Determination of Minimal Residual Disease in Multiple Myeloma: Does It Matter?

  • Shalin Kothari
  • Jens Hillengass
  • Philip L. McCarthy
  • Sarah A. HolsteinEmail author
Stem Cell Transplantation (R Maziarz, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Stem Cell Transplantation


Purpose of Review

The ability to detect minimal residual disease (MRD) in myeloma has improved due to advances in flow cytometry and sequencing methodologies. Here, we evaluate recent clinical trial data and explore the current and future roles of MRD assessment in the context of clinical trial design and clinical practice.

Recent Findings

A review of recent phase III studies reveals that achievement of MRD negativity is associated with improved progression-free survival (PFS) and/or overall survival (OS). Treatment arms that are more effective from a PFS or overall response rate perspective are also associated with superior MRD negativity rates. The current standard MRD methodologies are limited by requiring bone marrow samples and refinement of methodologies that can detect disease outside of the bone marrow is needed.


Currently, MRD is a prognostic biomarker and further efforts are required to determine whether it can serve as a surrogate endpoint. The use of MRD status to guide treatment decisions is currently not recommended outside the confines of a clinical trial.


Multiple myeloma Minimal residual disease Overall survival 



SK, JH, PLM, and SAH have no acknowledgments for this work.

Compliance with Ethical Standards

Conflict of Interest

Shalin Kothari declares no potential conflicts of interest. Jens Hillengass reports received honoraria and travel support from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Takeda and research funding from Celgene and Sanofi, outside the submitted work. Philip McCarthy reports receiving honoraria from Bristol-Myers Squibb, Celgene, Sanofi-Aventis, Takeda and Binding Site, research funding from Celgene, and has served on advisory committees/review panels/board membership for Bristol-Myers Squibb, Celgene, Sanofi-Aventis, Takeda, Binding Site and Karyopharm, outside the submitted work. Sarah Holstein reports receiving honoraria from Adaptive Biotechnologies, Celgene, Takeda and has served on advisory committees/review panels for Celgene, Takeda, Adaptive Biotechnologies, Sorrento, GlaxoSmithKline, outside the submitted work.

