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Journal Article•DOI•

Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis.

Nikhil C. Munshi1, Hervé Avet-Loiseau, Andy C. Rawstron2, Roger G. Owen2, J. Anthony Child3, Anjan Thakurta4, Paul Sherrington4, Mehmet Kemal Samur1, Anna Georgieva, Kenneth C. Anderson1, Walter M Gregory3 •
Harvard University1, St James's University Hospital2, University of Leeds3, Celgene4
01 Jan 2017-JAMA Oncology (American Medical Association)-Vol. 3, Iss: 1, pp 28-35
TL;DR: Quantitative evidence is provided to support the integration of MRD assessment as an end point in clinical trials of MM and an MRD-negative status after treatment for newly diagnosed MM is associated with long-term survival.
Abstract: Importance Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in patients with multiple myeloma (MM). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods. Objective To evaluate the utility of MRD detection in patients with newly diagnosed MM. Data Sources A Medline search was conducted for articles published in English between January 1990 and January 2016. Study Selection Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in 20 or more patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis. Data Extraction and Synthesis Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form. Main Outcomes and Measures The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other prespecified research questions were addressed qualitatively. Results Fourteen studies (n = 1273) provided data on the impact of MRD on PFS, and 12 studies (n = 1100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). An MRD-negative status was associated with significantly better PFS overall (hazard ratio [HR], 0.41; 95% CI, 0.36-0.48; P P P P Conclusions and Relevance Minimal residual disease-negative status after treatment for newly diagnosed MM is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of MM.

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  • Munshi, NC, Avet-Loiseau, H, Rawstron, AC et al. (8 more authors) (2017) Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis.
  • This is an author produced version of a paper published in JAMA Oncology.
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This is a repository copy of Association of Minimal Residual Disease With Superior
Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis.
White Rose Research Online URL for this paper:
http://eprints.whiterose.ac.uk/108927/
Version: Supplemental Material
Article:
Munshi, NC, Avet-Loiseau, H, Rawstron, AC et al. (8 more authors) (2017) Association of
Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple
Myeloma: A Meta-analysis. JAMA Oncology, 3 (1). pp. 28-35. ISSN 2374-2437
https://doi.org/10.1001/jamaoncol.2016.3160
© 2016, American Medical Association. This is an author produced version of a paper
published in JAMA Oncology. Uploaded in accordance with the publisher's self-archiving
policy.
eprints@whiterose.ac.uk
https://eprints.whiterose.ac.uk/
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Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright
exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy
solely for the purpose of non-commercial research or private study within the limits of fair dealing. The
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Rose Research Online record for this item. Where records identify the publisher as the copyright holder,
users can verify any specific terms of use on the publisher’s website.
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Study
First author & year
Hazard ratio
Overall hazard ratio: 0.57
95% CI: .46–.71,
P = .0000004
0 1 2 3 4
Total
Rawstron 2002
Ferrero 2014
Bakkus 2004
Dal Bo 2013
Paiva 2011 (CR)
Paiva 2008
Korthals 2012
Korthals 2013
Swedin 1998 (CR)
Rawstron 2013
Ludwig 2015 (CR)
Fukumoto 2016
2 4 6 8 10 12
Time (years)
MRD-negative
N = 660
χ
2
1
= 134.4
P < .00001
MRD-positive
N = 613
% PFS
20
40
60
80
100
Numbers at risk:
MRD –VE: 457 214 70 12 1
MRD +VE: 308 113 28 4 1
0
2 4 6 8 10 12
Time (years)
MRD-negative
N = 599
χ
2
1
= 25.27
P = .0000005
MRD-positive
N = 501
Cumulative % Surviving
20
40
60
80
100
Numbers at risk:
508 359 139 26 4
390 250 105 17 5
0
Hazard ratio for PFS
Hazard ratio for OS
Study
First author & year
Hazard ratio
Overall hazard ratio: 0.41
95% CI: .36–.48,
P < .0001
0 .5 1 1.5 2
Total
Rawstron 2002
San Miguel 2002
Ferrero 2014
Bakkus 2004
Dal Bo 2013
Paiva 2011
Paiva 2008
Korthals 2012
Korthals 2013
Swedin 1998 (CR)
Rawstron 2013
Roussel 2014
Fukumoto 2016
Sarasquete 2005
A B
C D
Citations
More filters
Journal Article•DOI•
Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group

[...]

