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  • Review Article
  • Published:

Minimal residual disease in multiple myeloma: bringing the bench to the bedside

Nature Reviews Clinical Oncology volume 12, pages 286–295 (2015)Cite this article

Subjects

Key Points

  • Outcomes of patients with multiple myeloma have improved substantially in the past decade

  • A large proportion of patients achieve a complete response to current therapies

  • More-sensitive assays for the detection of MRD are required

  • Standardization and guidelines on the use of MRD testing in clinical trials and in the clinic are required

Abstract

Outcomes for patients with multiple myeloma (MM) have improved substantially in the past decade, with improvements in both progression-free survival and overall survival. Many patients are now achieving a complete response to treatment, and consequently highly sensitive assays are needed for detection of minimal residual disease (MRD) in patients with MM. Results of multicolour flow cytometry and deep-sequencing studies suggest that among patients achieving a complete response, MRD-negative status is associated with significant improvements in progression-free survival and overall survival. Despite the increasing need for MRD testing in patients with MM, considerable heterogeneity in techniques for MRD detection hinders the clinical interpretation of their results. The criteria used to define MRD, strengths and weaknesses of the major types of tests (flow cytometry versus molecular testing), and the optimal sample type (bone marrow aspirate versus peripheral blood) are all unresolved dilemmas in MRD testing. This Review presents an overview of the various techniques for MRD detection in patients with MM. In addition, this article discusses challenges and opportunities for the routine use of MRD testing, possible future directions for clinical trials and implications for drug approval processes.

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Figure 1: Treatment response rates achieved with commonly used induction regimens in patients with MM.
Figure 2: Flow cytometry testing for minimal residual disease in patients with treated multiple myeloma.
Figure 3: Effect of sample size on flow cytometry testing for minimal residual disease in treated patients with multiple myeloma.

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References

  1. Kristinsson, S. Y., Anderson, W. F. & Landgren, O. Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia 28, 1346–1348 (2014).

    Article  CAS  Google Scholar 

  2. Turesson, I., Velez, R., Kristinsson, S. Y. & Landgren, O. Patterns of improved survival in patients with multiple myeloma in the twenty-first century: a population-based study. J. Clin. Oncol. 28, 830–834 (2010).

    Article  Google Scholar 

  3. Kumar, S. K. et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 28, 1122–1128 (2014).

    Article  CAS  Google Scholar 

  4. Jakubowiak, A. J. et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120, 1801–1809 (2012).

    Article  CAS  Google Scholar 

  5. Korde, N. et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed multiple myeloma (MM) patients. Blood 122, 538 (2013).

    Google Scholar 

  6. Kapoor, P. et al. Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma. J. Clin. Oncol. 31, 4529–4535 (2013).

    Article  Google Scholar 

  7. Paiva, B. et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 112, 4017–4023 (2008).

    Article  CAS  Google Scholar 

  8. Rawstron, A. C. et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J. Clin. Oncol. 31, 2540–2547 (2013).

    Article  Google Scholar 

  9. Martinez-Lopez, J. et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 123, 3073–3079 (2014).

    Article  CAS  Google Scholar 

  10. Mateos, M. V. et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N. Engl. J. Med. 369, 438–447 (2013).

    Article  CAS  Google Scholar 

  11. Ahn, I. E., Mailankody, S., Korde, N. & Landgren, O. Dilemmas in treating smoldering multiple myeloma. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2014.56.4351.

  12. Flanders, A., Stetler-Stevenson, M. & Landgren, O. Minimal residual disease testing in multiple myeloma by flow cytometry: major heterogeneity. Blood 122, 1088–1089 (2013).

    Article  CAS  Google Scholar 

  13. Roschewski, M. et al. Minimal residual disease: what are the minimum requirements? J. Clin. Oncol. 32, 475–476 (2014).

    Article  Google Scholar 

  14. US Food and Drug Administration. FDA-NCI roundtable: symposium on flow cytometry detection of minimal residual disease in multiple myeloma [online], (2014).

  15. Landgren, O. et al. Flow cytometry detection of minimal residual disease in multiple myeloma: lessons learned at FDA-NCI roundtable symposium. Am. J. Hematol. 89, 1159–1160 (2014).

    Article  Google Scholar 

  16. Blade, J. et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT European Group for Blood and Marrow Transplant. Br. J. Haematol. 102, 1115–1123 (1998).

    Article  CAS  Google Scholar 

  17. Rajkumar, S. V. et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117, 4691–4695 (2011).

    Article  CAS  Google Scholar 

  18. Mailankody, S. et al. Molecular and biologic markers of progression in monoclonal gammopathy of undetermined significance to multiple myeloma. Leuk. Lymphoma 51, 2159–2170 (2010).