Human and Animal Rights

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Costa LJ, Brill IK, Omel J, Godby K, Kumar SK, Brown EE. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States. Blood Adv. 2017;1:282–7.CrossRefGoogle Scholar
  2. 2••.
    . Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3:28–35 Meta-analysis of the association between MRD status and survival. CrossRefGoogle Scholar
  3. 3.
    •• 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:e328–46 Incorporation of MRD into the IMWG response criteria. CrossRefGoogle Scholar
  4. 4.
    Bird JM, Russell NH, Samson D. Minimal residual disease after bone marrow transplantation for multiple myeloma: evidence for cure in long-term survivors. Bone Marrow Transplant. 1993;12:651–4.PubMedGoogle Scholar
  5. 5.
    Stetler-Stevenson M, Paiva B, Stoolman L, Lin P, Jorgensen JL, Orfao A, et al. Consensus guidelines for myeloma minimal residual disease sample staining and data acquisition. Cytometry B Clin Cytom. 2016;90:26–30.CrossRefGoogle Scholar
  6. 6.
    Came N, Nguyen V, Westerman D, Harrison S. Aggressive and extramedullary plasma cell myeloma evade bone marrow flow cytometric minimal residual disease detection. Br J Haematol. 2016;173:947–9.CrossRefGoogle Scholar
  7. 7.
    • Flores-Montero J, de Tute R, Paiva B, Perez JJ, Bottcher S, Wind H, et al. Immunophenotype of normal vs. myeloma plasma cells: toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytom. 2016;90:61–72 Development of consensus panels for MRD assessment by flow cytometry. CrossRefGoogle Scholar
  8. 8.
    Orfao A, Garcia-Sanz R, Lopez-Berges MC, Belen Vidriales M, Gonzalez M, Caballero MD, et al. A new method for the analysis of plasma cell DNA content in multiple myeloma samples using a CD38/propidium iodide double staining technique. Cytometry. 1994;17:332–9.CrossRefGoogle Scholar
  9. 9.
    Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H, et al. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica. 2008;93:431–8.CrossRefGoogle Scholar
  10. 10.
    • Flores-Montero J, Sanoja-Flores L, Paiva B, Puig N, Garcia-Sanchez O, Bottcher S, et al. Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31:2094–103 Development of consensus panels for MRD assessment by flow cytometry. CrossRefGoogle Scholar
  11. 11.
    Roshal M, Flores-Montero JA, Gao Q, Koeber M, Wardrope J, Durie BGM, et al. MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods. Blood Advances. 2017;1:728–32.CrossRefGoogle Scholar
  12. 12.
    Soh KT, Tario JD Jr, Wallace PK. Diagnosis of plasma cell dyscrasias and monitoring of minimal residual disease by multiparametric flow cytometry. Clin Lab Med. 2017;37:821–53.CrossRefGoogle Scholar
  13. 13.
    Minarik J, Novak M, Flodr P, Balcarkova J, Mlynarcikova M, Krhovska P, et al. CD38-negative relapse in multiple myeloma after daratumumab-based chemotherapy. Eur J Haematol. 2017;99:186–9.CrossRefGoogle Scholar
  14. 14.
    Avet-Loiseau H, Corre J, Lauwers-Cances V, Chretien M-L, Robillard N, Leleu X, et al. Evaluation of minimal residual disease (MRD) by next generation sequencing (NGS) is highly predictive of progression free survival in the IFM/DFCI 2009 trial. Blood. 2015;126:191.Google Scholar
  15. 15.
    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;123:3073–9.CrossRefGoogle Scholar
  16. 16.
    Ladetto M, Bruggemann M, Monitillo L, Ferrero S, Pepin F, Drandi D, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2014;28:1299–307.CrossRefGoogle Scholar
  17. 17.
    • Mazzotti C, Buisson L, Maheo S, Perrot A, Chretien ML, Leleu X, et al. Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv. 2018;2:2811–3 Study demonstrating lack of concordance between marrow and blood MRD results using next-generation sequencing. CrossRefGoogle Scholar
  18. 18.
    Hillengass J, Landgren O. Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging “early myeloma”. Leuk Lymphoma. 2013;54:1355–63.CrossRefGoogle Scholar
  19. 19.
    Bergen HR 3rd, Dasari S, Dispenzieri A, Mills JR, Ramirez-Alvarado M, Tschumper RC, et al. Clonotypic light chain peptides identified for monitoring minimal residual disease in multiple myeloma without bone marrow aspiration. Clin Chem. 2016;62:243–51.CrossRefGoogle Scholar
  20. 20.
    Moreau P, Attal M, Caillot D, Macro M, Karlin L, Garderet L, et al. Prospective evaluation of magnetic resonance imaging and [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM study. J Clin Oncol. 2017;35:2911–8.CrossRefGoogle Scholar
  21. 21.
    Zamagni E, Patriarca F, Nanni C, Zannetti B, Englaro E, Pezzi A, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118:5989–95.CrossRefGoogle Scholar
  22. 22.
    Bartel TB, Haessler J, Brown TL, Shaughnessy JD Jr, van Rhee F, Anaissie E, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068–76.CrossRefGoogle Scholar
  23. 23.
    Pawlyn C, Fowkes L, Otero S, Jones JR, Boyd KD, Davies FE, et al. Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma? Leukemia. 2016;30:1446–8.CrossRefGoogle Scholar
  24. 24.
    Sachpekidis C, Mosebach J, Freitag MT, Wilhelm T, Mai EK, Goldschmidt H, et al. Application of (18)F-FDG PET and diffusion weighted imaging (DWI) in multiple myeloma: comparison of functional imaging modalities. Am J Nucl Med Mol Imaging. 2015;5:479–92.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Rasche L, Angtuaco E, McDonald JE, Buros A, Stein C, Pawlyn C, et al. Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood. 2017;130:30–4.CrossRefGoogle Scholar
