Establishment of new diagnostic Biomarker and Characterization of protective bone marrow niche in patients with multiple myeloma

Establishment of new diagnostic Biomarker and Characterization of protective bone marrow niche in patients with multiple myeloma - Predict

Status

Active, not recruiting

Phases

Unknown

Study type

Observational

Source

DRKS

Registry ID

DRKS00010830

Enrollment

160

Registered

2016-07-19

Start date

2016-08-01

Completion date

Unknown

Last updated

2025-04-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

C90

Interventions

Group 1: Diagnostic Biomarker and Characterization of protective bone marrow niche in patients with multiple myeloma and healthy persons (as reference)

Eligibility

Sex/Gender

All

Age

18 Years to No maximum

Inclusion criteria

Inclusion criteria: - =18 years - Symptomatic, IMiD-treated MM patients - MM patients under anti-myeloma therapy, containing IMiDs (vs. as controls other novel antimyeloma agents) - Routine bone marrow puncture during MM patient treatment course with IMiDs - Healthy persons undergoing bone surgery

Exclusion criteria

Exclusion criteria: - <18 years of age - Any kind of health and/or psychological problems which withhold the patient to understand and give his/her written informed consent to use the BM sample for this research project

Design outcomes

Primary

Measure	Time frame
1.) Investigation on the influence of IMiDs (Lenalidomide/Pomalidomide) on MRD clearance of MM patients. a) Influence of MRD clearance on PFS and OS in analogy to Rawstron AC et al. Blood 125:1932-5, 2015, where - MRD reduction (numerical and logarithmic decreases) was assessed on its influence on PFS and OS and - Conventional CR was compared to MRD-achievement in terms of influencing both PFS and OS. This proposal theories are, that a) remission induction with IMIDs is substantial, however, remission induction via EBMT and IMWG criteria is less sensitive than via MRD detection, b) which FACS-based MRD protocol (6-color panel, 8 color panel, 10 color panel) should best be used and recommended can and will be elucidated with this grant proposal. c) MRD clearance with IMID treatment does significantly impact both PFS and OS; whether there is logarithmic MRD reduction or lesser over time and how this translates into PFS/OS increases, will also be addressed in this work proposal and d) MRD-guided treatment over prolonged course of IMID-based antimyeloma treatment may help to elucidate and better understand the IMID remission induction and profit for MM patients, which could then be recommended for other MM groups. 2) Elucidation of the influence of epigenetic drugs ( each HDAC6-, Class-I-HDAC- and panHDAC-inhibitor as well as SIRT2-inhibitor; Rumpf et al. Nat. commun 2015, Senger et al. J Med Chem. 2016) on a) the expression pattern of new targets (e.g. cereblon and adhesion molecules) and b) BM microenvironment (BMM) in MM. For this purpose and to best mimic the BM niche, an implementation of an appropriate and nevertheless easy to handle 3D co-culture model is required. By means of the “Freiburg agarose-based matrix model” we simulate simplified in vivo conditions and determine treatment response (viability, apoptosis) and alteration of expression pattern via flow cytometry, fluorescent imaging, western blot and viability assays.	—

Measure

Time frame

1.) Investigation on the influence of IMiDs (Lenalidomide/Pomalidomide) on MRD clearance of MM patients. a) Influence of MRD clearance on PFS and OS in analogy to Rawstron AC et al. Blood 125:1932-5, 2015, where - MRD reduction (numerical and logarithmic decreases) was assessed on its influence on PFS and OS and - Conventional CR was compared to MRD-achievement in terms of influencing both PFS and OS. This proposal theories are, that a) remission induction with IMIDs is substantial, however, remission induction via EBMT and IMWG criteria is less sensitive than via MRD detection, b) which FACS-based MRD protocol (6-color panel, 8 color panel, 10 color panel) should best be used and recommended can and will be elucidated with this grant proposal. c) MRD clearance with IMID treatment does significantly impact both PFS and OS; whether there is logarithmic MRD reduction or lesser over time and how this translates into PFS/OS increases, will also be addressed in this work proposal and d) MRD-guided treatment over prolonged course of IMID-based antimyeloma treatment may help to elucidate and better understand the IMID remission induction and profit for MM patients, which could then be recommended for other MM groups. 2) Elucidation of the influence of epigenetic drugs ( each HDAC6-, Class-I-HDAC- and panHDAC-inhibitor as well as SIRT2-inhibitor; Rumpf et al. Nat. commun 2015, Senger et al. J Med Chem. 2016) on a) the expression pattern of new targets (e.g. cereblon and adhesion molecules) and b) BM microenvironment (BMM) in MM. For this purpose and to best mimic the BM niche, an implementation of an appropriate and nevertheless easy to handle 3D co-culture model is required. By means of the “Freiburg agarose-based matrix model” we simulate simplified in vivo conditions and determine treatment response (viability, apoptosis) and alteration of expression pattern via flow cytometry, fluorescent imaging, western blot and viability assays.

