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BIOMARKER:

Chr del(1p)

4ms
Cytogenetic Profile in Monoclonal Gammopathy of Undetermined Significance, Smoldering and Symptomatic Multiple Myeloma: A Study of 1087 Patients with Highly Purified Plasma Cells. (PubMed, Cancers (Basel))
Chromosome 1 structural abnormalities were the most prevalent, found in 65% of cases. The frequent presence of subclones and composite karyotypes underscored the genomic heterogeneity and instability in this cohort.
Journal
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CCND1 (Cyclin D1)
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Chr del(17p) • MYC rearrangement • Chr del(1p)
4ms
Whole-Genome Sequencing for Copy Number Abnormalities in Multiple Myeloma Supersedes Karyotype Analysis and Fluorescent in Situ Hybridization (ASH 2023)
ConclusionsLeukoPrint is an automated, convenient and cost-effective approach to depict CNA profile in genomic DNA or cfDNA. This method is superior to conventional approaches when used for CNA testing, and the practice of this method could improve prognostic stratification of MM patients.
Whole genome sequencing
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SDC1 (Syndecan 1)
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Chr del(13)(q14) • Chr del(1p)
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LeukoPrint®
5ms
Genome Sequencing to Discover Drivers of Clonal Expansion in Smoldering Multiple Myeloma (ASH 2023)
In addition to well-characterized MM drivers (KRAS, NRAS, etc.), 16 new candidate genes were found significantly mutated, including IKFZ3 (Aiolos), a transcription factor and direct target of degradation with lenalidomide therapy, harboring frameshift and stop-gain mutations in the protein dimerization domain which could affect complete differentiation of plasma cells...Conclusion These results highlight the power of genomic profiling in MM for early detection, discovery of novel drivers, monitoring of clonal selection and transformation to malignant disease. We show SMM is not a simple genomically-mature disorder, but rather a dynamic state with competing subclones, which could be leveraged for therapeutic interventions.
IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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KRAS mutation • KRAS G12 • NRAS Q61 • KRAS G12S • KRAS G13 • NRAS G13 • KRAS A146 • KRAS Q61 • NRAS A146 • Chr del(1p) • NRAS G12S
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lenalidomide
5ms
RADAR Trial: MRD Response Adapted Trial for Newly Diagnosed Transplant Eligible Myeloma Patients (ASH 2023)
Eligible patients receive induction with 4 cycles of RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Patients with high-risk disease receive Isatuximab in addition to RCyBorD during induction...This work is also supported by Core Clinical trials unit infrastructure from Cancer Research UK ( C7852/A25447). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the abstract
Clinical • IO biomarker
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LY9 (Lymphocyte Antigen 9) • SLAMF7 (SLAM Family Member 7)
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Chr del(1p)
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lenalidomide • bortezomib • cyclophosphamide • Sarclisa (isatuximab-irfc) • melphalan
5ms
Chromothripsis and Genomic Complexity As Pejorative Prognostic Markers in Pediatric and Adult T-ALL (ASH 2023)
Our study demonstrated that the whole genome analysis of imbalances provides new insights to refine the risk stratification in T-ALL. Notably, genomic complexity (≥ 15 genomic imbalances) and chromothripis demonstrated an association with an inferior outcome in terms of EFS and CIR in pediatric and adult T-ALL.
Clinical
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • NF1 (Neurofibromin 1) • ETV6 (ETS Variant Transcription Factor 6) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CREBBP (CREB binding protein) • PTPN2 (Protein Tyrosine Phosphatase Non-Receptor Type 2) • SH2B3 (SH2B Adaptor Protein 3) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • AFDN (Afadin, Adherens Junction Formation Factor) • CASP8AP2 (Caspase 8 Associated Protein 2) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit) • RPL22 (Ribosomal Protein L22)
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Chr del(13)(q14) • Chr del(1p)
5ms
Multiple Myeloma B Cells and Pre-Plasma Cells Are Important Reservoirs for Myeloma Relapse Following Plasma Cell-Directed Therapy and Prevent Cure with Standard Therapies (ASH 2023)
Disease relapse typically occurs regardless of treatment with proteasome inhibitors (such as bortezomib and carfilzomib), immunomodulatory drugs (such as lenalidomide and pomalidomide), anti-CD38 monoclonal antibodies (such as daratumumab and isatuximab) or myeloablative melphalan and autologous stem cell transplantation, and also occurs following treatment with immunotherapeutics such as bispecific antibodies and/or CAR-T cells (targeting BCMA, FcRH5 or GPRC5D). We propose that cure of MM requires eradication of MM progenitor cells alongside plasma cells. We are currently conducting scRNA-seq and CITE-seq studies of primary MM samples to further characterize MM progenitor cells for gene and protein expression in order to define their optimal therapeutic targets.