Michele Cavo1, Evangelos Terpos2, Cristina Nanni, Philippe Moreau, Suzanne Lentzsch3, Sonja Zweegman4, Jens Hillengass5, Monika Engelhardt6, Saad Z. Usmani7, David H. Vesole, Jesús F. San-Miguel8, Shaji Kumar9, Paul G. Richardson10, Joseph R. Mikhael9, Fernando Leal da Costa11, Meletios A. Dimopoulos2, Chiara Zingaretti, Niels Abildgaard12, Hartmut Goldschmidt5, Robert Z. Orlowski13, Wee Joo Chng14, Hermann Einsele, Sagar Lonial15, Bart Barlogie, Kenneth C. Anderson10, S. Vincent Rajkumar9, Brian G.M. Durie16, Elena Zamagni1 •
University of Bologna1, National and Kapodistrian University of Athens2, Columbia University Medical Center3, VU University Medical Center4, University Hospital Heidelberg5, University of Freiburg6, Carolinas Healthcare System7, University of Navarra8, Mayo Clinic9, Harvard University10, Instituto Português de Oncologia Francisco Gentil11, Odense University Hospital12, University of Texas MD Anderson Cancer Center13, University Health System14, Emory University15, Cedars-Sinai Medical Center16
01 Apr 2017-Lancet Oncology
TL;DR: Based on the ability of 18F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism.
Abstract: The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of 18fluorodeoxyglucose (18F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. 18F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of 18F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of 18F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. 18F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.

338 citations

Journal Article•DOI•
Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma

[...]

Aurore Perrot, Valérie Lauwers-Cances, Jill Corre1, Jill Corre2, Nelly Robillard, Cyrille Hulin, Marie-Lorraine Chretien, Thomas Dejoie, Sabrina Maheo2, Sabrina Maheo1, Anne-Marie Stoppa, Brigitte Pegourie3, Lionel Karlin, Laurent Garderet, Bertrand Arnulf4, Chantal Doyen5, Nathalie Meuleman6, Bruno Royer, Jean-Richard Eveillard, Lotfi Benboubker, Mamoun Dib, Olivier Decaux, Arnaud Jaccard, Karim Belhadj, Sabine Brechignac, Brigitte Kolb, Cecile Fohrer, Mohamad Mohty, Margaret Macro, Paul G. Richardson7, Victoria Carlton, Martin Moorhead, Thomas D. Willis, Malek Faham, Kenneth C. Anderson7, Jean-Luc Harousseau, Xavier Leleu, Thierry Facon, Philippe Moreau, Michel Attal, Hervé Avet-Loiseau1, Hervé Avet-Loiseau2, Nikhil C. Munshi7 •
Paul Sabatier University1, French Institute of Health and Medical Research2, University of Grenoble3, Saint Louis University Hospital4, Université catholique de Louvain5, Institut Jules Bordet6, Harvard University7
06 Dec 2018-Blood
TL;DR: The findings confirm the value of MRD status, as determined by NGS, as a prognostic biomarker in multiple myeloma, and suggest that this approach could be used to adapt treatment strategies in future clinical trials.

278 citations

Journal Article•DOI•
Clinical Applications and Future Directions of Minimal Residual Disease Testing in Multiple Myeloma.

[...]