    Article  Google Scholar 

  19. Rawstron, A. C. et al. Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation. Blood 100, 3095–3100 (2002).

    Article  CAS  Google Scholar 

  20. Rawstron, A. C. et al. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica 93, 431–438 (2008).

    Article  Google Scholar 

  21. Paiva, B. et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J. Clin. Oncol. 29, 1627–1633 (2011).

    Article  CAS  Google Scholar 

  22. VanDongen, J. J. et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia 26, 1908–1975 (2012).

    Article  CAS  Google Scholar 

  23. Paiva, B. et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood 119, 687–691 (2012).

    Article  CAS  Google Scholar 

  24. Mateos, M. V. et al. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood http://dx.doi.org/10.1182/blood-2014-05-573733.

  25. Corradini, P. et al. High-dose sequential chemoradiotherapy in multiple myeloma: residual tumor cells are detectable in bone marrow and peripheral blood cell harvests and after autografting. Blood 85, 1596–1602 (1995).

    CAS  PubMed  Google Scholar 

  26. Ladetto, M. et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia 28, 1299–1307 (2014).

    Article  CAS  Google Scholar 

  27. Puig, N. et al. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia 28, 391–397 (2014).

    Article  CAS  Google Scholar 

  28. Korthals, M. et al. The level of minimal residual disease in the bone marrow of patients with multiple myeloma before high-dose therapy and autologous blood stem cell transplantation is an independent predictive parameter. Biol. Blood Marrow Transplant. 18, 423–431 (2012).

    Article  Google Scholar 

  29. Martinez-Lopez, J. et al. Clinical applicability and prognostic significance of molecular response assessed by fluorescent-PCR of immunoglobulin genes in multiple myeloma. Results from a GEM/PETHEMA study. Br. J. Haematol. 163, 581–589 (2013).

    Article  CAS  Google Scholar 

  30. Faham, M. et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood 120, 5173–5180 (2012).

    Article  CAS  Google Scholar 

  31. Logan, A. C. et al. High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment. Proc. Natl Acad. Sci. USA 108, 21194–21199 (2011).

    Article  CAS  Google Scholar 

  32. Shim, Y. K. et al. Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding. Blood 123, 1319–1326 (2014).

    Article  CAS  Google Scholar 

  33. Zamagni, E. et al. Prognostic relevance of 18F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood 118, 5989–5995 (2011).

    Article  CAS  Google Scholar 

  34. Schwarzenbach, H., Hoon, D. S. & Pantel, K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev. Cancer 11, 426–437 (2011).

    Article  CAS  Google Scholar 

  35. Dawson, S. J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).

    Article  CAS  Google Scholar 

  36. Vij, R. et al. Deep sequencing reveals myeloma cells in peripheral blood in majority of multiple myeloma patients. Clin. Lymphoma Myeloma Leuk. 14, 131–139 (2014).

    Article  Google Scholar 

  37. Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).

    Article  CAS  Google Scholar 

  38. Bolli, N. et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat. Commun. 5, 2997 (2014).

    Article  Google Scholar 

  39. Lohr, J. G. et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 25, 91–101 (2014).

    Article  CAS  Google Scholar 

  40. Martinez-Lopez, J. et al. Deep sequencing reveals oligoclonality at the immunoglobulin locus in multiple myeloma patients. Blood 122, 401 (2013).

    Google Scholar 

  41. Huff, C. A. & Matsui, W. Multiple myeloma cancer stem cells. J. Clin. Oncol. 26, 2895–2900 (2008).

    Article  Google Scholar 

  42. Trepel, M. et al. Phenotypic detection of clonotypic B cells in multiple myeloma by specific immunoglobulin ligands reveals their rarity in multiple myeloma. PLoS ONE 7, e31998 (2012).

    Article  CAS  Google Scholar 

  43. Thiele, B. et al. Next-generation sequencing of peripheral B-lineage cells pinpoints the circulating clonotypic cell pool in multiple myeloma. Blood 123, 3618–3621 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

S.M. and M.S.-S. gratefully acknowledge support from the Intramural Research Program of the National Cancer Institute, Bethesda, MD, USA.

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Authors and Affiliations

  1. Multiple Myeloma Section, Lymphoid Malignancies Branch, Centre for Cancer Research, National Institutes of Health, National Cancer Institute, 9000 Rockville Pike, Bethesda, 20892, MD, USA

    Sham Mailankody

  2. Flow Cytometry Laboratory, Laboratory of Pathology, National Institutes of Health, National Cancer Institute, 9000 Rockville Pike, Bethesda, 20892, MD, USA

    Maryalice Stetler-Stevenson

  3. Myeloma Service, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, 10065, NY, USA

    Neha Korde, Alexander M. Lesokhin, Nikoletta Lendvai, Hani Hassoun & Ola Landgren

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Contributions

S.M., N.K., M.S.-S. and O.L. researched the data for the article. S.M. and O.L. wrote the manuscript. All authors contributed to discussions of content, and reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Ola Landgren.

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Competing interests

O.L. declares that he has acted as a consultant for BMJ Publishing, Celgene, Millennium, Medscape, and Onyx. The other authors declare no competing interests.

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Mailankody, S., Korde, N., Lesokhin, A. et al. Minimal residual disease in multiple myeloma: bringing the bench to the bedside. Nat Rev Clin Oncol 12, 286–295 (2015). https://doi.org/10.1038/nrclinonc.2014.239

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