—

Secondary

Measure	Time frame
1) Establishment of 6, 8 or 10 color MRD panel for FACS analysis to a) analyze BM samples using these 3 panels and comparison. b) Description of MRD clearance at different points of the disease and subsequent follow-up. d) Investigation of the influence of lenalidomid and other IMiDs on CD54 (ICAM-1) as a potentially very relevant novel marker for MRD diagnostics in MM in combination with the established multicolor panels. e) Additionally investigation of the cereblon pathway with the components cereblon, cullin 4 (Cul4) and its binding partners ikaros (IKZF1) and aiolos (IKZF3) as well as its downstream targets interferon regulatory factor 4 (IRF4) using FACS analysis for the analysis of the expression frequences in case this is the relevant pathyway of the effect of IMiDs. f) Next Generation Sequencing (NGS) analysis is performed in corporation and collaboration with our NGS core group (Dr. D. Pfeifer) and the research group of PD Dr. R. Claus (both UKF) to assess specific genetic changes of relevant genes, such as cereblon, Cul4, IKZF1/3 and IRF4/8 to potentially discover novel relevant mutations that could be relevant for higher/lower expression of these proteins and could generate new insight into resistance mechansisms towards IMiDs. g) Establishment of a Polymerase Chain Reaction (PCR) protocol for the Cereblon gene and other relevant genes of the pathway (dependent on the results generated in e)+f)) will be highly useful to implement. This could then be used as future diagnostics, since NGS is expensive and time-consuming. 2a) Based on the 3D co-culture study we aim to derive rational drug combinations of epi-drugs and IMiDs as well as biologicals, which need to be further verified in vitro and in the mouse model settings. 2b) IMiD based novel and rational drug combination studies for novel phase I/II studies/proposals.	—

Measure

Time frame

1) Establishment of 6, 8 or 10 color MRD panel for FACS analysis to a) analyze BM samples using these 3 panels and comparison. b) Description of MRD clearance at different points of the disease and subsequent follow-up. d) Investigation of the influence of lenalidomid and other IMiDs on CD54 (ICAM-1) as a potentially very relevant novel marker for MRD diagnostics in MM in combination with the established multicolor panels. e) Additionally investigation of the cereblon pathway with the components cereblon, cullin 4 (Cul4) and its binding partners ikaros (IKZF1) and aiolos (IKZF3) as well as its downstream targets interferon regulatory factor 4 (IRF4) using FACS analysis for the analysis of the expression frequences in case this is the relevant pathyway of the effect of IMiDs. f) Next Generation Sequencing (NGS) analysis is performed in corporation and collaboration with our NGS core group (Dr. D. Pfeifer) and the research group of PD Dr. R. Claus (both UKF) to assess specific genetic changes of relevant genes, such as cereblon, Cul4, IKZF1/3 and IRF4/8 to potentially discover novel relevant mutations that could be relevant for higher/lower expression of these proteins and could generate new insight into resistance mechansisms towards IMiDs. g) Establishment of a Polymerase Chain Reaction (PCR) protocol for the Cereblon gene and other relevant genes of the pathway (dependent on the results generated in e)+f)) will be highly useful to implement. This could then be used as future diagnostics, since NGS is expensive and time-consuming. 2a) Based on the 3D co-culture study we aim to derive rational drug combinations of epi-drugs and IMiDs as well as biologicals, which need to be further verified in vitro and in the mouse model settings. 2b) IMiD based novel and rational drug combination studies for novel phase I/II studies/proposals.

—

Countries

Germany

Contacts

Public ContactSandra Dold

Universitätsklinikum Freiburg, Klinik für Innere Medizin I

sandra.dold@uniklinik-freiburg.de+49-761-270-72860

Outcome results

None listed

Source: DRKS (via WHO ICTRP) · Data processed: Feb 4, 2026