Comparative analysis of minimal residual disease detection by multiparameter flow cytometry and enhanced ASO RQ-PCR in multiple myeloma

Silvennoinen, Raija; Lundán, Tuija; Kairisto, Veli; Tt, Pelliniemi; Putkonen, Matti; Anttila, Pekka; Huotari, Virva; Mäntymaa, Pentti; Siitonen, Sanna; Uotila, Lasse; Penttila, T-L; Juvonen, Vesa; Selander, Tuomas; Remes, Kari

doi:10.1038/bcj.2014.69

Cited by 30 publications

(34 citation statements)

References 27 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…86 Subsequent comparisons between PCR-and MFC-based MRD monitoring showed that, except for a few discordant cases, both techniques provided highly concordant results (Figure 3). 60,64,87,88 The initial positive experience by the Spanish and United Kingdom groups led to the implementation of their corresponding 4-and 6-color MFC approaches in large clinical trials. In the Programa para el Estudio de la Terapéutica en Hemopatías Malignas/ Grupo Español de MM (PETHEMA/GEM) 2000 study, flow MRD was identified as the most relevant prognostic factor in a series of 295 newly diagnosed MM patients receiving uniform treatment including HDT/SCT.…”

Section: Transplant-eligible Patientsmentioning

confidence: 99%

New criteria for response assessment: role of minimal residual disease in multiple myeloma

Paiva

Dongen

Órfão

2015

Blood

260

271

View full text Add to dashboard Cite

Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as acute lymphoblastic leukemia. In multiple myeloma (MM), the majority of patients will inevitably relapse despite achievement of progressively higher complete remission (CR) rates. Novel treatment protocols with inclusion of antibodies and small molecules might well be able to further increase remission rates and potentially also cure rates. Therefore, MRD diagnostics becomes essential to assess treatment effectiveness. This review summarizes reports from the past 2 decades, which demonstrate that persistent MRD by multiparameter flow cytometry, polymerase chain reaction, next-generation sequencing, and positron emission tomography/computed tomography, predicts significantly inferior survival among CR patients. We describe the specific features of currently available techniques for MRD monitoring and outline the arguments favoring new criteria for response assessment that incorporate MRD levels. Extensive data indicate that MRD information can potentially be used as biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions, and act as surrogate for overall survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in MM, which implies systematic usage of highly sensitive, cost-effective, readily available, and standardized MRD techniques.

show abstract

Section: Transplant-eligible Patientsmentioning

confidence: 99%

New criteria for response assessment: role of minimal residual disease in multiple myeloma

Paiva

Dongen

Órfão

2015

Blood

260

271

View full text Add to dashboard Cite

show abstract

“…Firstly, clonality, i.e., the clonal Ig gene rearrangement(s) presenting in tumour PCs, from diagnostic BM samples is detected by qualitative PCR using consensus primers for genomic DNA (or cDNA in some studies (Ladetto et al , ; Rasmussen et al , ; Verhagen et al , ; Gerard et al , ; Sarasquete et al , ). In this regard, consensus primers developed by the BIOMED‐2 group in the form of several multiplex primer sets are the most widely used (van Dongen et al , ; Sarasquete et al , ; Martinez‐Lopez et al , ; Puig et al , ; Silvennoinen et al , ). Multiple immunoglobulin gene rearrangements are used as MRD targets in MM, including IGH complete VDJ and IGH incomplete DJ rearrangements, IGK deletion (Kde), IGK VJ and IGL VJ rearrangements (Gonzalez et al , ; Puig et al , ; Silvennoinen et al , ; Bai et al , ).…”

Section: Allele‐specific Oligonucleotide Pcrmentioning

confidence: 99%

“…In this regard, consensus primers developed by the BIOMED‐2 group in the form of several multiplex primer sets are the most widely used (van Dongen et al , ; Sarasquete et al , ; Martinez‐Lopez et al , ; Puig et al , ; Silvennoinen et al , ). Multiple immunoglobulin gene rearrangements are used as MRD targets in MM, including IGH complete VDJ and IGH incomplete DJ rearrangements, IGK deletion (Kde), IGK VJ and IGL VJ rearrangements (Gonzalez et al , ; Puig et al , ; Silvennoinen et al , ; Bai et al , ). Clonal PCR bands are sequenced by Sanger sequencing, and sequencing data is analysed with the ImMunoGeneTics (IMGT) V‐QUEST system (http://www.imgt.org) or the National Center for Biotechnology Information Basic Local Alignment Search Tool (NCBI BLAST; https://blast.ncbi.nlm.nih.gov/) to identify the patient‐specific sequence of the corresponding tumour PC CDR3 region.…”

Section: Allele‐specific Oligonucleotide Pcrmentioning

confidence: 99%

Molecular detection of minimal residual disease in multiple myeloma

2017

View full text Add to dashboard Cite

Despite the significantly higher complete remission rates and improved survival achieved in the last decade, multiple myeloma (MM) patients continue to relapse due to persistence of minimal residual disease (MRD). Generally, MRD refers to persistence of low levels of disease in the order of one tumour cell in ≥10 normal cells. Currently, molecular and immunophenotypic techniques are employed for MRD detection. This review focuses on MRD detection by molecular techniques, including allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), next-generation sequencing (NGS) and digital PCR (dPCR), in addition to a brief description of, and comparison with, multiparameter flow cytometry. The basic principles, technical advantages and limitations, and the clinical impact of all three molecular techniques are reviewed and compared. They all have a sensitivity of at least 10 , among which ASO real-time quantitative PCR is the most well-standardized, and NGS carries the highest sensitivity and applicability, while dPCR is still under investigation. Furthermore, molecular MRD negativity is a favourable prognostic factor for survival of patients with MM. However, several challenges inherent to molecular detection of MRD still remain to be overcome, particularly false negativity and failure to detect extramedullary disease. Finally, detection of MRD from peripheral blood remains challenging.

show abstract

“…Thus, 20 clinical trials of newly diagnosed myeloma patients with information on MRD and clinical outcomes were identified and assessed for inclusion in this metaanalysis. Upon careful review of the 20 identified studies (12-14, 16, 18, 21, 58-71), four studies were excluded because they reported on ASCT (61-63, 71); seven were excluded because they did not evaluate the association between MRD status and PFS and/or OS (16,21,(64)(65)(66)(67)(68); four were excluded because they analyzed overlapping cohorts of patients (duplicates) (13,14,18,69); and one was excluded because the timing of MRD analysis was not specified (70). Four studies with information on MRD status and HR for PFS were included in the final analysis (12,(58)(59)(60).…”

Section: Mskcc/nci Meta-analysismentioning

confidence: 99%

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications

Anderson

Auclair

Kelloff

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10 to 10 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. .

show abstract

Comparative analysis of minimal residual disease detection by multiparameter flow cytometry and enhanced ASO RQ-PCR in multiple myeloma

Cited by 30 publications

References 27 publications

New criteria for response assessment: role of minimal residual disease in multiple myeloma

New criteria for response assessment: role of minimal residual disease in multiple myeloma

Molecular detection of minimal residual disease in multiple myeloma

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications

Contact Info

Product

Resources

About