Stefania Oliva1, Mattia D'Agostino1, Mario Boccadoro1, Alessandra Larocca1•
University of Turin1
31 Jan 2020-Frontiers in Oncology
TL;DR: This mini-review will focus on currently available techniques and data on MRD testing and their potential future applications.
Abstract: In the last years, the life expectancy of multiple myeloma (MM) patients has substantially improved thanks to the availability of many new drugs. Our ability to induce deep responses has improved as well, and the treatment goal in patients tolerating treatment moved from the delay of progression to the induction of the deepest possible response. As a result of these advances, a great scientific effort has been made to redefine response monitoring, resulting in the development and validation of high-sensitivity techniques to detect minimal residual disease (MRD). In 2016, the International Myeloma Working Group (IMWG) updated MM response categories defining MRD-negative responses both in the bone marrow (assessed by next-generation flow cytometry or next-generation sequencing) and outside the bone marrow. MRD is an important factor independently predicting prognosis during MM treatment. Moreover, using novel combination therapies, MRD-negative status can be achieved in a fairly high percentage of patients. However, many questions regarding the clinical use of MRD status remain unanswered. MRD monitoring can guide treatment intensity, although well-designed clinical trials are needed to demonstrate this potential. This mini-review will focus on currently available techniques and data on MRD testing and their potential future applications.

254 citations

Journal Article•DOI•
B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches.

[...]

Nina Shah1, Ajai Chari2, Emma C. Scott3, Khalid Mezzi4, Saad Z. Usmani •
University of California, San Francisco1, Mount Sinai Hospital2, GlaxoSmithKline3, Amgen4
13 Feb 2020-Leukemia
TL;DR: Clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM and suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.
Abstract: Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody–drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody–drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

220 citations

Cites background from "Association of Minimal Residual Dis..."

  • ...The use of MRD endpoints in clinical studies of hematologic malignancies has been increasing over time, and achieving MRD negativity is associated with better clinical outcomes [42, 44]....

    [...]

Journal Article•DOI•
Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

[...]

M.A. Dimopoulos1, P. Moreau, E. Terpos1, M.V. Mateos, Sonja Zweegman2, Gordon Cook3, Michel Delforge4, Roman Hájek5, Fredrik Schjesvold6, Michele Cavo7, H. Goldschmidt8, Thierry Facon, H. Einsele, Mario Boccadoro9, Jesús F. San-Miguel10, Pieter Sonneveld11, U. Mey •
National and Kapodistrian University of Athens1, VU University Amsterdam2, University of Leeds3, Katholieke Universiteit Leuven4, University of Ostrava5, Oslo University Hospital6, University of Bologna7, University Hospital Heidelberg8, University of Turin9, University of Navarra10, Erasmus University Rotterdam11
01 Mar 2021-Annals of Oncology

217 citations

References
More filters
Journal Article•DOI•
Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1

[...]

S. Vincent Rajkumar1, Jean Luc Harousseau2, Brian G.M. Durie3, Kenneth C. Anderson4, Meletios A. Dimopoulos5, Robert A. Kyle1, Joan Bladé6, Paul G. Richardson4, Robert Z. Orlowski, David S. Siegel7, Sundar Jagannath8, Thierry Facon9, Hervé Avet-Loiseau2, Sagar Lonial10, Antonio Palumbo11, Jeffrey A. Zonder12, Heinz Ludwig, David H. Vesole7, O. Sezer13, Nikhil C. Munshi4, Nikhil C. Munshi14, Jesús F. San Miguel15 •
Mayo Clinic1, University of Nantes2, Cedars-Sinai Medical Center3, Harvard University4, National and Kapodistrian University of Athens5, University of Barcelona6, Hackensack University Medical Center7, Icahn School of Medicine at Mount Sinai8, Lille University of Science and Technology9, Emory University10, University of Turin11, Wayne State University12, University of Hamburg13, United States Department of Veterans Affairs14, University of Salamanca15
05 May 2011-Blood
TL;DR: It is proposed that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript, and detailed definitions for patient populations, lines of therapy, and specific endpoints are provided.

854 citations

Journal Article•DOI•
A general parametric approach to the meta-analysis of randomized clinical trials.

[...]

