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Methods for detection of plasma cell dyscrasia

a plasma cell and detection method technology, applied in the field of plasma cell dyscrasia detection, can solve the problems of low progression-free survival rate of patients, poor overall survival, and difficulty in cytogenetic approaches, and achieve high sensitivity and specificity.

Inactive Publication Date: 2019-01-24
LIQUID BIOPSY RES LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a tool for detecting plasma cell dyscrasias, such as MGUS and myeloma, with high sensitivity and specificity. The tool uses a combination of biomarkers to predict the presence or absence of a plasma cell dyscrasia with a high degree of accuracy. The method can also be used to determine if the plasma cell dyscrasia is stable or progressive. This information can help guide treatment decisions for patients with plasma cell dyscrasias.

Problems solved by technology

This is attributed to innovative treatments and the widespread use of proteasome inhibitors and immunomodulatory drugs but many patients exhibit low progression-free survival rates and have a poor overall survival.
While useful, cytogenetic approaches become problematic when two markers predicting opposing outcomes coexist in the same patient.
They are also only of modest assistance in indicating appropriate therapeutic strategies and none of them provide predictive information.
The prognostic utility of these signatures either alone, in combination with other prognostic gene expression signatures or staging systems, have been demonstrated but they function poorly for defining minimal residual disease and do not provide predictive value.
Moreover, early detection of changes in clonality or the identification of molecular markers of poor prognosis are required.

Method used

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  • Methods for detection of plasma cell dyscrasia
  • Methods for detection of plasma cell dyscrasia
  • Methods for detection of plasma cell dyscrasia

Examples

Experimental program
Comparison scheme
Effect test

example 1

Derivation of a 32-Marker Gene Panel

[0086]Raw probe intensities (n=1,354,896 features) from n=15 peripheral blood mononuclear cell samples were used to identify genes that best discriminated between controls and multiple myeloma using the transcriptional profile of GSE7116. Following removal of outliers, a total of 31 target transcripts (26 genes, 5 splice variants) and one house-keeping gene was identified in an unbiased manner as potential markers of myeloma (Table 2; FIG. 1). These genes were demonstrated to be expressed in multiple myeloma cell lines, IM-9 (normal diploid karyotype) and MM1R (dexamethasone-resistant), identifying they are produced by transformed B-lymphoblasts.

[0087]Then an artificial intelligence model of myeloma disease dynamics was built using normalized gene expression of these 31 markers (normalized to the housekeeping gene, TPT1) in whole blood from Controls (n=45), Responders / Stable (n=24: stable disease), and Newly Diagnosed / Relapsed (n=66: progressive d...

example 2

Diagnosis: Identification of Samples as Myeloma

[0088]In the test set 1, the data for the utility of the test to differentiate patients with active myeloma disease (n=57) from controls (n=23) are included in Table 3. The receiver operator cuver analysis and metrics are included in FIG. 2B. The score exhibited an area under the curve (AUC) of 0.99. The metrics are: sensitivity >95%, specificity 100%, PPV 100%, NPV 88.5%. The overall accuracy is 96%. The tool can therefore differentiate between controls and aggressive and stable myeloma disease.

[0089]Specific evaluation of the MGUS identified significant differences between this plasma cell dyscrasia (n=18; MyelomX=39±9) and controls (n=155, 12±8, p<0.0001) (FIG. 3A). The AUC for differentiating MGUS from controls 0.97 (FIG. 3B).

[0090]Specific evaluation of the multiple myeloma sub-groups identified significant differences between newly diagnosed patients (n=53; MyelomX=75±25), clinically stable disease (n=56, 31±20, p<0.0001) and refr...

example 3

Identification of Minimal Residual Disease

[0092]Effective therapy (n=40), decreased the score from 59±14 to 35±12 which was associated with complete remissions (FIG. 6). Evaluation of the MRD group identified ten patients all with high scores (≥40) who relapsed at an early time point (within one year). The MyelomX score can therefore biochemically define MRD and identify those who have progressive disease and will relapse at an early time-point.

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Abstract

The present invention is directed to methods for detecting a plasma cell dyscrasia like myeloma or MGUS, methods for determining whether a plasma cell dyscrasiais stable or progressive, methods for determining a risk for disease relapse, and methods for determining a response by a subject having a plasma cell dyscrasia to a therapy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 535,419, filed Jul. 21, 2017, the contents of which are hereby incorporated by reference.INCORPORATION BY REFERENCE OF SEQUENCE LISTING[0002]The contents of the text file named “LBIO-002_001US Seq Listing.txt”, which was created on Jul. 16, 2018 and is 276 KB in size, are hereby incorporated by reference in their entireties.FIELD OF THE INVENTION[0003]The present invention relates to plasma cell dyscrasia detection.BACKGROUND OF THE INVENTION[0004]Multiple myeloma is an incurable hematological malignancy of end-stage B-lineage or plasma cells. This clonal plasma cell malignancy accounts for ˜2% of all cancer cases and approximately 10% of hematologic malignancies. It is the third most common B cell malignancy after diffuse B-cell lymphoma and chronic lymphocytic leukemia. The incidence is estimated at (˜1 / 100,000 incidence in the US). In 2017, more ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/574G01N33/68G16H50/30
CPCG01N33/57426G01N33/6857G01N33/6818G16H50/30G01N33/57488G01N2800/7028G01N2800/52G01N2800/60G01N2800/54C12Q1/6886C12Q2600/112C12Q2600/118C12Q2600/158
Inventor MODLIN, IRVIN MARKKIDD, MARKDROZDOV, IGNAT
Owner LIQUID BIOPSY RES LLC
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