In vivo quantitative assessment of therapeutic response to bortezomib therapy in disseminated animal models of multiple myeloma with [ <sup>18</sup>F]FDG and [ <sup>64</sup>Cu]Cu-LLP2A PET

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Abstract

Background

Multiple myeloma (MM) is a disease of cancerous plasma cells in the bone marrow. Imaging-based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4, CD49d/CD29) is overexpressed in MM cells. Here, we evaluated [ ¹⁸F]FDG and VLA4 targeted [ ⁶⁴Cu]Cu-LLP2A for quantitative PET imaging in disseminated MM models of variable VLA4 expression, following bortezomib therapy.

Methods

In vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (C: luciferase and G: green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1 mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no tumor) were longitudinally imaged with [ ¹⁸F]FDG (7.4–8.0 MBq) and [ ⁶⁴Cu]Cu-LLP2A (2–3 MBq; Molar Activity: 44.14 ± 1.40 MBq/nmol) PET, respectively.

Results

Flow cytometry confirmed high expression of CD49d in U266 cells (> 99%) and moderate expression in MM.1S cells (~ 52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [ ⁶⁴Cu]Cu-LLP2A localized with a significantly higher SUV _mean in spine (0.58 versus 0.31, p < 0.01) and femur (0.72 versus 0.39, p < 0.05) at week 4 post-tumor inoculation. There was a four-fold higher uptake of [ ⁶⁴Cu]Cu-LLP2A (SUV _mean) in untreated U266-CG mice compared to treated mice at 3 weeks post-treatment. Compared to [ ⁶⁴Cu]Cu-LLP2A, [ ¹⁸F]FDG PET detected treatment-related changes at later time points.

Conclusion

[ ⁶⁴Cu]Cu-LLP2A is a promising tracer for timely in vivo assessment of therapeutic response in disseminated models of MM.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13550-021-00840-4.

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This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.

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The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with (18)F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0. PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors' experience, draft criteria were formulated for PET tumor response to treatment. Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has limitations in response assessments. For example, despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcoma, hepatomas, mesothelioma, and gastrointestinal stromal tumor. CT tumor density, contrast enhancement, or MRI characteristics appear more informative than size but are not yet routinely applied. RECIST criteria may show progression of tumor more slowly than WHO criteria. RECIST 1.1 criteria (assessing a maximum of 5 tumor foci, vs. 10 in RECIST) result in a higher complete response rate than the original RECIST criteria, at least in lymph nodes. Variability appears greater in assessing progression than in assessing response. Qualitative and quantitative approaches to (18)F-FDG PET response assessment have been applied and require a consistent PET methodology to allow quantitative assessments. Statistically significant changes in tumor standardized uptake value (SUV) occur in careful test-retest studies of high-SUV tumors, with a change of 20% in SUV of a region 1 cm or larger in diameter; however, medically relevant beneficial changes are often associated with a 30% or greater decline. The more extensive the therapy, the greater the decline in SUV with most effective treatments. Important components of the proposed PERCIST criteria include assessing normal reference tissue values in a 3-cm-diameter region of interest in the liver, using a consistent PET protocol, using a fixed small region of interest about 1 cm(3) in volume (1.2-cm diameter) in the most active region of metabolically active tumors to minimize statistical variability, assessing tumor size, treating SUV lean measurements in the 1 (up to 5 optional) most metabolically active tumor focus as a continuous variable, requiring a 30% decline in SUV for "response," and deferring to RECIST 1.1 in cases that do not have (18)F-FDG avidity or are technically unsuitable. Criteria to define progression of tumor-absent new lesions are uncertain but are proposed. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria have limitations, particularly in assessing the activity of newer cancer therapies that stabilize disease, whereas (18)F-FDG PET appears particularly valuable in such cases. The proposed PERCIST 1.0 criteria should serve as a starting point for use in clinical trials and in structured quantitative clinical reporting. Undoubtedly, subsequent revisions and enhancements will be required as validation studies are undertaken in varying diseases and treatments.

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Author and article information

Contributors

Monica Shokeen:

ORCID: http://orcid.org/0000-0001-8114-9584

shokeenm@wustl.edu

Journal

Journal ID (nlm-ta): EJNMMI Res

Journal ID (iso-abbrev): EJNMMI Res

Title: EJNMMI Research

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Electronic): 2191-219X

Publication date (Electronic): 29 September 2021

Publication date PMC-release: 29 September 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 97

Affiliations

[1 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Radiology, Mallinckrodt Institute of Radiology, , Washington University School of Medicine, ; 4515 McKinley Avenue, 2nd floor, St. Louis, MO 63110 USA

[2 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Internal Medicine, , Washington University School of Medicine, ; St. Louis, MO USA

[3 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Medicine, , Washington University School of Medicine, ; St. Louis, MO USA

[4 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Biomedical Engineering, , Washington University in St. Louis, ; St. Louis, MO USA

[5 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Biochemistry and Molecular Biophysics, , Washington University School of Medicine, ; St. Louis, MO USA

Author information

Monica Shokeen http://orcid.org/0000-0001-8114-9584

Article

Publisher ID: 840

DOI: 10.1186/s13550-021-00840-4

PMC ID: 8481408

PubMed ID: 34586539

SO-VID: dd846866-804b-4feb-a4d4-f17d75a85d60

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 June 2021

Date accepted : 13 September 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, national institutes of health;

Award ID: U54CA199092

Award ID: R01CA176221

Award ID: R01 CA248493

Award ID: U24CA209837

Award Recipient : Samuel Achilefu Kooresh I. Shoghi Monica Shokeen

Custom metadata

ScienceOpen disciplines: Radiology & Imaging

Keywords: therapy response,very late antigen-4 (vla4),[64cu]cu-llp2a,[18f]fdg,multiple myeloma (mm),bortezomib (proteasome inhibitor) therapy

Data availability:

ScienceOpen disciplines: Radiology & Imaging

Keywords: therapy response, very late antigen-4 (vla4), [64cu]cu-llp2a, [18f]fdg, multiple myeloma (mm), bortezomib (proteasome inhibitor) therapy