Anne Whitehead1, John Whitehead1•
University of Reading1
01 Nov 1991-Statistics in Medicine
TL;DR: A general parametric approach is presented, which utilizes efficient score statistics and Fisher's information, and relates this to different methods suggested by previous authors.
Abstract: Meta-analysis provides a systematic and quantitative approach to the summary of results from randomized studies. Whilst many authors have published actual meta-analyses concerning specific therapeutic questions, less has been published about comprehensive methodology. This article presents a general parametric approach, which utilizes efficient score statistics and Fisher's information, and relates this to different methods suggested by previous authors. Normally distributed, binary, ordinal and survival data are considered. Both the fixed effects and random effects model for treatments are described.

728 citations

"Association of Minimal Residual Dis..." refers methods in this paper

  • ...Hazard ratio forest plots were then generated using the inverse variance weighting method, as described in detail by Whitehead and Whitehead.(11) Cox proportional hazards Key Points...

    [...]

Journal Article•DOI•
Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation.

[...]

Bruno Paiva, María-Belén Vidriales1, Jorge Cerveró, Gema Mateo1, José J. Pérez, Maria Angeles Montalbán, Anna Sureda, Laura Montejano, Norma C. Gutiérrez1, Alfonso García de Coca, Natalia de las Heras, Maria V. Mateos1, Maria Consuelo López-Berges, Raimundo García-Boyero, Josefina Galende, José Augusto Evangelho Hernandez, Luis Palomera, Dolores Carrera, Rafael Martínez, Javier de la Rubia, Alejandro Martín, Joan Bladé, Juan J. Lahuerta, Alberto Orfao2, Alberto Orfao1, Jesús F. San Miguel1, Pethema Cooperative Study Groups •
Spanish National Research Council1, University of Salamanca2
15 Nov 2008-Blood
TL;DR: The findings demonstrate the clinical importance of MRD evaluation by MFC, and illustrate the need for further refinement of MM re-sponse criteria.

430 citations

Journal Article•DOI•
Why do we need systematic overviews of randomized trials

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Richard Peto1•
University of Oxford1
01 Apr 1987-Statistics in Medicine

390 citations

Journal Article•DOI•
Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma

[...]

Joaquin Martinez-Lopez, Juan J. Lahuerta, Francois Pepin, Marcos González1, Santiago Barrio, Rosa Ayala, Noemi Puig1, Maria Angeles Montalbán, Bruno Paiva2, Li Weng, Cristina Jimenez1, María Sopena, Martin Moorhead, Teresa Cedena, Immaculada Rapado, Maria-Victoria Mateos1, Laura Rosiñol, Albert Oriol, María Jesús Blanchard, Rafael Martínez, Joan Bladé, Jesus San Miguel2, Malek Faham, Ramón García-Sanz1 •
Spanish National Research Council1, Chartered Institute of Management Accountants2
15 May 2014-Blood
TL;DR: The prognostic value of minimal residual disease (MRD) detection in multiple myeloma patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy was assessed.

370 citations

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International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma

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The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version refer to the White Rose Research Online record for this item. 

Numbers at risk:MRD –VE: 457 214 70 12 1MRD +VE: 308 113 28 4 10 2 4 6 8 10 12Time (years)MRD-negativeN = 599χ2 1 = 25.27 P = .0000005MRD-positiveN = 501C u mu lati v e %S u rviv ing20406080100Numbers at risk:508 359 139 26 4390 250 105 17 50Hazard ratio for PFSHazard ratio for OSStudyFirst author & yearHazard ratioOverall hazard ratio: 0.4195% CI: .36–.48,P < .00010 .5 1 1.5 2TotalRawstron 2002San Miguel 2002Ferrero 2014Bakkus 2004Dal Bo 2013Paiva 2011Paiva 2008Korthals 2012Korthals 2013Swedin 1998 (CR)Rawstron 2013Roussel 2014Fukumoto 2016Sarasquete 2005A BC D