Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Plasma Cell Disorders

Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis

Abstract

Driven by access to better drugs, on average, newly diagnosed multiple myeloma patients have over 10 years overall survival. Using modern combination therapies—with or without the addition of high-dose melphalan and autologous stem cell transplantation—up to 80% of patients reach a complete response. As a logical and necessary step forward, clinical studies have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. In this context, MRD has been proposed as a regulatory end point for drug approval in newly diagnosed multiple myeloma. To better define the role of MRD negativity in relation to clinical outcomes, we undertook a meta-analysis including published clinical trials of newly diagnosed multiple myeloma patients. We applied a random effects model which weighted studies using the inverse–variance method. Studies were combined on the scale of the logarithm of the hazard ratio (HR) and the corresponding s.d. We found that MRD negativity (versus positivity) was associated with better PFS (HR=0.35; 95% confidence interval (CI) 0.27–0.46; P<0.001) and overall survival (HR=0.48; 95% CI 0.33–0.70; P<0.001). Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Kristinsson SY, Anderson WF, Landgren O . Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia 2014; 28: 1346–1348.

    Article  CAS  PubMed  Google Scholar 

  2. US Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. 2016 Available at: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm.

  3. Mailankody S, Korde N, Lesokhin AM, Lendvai N, Hassoun H, Stetler-Stevenson M et al. Minimal residual disease in multiple myeloma: bringing the bench to the bedside. Nat Rev Clin Oncol 2015; 12: 286–295.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gormley NJ, Turley DM, Dickey JS, Farrell AT, Reaman GH, Stafford E et al. Regulatory perspective on minimal residual disease flow cytometry testing in multiple myeloma. Cytometry B Clin Cytom 2016; 90: 73–80.

    Article  PubMed  Google Scholar 

  5. Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol 2015; 1: 746–754.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mateos MV, Oriol A, Martinez-Lopez J, Teruel AI, Lopez de la Guia A, Lopez J et al. GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood 2014; 124: 1887–1893.

    Article  CAS  PubMed  Google Scholar 

  7. Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 2008; 112: 4017–4023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Silvennoinen R, Kairisto V, Pelliniemi TT, Putkonen M, Anttila P, Saily M et al. Assessment of molecular remission rate after bortezomib plus dexamethasone induction treatment and autologous stem cell transplantation in newly diagnosed multiple myeloma patients. Br J haematol 2013; 160: 561–564.

    Article  CAS  PubMed  Google Scholar 

  9. Team RC R: A language and environment for statistical computing. R Foundation for Statistical Computing: Vienna, Austria, 2015.

  10. Viechtbauer W . Conducting meta-analyses in R with the metafor package. J Stat Softw 2010; 36: 1–48.

    Article  Google Scholar 

  11. Cavo M, Terragna C, Martinelli G, Ronconi S, Zamagni E, Tosi P et al. Molecular monitoring of minimal residual disease in patients in long-term complete remission after allogeneic stem cell transplantation for multiple myeloma. Blood 2000; 96: 355–357.

    CAS  PubMed  Google Scholar 

  12. Corradini P, Cavo M, Lokhorst H, Martinelli G, Terragna C, Majolino I et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood 2003; 102: 1927–1929.

    Article  CAS  PubMed  Google Scholar 

  13. Galimberti S, Benedetti E, Morabito F, Papineschi F, Callea V, Fazzi R et al. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res 2005; 29: 961–966.

    Article  CAS  PubMed  Google Scholar 

  14. Kroger N, Zagrivnaja M, Schwartz S, Badbaran A, Zabelina T, Lioznov M et al. Kinetics of plasma-cell chimerism after allogeneic stem cell transplantation by highly sensitive real-time PCR based on sequence polymorphism and its value to quantify minimal residual disease in patients with multiple myeloma. Exp Hematol 2006; 34: 688–694.

    Article  PubMed  Google Scholar 

  15. Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol 2010; 28: 2077–2084.

    Article  CAS  PubMed  Google Scholar 

  16. Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O et al. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol 2013; 31: 247–255.

    Article  CAS  PubMed  Google Scholar 

  17. Martinelli G, Terragna C, Lemoli RM, Cavo M, Benni M, Motta MR et al. Clinical and molecular follow-up by amplification of the CDR-III IgH region in multiple myeloma patients after autologous transplantation of hematopoietic CD34+ stem cells. Haematologica 1999; 84: 397–404.

    CAS  PubMed  Google Scholar 

  18. Powles R, Sirohi B, Kulkarni S, Bhagwati N, Saso R, Raje N et al. Acute lymphoblastic leukaemia-type intensive chemotherapy to eliminate minimal residual disease after high-dose melphalan and autologous transplantation in multiple myeloma - a phase I/II feasibility and tolerance study of 17 patients. Bone Marrow Transplant 2000; 25: 949–956.

    Article  CAS  PubMed  Google Scholar 

  19. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE 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 2013; 31: 2540–2547.

    Article  PubMed  Google Scholar 

  20. Rawstron AC, Gregory WM, de Tute RM, Davies FE, Bell SE, Drayson MT et al. Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction. Blood 2015; 125: 1932–1935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol 2014; 32: 2712–2717.

    Article  CAS  PubMed  Google Scholar 

  22. Martinez-Lopez J, Lahuerta JJ, Pepin F, Gonzalez M, Barrio S, Ayala R et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 2014; 123: 3073–3079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Paiva B, Gutierrez NC, Rosinol L, Vidriales MB, Montalban MA, Martinez-Lopez J 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 2012; 119: 687–691.

    Article  CAS  PubMed  Google Scholar 

  24. Paiva B, Martinez-Lopez J, Vidriales MB, Mateos MV, Montalban MA, Fernandez-Redondo E et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J Clin Oncol 2011; 29: 1627–1633.

    Article  CAS  PubMed  Google Scholar 

  25. Silvennoinen R, Lundan T, Kairisto V, Pelliniemi TT, Putkonen M, Anttila P et al. Comparative analysis of minimal residual disease detection by multiparameter flow cytometry and enhanced ASO RQ-PCR in multiple myeloma. Blood cancer J 2014; 4: e250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M et al. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia 2015; 29: 689–695.

    Article  CAS  PubMed  Google Scholar 

  27. Ahn IE, Mailankody S, Korde N, Landgren O . Dilemmas in treating smoldering multiple myeloma. J Clin Oncol 2015; 33: 115–123.

    Article  PubMed  Google Scholar 

  28. Landgren O, Gormley N, Turley D, Owen RG, Rawstron A, Paiva B et al. Flow cytometry detection of minimal residual disease in multiple myeloma: Lessons learned at FDA-NCI roundtable symposium. Am J Hematol 2014; 89: 1159–1160.

    Article  PubMed  Google Scholar 

  29. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S 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 2012; 120: 1801–1809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al. International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016; 17: e328–e346.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the International Myeloma Foundation (IMF) in Los Angeles, USA, and we thank our Core Grant (P30 CA008748) for grant support of this work. We also thank authors who provided additional information regarding the included studies.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to O Landgren.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Landgren, O., Devlin, S., Boulad, M. et al. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis. Bone Marrow Transplant 51, 1565–1568 (2016). https://doi.org/10.1038/bmt.2016.222

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2016.222

This article is cited by

Search

Quick links