Minimal residual disease in multiple myeloma: are we there yet?

Multiple myeloma (MM) is one of the common hematological malignancies and, according to SEER data, 32,000 newly diagnosed cases are reported per year. It accounts for 1.8% of all cancers and around 17% of all hematological malignancies in the USA [1]. The presentation of MM is variable, with patients usually presenting with back pain, anemia and/or renal failure, while a small percentage of patients present with explosive clinical course, which can be life threatening. Despite several new drugs being approved by the US FDA (MD, USA) in the past few years, MM remains incurable and the overall survival (OS) of newly diagnosed high-risk MM patients is poor. Some of the challenges in achieving long-term remission or potential cure in MM patients are intraclonal and interclonal heterogeneity and lack of reliable indicators of deep treatment response. Minimal residual disease (MRD) assay is one such tool for measuring deeper response to treatment which, if sustained, could pave the way for cure. In an attempt to facilitate accurate comparison of novel treatment strategies, in 2006 the International Myeloma Working Group (IMWG) developed the first international consensus criteria for response evaluation in MM based on the guidelines published by the European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry (EBMT/IBMTR) in 1998 [2,3]. Complete response (CR) was defined as absence of monoclonal protein in the serum and/or urine and bone marrow showing less than 5% plasma cells. To refine the response assessment, the 2011 IMWG guidelines introduced four-color flow cytometry and allele specific oligonucleotide-PCR (ASO-PCR) to define immunophenotypic CR and molecular CR as new criteria [4]. This could be considered an early version of today’s MRD. Attainment of CR using the conventional serological and morphological assessment has been shown to result in prolonged survival [5]. However, MM is still incurable and several patients experience disease relapse eventually. This highlights the fact that the current tools of assessment of tumor burden cannot measure the disease in its entirety and it is this small population of myeloma cells termed residual disease that could lead to relapse. This has led to efforts to create tools, both imaging and molecular, which are more efficient to evaluate deeper responses that eventually culminated in the concept of MRD. IMWG, in their updated consensus response criteria in 2016, has further clarified several aspects of MRD assessment, methods of MRD detection and expanded the response criteria by incorporating imaging-based MRD negativity to rule out the presence of extramedullary disease [6]. Methods to measure MRD can be broadly classified as molecular methods that measure medullary disease (disease in the bone marrow) and imaging techniques that measure extra medullary disease (disease outside the marrow). Multiparameter flow cytometry (MFC), ASO-PCR and next-generation sequencing (NGS) measure residual disease using bone marrow aspirate. Imaging modalities such as MRI and PET-computed tomography (PET/CT) are used to assess extra medullary disease. MFC relies on the distinction of malignant plasma cells from normal plasma cells based on the expression of a range of phenotypic aberrancies, such as the expression of cytogenetic differentiation markers [7]. Initially four-color and six-color panels were used and currently eight-color and ten-color antibody panels are used. The first report of the prognostic value of MRD measurement in MM using MFC was made by Rawstron and San Miguel separately in 2002 [8,9]. MRD status based on MFC with a sensitivity of 10-4–10-5 has been shown to have a significant impact