We searched PubMed for articles published in English between Jan 1, 1980, and June 30, 2014, that contained the term “myeloma” and any one of the following terms: “response” or “minimal residual disease” or “imaging” or “bone marrow” or “monoclonal protein”. We also reviewed recent reviews on multiple myeloma. Members of the International Myeloma Working Group were then asked to identify any appropriate citation that was of interest but not detected by the search strategy.
ReviewInternational Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma
Introduction
The treatment landscape for multiple myeloma has been radically transformed during the past decade by the introduction of several new drugs with different mechanisms of action, which has led to improved survival for patients with multiple myeloma.1, 2 Progress has been made in other areas, including an improved understanding of disease biology, enhanced diagnostic criteria, availability of sensitive and specific tools for disease prognostication, increasingly effective treatment strategies, and enhanced supportive care.3, 4, 5, 6, 7, 8, 9, 10 The most recent iteration of the response criteria was developed in 200611 by the International Myeloma Working Group (appendix). Response evaluation in multiple myeloma has traditionally been based on the assessment of serum and urine monoclonal protein concentrations via protein electrophoresis or immunofixation, or both, as a surrogate for tumour burden, allowing for the detection of trace amounts of paraprotein.11 The response criteria for multiple myeloma have evolved considerably since then with the substitution of monoclonal protein concentrations for synthetic rates and the use of different cutoffs for monoclonal protein concentrations, as well as inclusion of serum free light chain (sFLC) values for the assessment of oligo-secretory myeloma. Traditional quantitation of bone marrow plasma cells was performed on trephine biopsies (with a combination of haemotoxylin and eosin stains and immunohistochemistry) or bone marrow aspirates (with or without clot section). The importance of bone marrow plasma-cell quantitation for accurate response assessment (even in patients with negative serum and urine immunofixation) has been confirmed.12 The original definition of a complete response only required bone marrow with less than 5% plasma cells, irrespective of their clonal nature.11 The definition was further refined to stringent complete response, by the addition of the sFLC assay plus immunohistochemical clonal assessment on the trephine biopsy.11, 13 Additional clarifications, especially with respect to the use of sFLC, were introduced during the International Myeloma Workshop in 2011.14
The consensus criteria were uniformly incorporated into clinical trials, allowing improved comparison of different drugs, drug combinations, and treatment strategies, and the revisions over the years have allowed them to remain applicable despite advances in treatment. With older therapies, including autologous stem-cell transplantation (ASCT), less than half of patients achieve a complete response.15, 16 With the introduction of more effective multidrug combinations in the past 15 years, especially when used with ASCT, post-transplant consolidation, and prolonged maintenance therapy, nearly all patients achieve a treatment response, with more than 50% of these patients reaching a complete response in some studies.17, 18, 19, 20, 21 Frustratingly, most patients relapse despite achieving such deep responses, reflecting a persistent disease that cannot be detected with the recommended disease evaluation techniques. Consequently, new methods are urgently required to detect and quantify the level of minimal residual disease beyond the detection of the present clinical response criteria, and the definition of disease response needs to be revised for it to evolve with the changing treatment framework. In this Review, we report the new International Myeloma Working Group consensus criteria for redefining disease response with a particular emphasis on the definitions and methods to assess minimal residual disease.
Section snippets
Depth of response and long-term outcome
The association between depth of response and long-term outcomes is a hotly debated topic in multiple myeloma. This debate has been particularly contentious for complete response, which has been generally considered as the deepest response level and a surrogate for improved outcome after any given treatment.22, 23, 24, 25 The relationship between complete response and progression-free survival, or time-to-progression, has been more consistent than the relationship between complete response and
Detection of minimal residual disease in bone marrow
Bone marrow examination has been the cornerstone of disease assessment in the absence of a measurable monoclonal protein in the serum or urine, whether this represents non-secretory disease or complete response to therapy (ie, complete response or stringent complete response).11, 12 Increasingly, sensitive assays have been adopted for the evaluation of bone marrow aspirates, including multiparametric flow cytometry (MFC), allele-specific oligonucleotide (ASO)-qPCR and next-generation sequencing
ASO-qPCR
Another method that has been studied extensively in the past is ASO-qPCR, and it has been compared head-to-head with MFC assays (table 2). Use of ASO-qPCR to identify clonal multiple myeloma plasma-cell-specific immunoglobulin heavy chain (IGH) gene rearrangements allows the detection of very low levels of multiple myeloma plasma cells with a sensitivity that can detect one in 105 cells. Therefore, unlike the early PCR methods that were qualitative and semi-quantitative, ASO-qPCR provides an
Detection of extramedullary disease
Present approaches for the detection and measurement of tumour burden after therapy rely on bone marrow assessment. However, bone marrow involvement in multiple myeloma can be heterogeneous, thus increasing the likelihood of a false-negative assessment. Furthermore, such involvement does not allow detection of the disease outside the bone marrow. Extramedullary disease is increasingly seen in the clinic as a result of sensitive imaging studies and extended survival of patients with multiple
Special considerations based on therapy
Monoclonal antibodies are a promising area for the treatment of multiple myeloma, and several will be available in the clinic in the future. Use of monoclonal antibodies can present unique challenges for clinical response assessment techniques. These challenges include interference with the monoclonal protein assessment on serum protein electrophoresis, or immunofixation, and with MFC-based assessment of monoclonal plasma cells in the bone marrow aspirates.
The monoclonal antibodies that have
Updated consensus response criteria
The present iteration of the International Myeloma Working Group consensus response criteria has been crucial in light of the progress witnessed over the past decade in the development of new drugs and treatment approaches, including high-dose therapy, consolidation, and maintenance approaches. Ambiguities and nuances have become apparent in these criteria as they are used in multicentre clinical trials performed across different geographical regions, with highly effective treatment regimens,
Baseline measurements and required testing during follow-up
In addition to tumour burden-based response assessment, other laboratory measurements have been incorporated into the current response criteria to define a category of clinical progression. This categorisation is particularly important as oncologists increasingly encounter oligo-secretory disease or non-secretory disease in patients who had measurable levels of monoclonal protein at the time of diagnosis. While we believe that this situation reflects clonal evolution of the multiple myeloma
Future directions
The development of an accurate framework for the assessment of minimal residual disease is a work in progress and this report is the first and probably the most important step in that direction. Ongoing work will continue to define what level of minimal residual disease is clinically relevant and when it should be evaluated. Specific aspects of disease biology will also need to be incorporated into future definitions of the minimal residual disease state (eg, identification of minimal residual
Conclusion
The proposed guidelines form a framework for future investigation into minimal residual disease in multiple myeloma. Prospective studies are being incorporated in newly designed clinical trials, and we encourage new studies to incorporate (whenever reasonable) minimal residual disease monitoring by next-generation flow or next-generation sequencing, or both.59, 60 In addition, existing archived samples from various clinical trials and different institutions are being evaluated for the
Search strategy and selection criteria
This online
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