  26. 26.
    Pandit-Taskar N. Functional imaging methods for assessment of minimal residual disease in multiple myeloma: current status and novel ImmunoPET based methods. Semin Hematol. 2018;55:22–32.CrossRefGoogle Scholar
  27. 27.
    Ghai A, Maji D, Cho N, Chanswangphuwana C, Rettig M, Shen D, et al. Preclinical development of CD38-targeted [(89)Zr]Zr-DFO-daratumumab for imaging multiple myeloma. J Nucl Med. 2018;59:216–22.CrossRefGoogle Scholar
  28. 28.
    Pugh TJ. Circulating tumour DNA for detecting minimal residual disease in multiple myeloma. Semin Hematol. 2018;55:38–40.CrossRefGoogle Scholar
  29. 29.
    Thoren KL. Mass spectrometry methods for detecting monoclonal immunoglobulins in multiple myeloma minimal residual disease. Semin Hematol. 2018;55:41–3.CrossRefGoogle Scholar
  30. 30.
    Barnidge DR, Dasari S, Botz CM, Murray DH, Snyder MR, Katzmann JA, et al. Using mass spectrometry to monitor monoclonal immunoglobulins in patients with a monoclonal gammopathy. J Proteome Res. 2014;13:1419–27.CrossRefGoogle Scholar
  31. 31.
    Holstein SA, Avet-Loiseau H, Hahn T, Ho CM, Lohr JG, Munshi NC, et al. BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling: summary and recommendations from the organizing committee. Biol Blood Marrow Transplant. 2018;24:641–8.CrossRefGoogle Scholar
  32. 32.
    Lahuerta JJ, Paiva B, Vidriales MB, Cordon L, Cedena MT, Puig N, et al. Depth of response in multiple myeloma: a pooled analysis of three PETHEMA/GEM clinical trials. J Clin Oncol. 2017;35:2900–10.CrossRefGoogle Scholar
  33. 33.
    Landgren O, Devlin S, Boulad M, Mailankody S. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis. Bone Marrow Transplant. 2016;51:1565–8.CrossRefGoogle Scholar
  34. 34.
    Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518–28.CrossRefGoogle Scholar
  35. 35.
    Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20.CrossRefGoogle Scholar
  36. 36.
    Perrot A, Lauwers-Cances V, Corre J, Robillard N, Hulin C, Chretien ML, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132:2456–64.CrossRefGoogle Scholar
  37. 37.
    Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood. 2018;132:LBA-2.Google Scholar
  38. 38.
    de Tute RM, Cairns D, Rawstron A, Pawlyn C, Davies FE, Jones JR, et al. Minimal residual disease in the maintenance setting in myeloma: prognostic significance and impact of lenalidomide. Blood. 2017;130:904.Google Scholar
  39. 39.
    Gambella M, Omede P, Spada S, Muccio VE, Gilestro M, Saraci E, et al. Minimal residual disease by flow cytometry and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction in patients with myeloma receiving lenalidomide maintenance: a pooled analysis. Cancer 2018.
  40. 40.
    Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103:2079–87.CrossRefGoogle Scholar
  41. 41.
    Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018;103:2088–96.CrossRefGoogle Scholar
  42. 42.
    Anderson KC, Auclair D, Kelloff GJ, Sigman CC, Avet-Loiseau H, Farrell AT, et al. The role of minimal residual disease testing in myeloma treatment selection and drug development: current value and future applications. Clin Cancer Res. 2017;23:3980–93.CrossRefGoogle Scholar
  43. 43.
    Amur S, LaVange L, Zineh I, Buckman-Garner S, Woodcock J. Biomarker qualification: toward a multiple stakeholder framework for biomarker development, regulatory acceptance, and utilization. Clin Pharmacol Ther. 2015;98:34–46.CrossRefGoogle Scholar
  44. 44.
    Holstein SA, Ye JC, Howard A, Bhutani M, Gormley N, Hahn T, et al. Summary of the second annual BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling. Biol Blood Marrow Transplant 2018.
  45. 45.
    • 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. FDA perspective on MRD testing in myeloma. Google Scholar
  46. 46.
    Flanders A, Stetler-Stevenson M, Landgren O. Minimal residual disease testing in multiple myeloma by flow cytometry: major heterogeneity. Blood. 2013;122:1088–9.CrossRefGoogle Scholar
  47. 47.
    Gay F, Cerrato C, Rota Scalabrini D, Galli M, Belotti A, Zamagni E, et al. Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM). Blood. 2018;132:121.Google Scholar
  48. 48.
    Oliva S, Gambella M, Gilestro M, Muccio VE, Gay F, Drandi D, et al. Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis. Oncotarget. 2017;8:5924–35.PubMedGoogle Scholar
  49. 49.
    Voorhees PM, Rodriguez C, Reeves B, Nathwani N, Costa LJ, Lutska Y, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (Dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; Dara-Vrd) vs. Vrd in patients (Pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). Blood. 2018;132:151.Google Scholar
  50. 50.
    Zimmerman T, Raje NS, Vij R, Reece D, Berdeja JG, Stephens LA, et al. Final results of a phase 2 trial of extended treatment (tx) with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (KRd) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). Blood. 2016;128:675.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Shalin Kothari
    • 1
  • Jens Hillengass
    • 1
  • Philip L. McCarthy
    • 1
  • Sarah A. Holstein
    • 2
    Email author
  1. 1.Department of MedicineRoswell Park Comprehensive Cancer CenterBuffaloUSA
  2. 2.Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaUSA

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