analysis, MRD negativity correlated with both PFS and OS, independent of the type of treatment, type/sensitivity of MRD assay, and other known prognostic factors including adverse cytogenetics. The median PFS was 54 versus 26 months and median OS was 98 versus 82 months for MRD-negative versus MRD-positive patients. MRD fared superior to conventional CR in predicting survival outcomes. Among patients with CR, those who remained MRD- positive had a shorter median PFS of 34 versus 56 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.34–0.56; p<0.001) and median OS of 82 versus 112 months (HR 0.47; 95% CI, 0.33–0.67; p<0.001) compared with MRD-negative patients. The greatest impact of MRD negativity was seen in patients receiving ASCT as frontline treatment, and in those with standard risk cytogenetics. The worst results were seen in patients with high-risk cytogenetics who remained MRD-positive (p<0.001). Similarly, in another meta-analysis, Landgren and colleagues found that MRD negativity (versus positivity) was associated with better PFS (HR, 0.35; 95% CI, 0.27–0.46; p<0.001) and OS (HR, 0.48; 95% CI, 0.33–0.70; p<0.001). 5 Several methods of MRD analysis are available for multiple myeloma. The MFC assay has gained wide acceptance, owing to easy availability, short turnaround time, and relatively low cost, however, there are a few limitations of this technique, namely low sensitivity (up to 1 × 10 −4 or −5 ) and lack of standardization among laboratories. The recent advances in the next-generation flow cytometry technology with the usage of eight or more colors/markers for an increased specificity allow TOU CH MED ICA L MEDIA 75