IO biomarker
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CD20 (Membrane Spanning 4-Domains A1) • SDC1 (Syndecan 1) • IRF4 (Interferon regulatory factor 4)
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Chr del(17p) • Chr del(1p)
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lenalidomide • bortezomib • Darzalex (daratumumab) • carfilzomib • pomalidomide • Sarclisa (isatuximab-irfc) • melphalan
6ms
Selinexor, Daratumumab, Carfilzomib and Dexamethasone for the Treatment of High-Risk, Recurrent or Refractory Multiple Myeloma (clinicaltrials.gov)
P2, N=52, Recruiting, Academic and Community Cancer Research United | Trial primary completion date: Dec 2023 --> Sep 2024
Trial primary completion date
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Chr t(4;14) • Chr t(14;16) • Chr del(1p)
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Xpovio (selinexor) • Darzalex (daratumumab) • carfilzomib
7ms
Small nucleotide, copy number and structural variants cooperate to hijack driver genes in extramedullary progression of myeloma (IMW 2023)
The MAPK DM, high TMB and persistent genomic instability suggest roles for MAPK-targeted therapies, immunotherapies and DNA damage repair pathway inhibitors, respectively, in EMD. Recurrent codon 61 mutations in RAS suggest a specific role in EMD progression.
Tumor mutational burden • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3)
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TP53 mutation • BRAF V600E • KRAS mutation • TMB-H • NRAS mutation • BRAF V600 • RAS mutation • NRAS Q61 • KRAS G13 • NRAS G13 • KRAS Q61 • BRAF G469A • NRAS G13R • KRAS A146V • NRAS A146 • Chr del(1p)
7ms
High-risk cytogenetic abnormalities in Multiple Myeloma: PETHEMA-GEM experience. (IMW 2023)
In conclusion, our study confirmed the prognostic significance of high-risk cytogenetic abnormalities in a large cohort of MM patients. We also demonstrated the importance of considering the co-occurrence of high-risk alterations to accurately assess prognosis. Thus, while del(17p) retains its adverse prognosis even as a solitary abnormality, the negative prognosis of 1q gains was mitigated if this abnormality occured as the sole aberration.
IO biomarker
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CD38 (CD38 Molecule)
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IGH translocation • Chr del(1p)
8ms
Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma. (PubMed, J Clin Oncol)
Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.
Journal
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Chr t(4;14) • Chr t(14;16) • Chr del(1p)
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lenalidomide • bortezomib • cyclophosphamide • Darzalex (daratumumab) • carfilzomib
11ms
APPLICATION OF WHOLE-GENOME SEQUENCING FOR COPY NUMBER ABNORMALITY IN MULTIPLE MYELOMA (EHA 2023)
sWGS is superior to conventional approaches when used for CNA testing, the practice of this method maybe improves prognostic stratification of MM patients and the clinical significance of some variation remains to be studied.
SDC1 (Syndecan 1)
|
Chr del(13)(q14) • Chr del(1p)
|
LeukoPrint®
11ms
DARATUMUMAB PLUS POMALIDOMIDE AND DEXAMETHASONE (DPD) IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA AND 17P DELETION: UPDATED ANALYSIS OF THE DEDALO PHASE II TRIAL (EHA 2023)
Key eligibility criteria included relapsed or relapsed/refractory MM; ≤3 prior therapy lines; del(17p) detected by fluorescence in situ hybridization (FISH) in ≥10% of plasma cells at any time of MM history; absence of refractoriness or intolerance to pomalidomide and to an anti-CD38 monoclonal antibody; previous exposure to lenalidomide (Len)...Pts received continuous treatment with daratumumab (1800 mg sc or 16 mg/kg iv) weekly during cycles 1–2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter; oral pomalidomide (4 mg, once daily on days 1–21); and oral or iv dexamethasone (40 mg once daily on days 1,8,15,22; 20 mg for those aged ≥75 years [yr]) at each 28-day cycle... DPd is an option for pts of all ages, showing a promising response in this difficult-to-treat population.
Clinical • P2 data • IO biomarker
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TP53 (Tumor protein P53)
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TP53 mutation • Chr del(17p) • Chr del(1p)
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lenalidomide • Darzalex (daratumumab) • pomalidomide • dexamethasone injection
1year
Describing the molecular landscape of extramedullary multiple myeloma using whole genome sequencing: Insights into pathology and therapeutic targets (AACR 2023)
MAPK DM were frequent in EMD, and detectable in ctDNA, suggesting roles for both MAPK-targeted therapies and for ctDNA as a biomarker in these patients. A high TMB was identified in patients lacking a MAPK driver mutation; immunotherapy should be considered in this subgroup.
Tumor mutational burden • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3)
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TP53 mutation • BRAF V600E • KRAS mutation • TMB-H • NRAS mutation • BRAF V600 • NRAS Q61 • KRAS G13 • NRAS G13 • KRAS Q61 • BRAF G469A • NRAS G13R • KRAS A146V • NRAS A146 • Chr del(1p)
over1year
Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial. (PubMed, Lancet Oncol)
This preplanned analysis of the FORTE trial showed that carfilzomib-based induction-intensification-consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need.
P2 data • Journal
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SDC1 (Syndecan 1)
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Chr t(4;14) • Chr t(14;16) • SDC1 positive • Chr del(1p)
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lenalidomide • cyclophosphamide • carfilzomib • melphalan
over1year
Dedalo: Phase II Study of Daratumumab Plus Pomalidomide and Dexamethasone (DPd) in Patients with Relapsed/Refractory Multiple Myeloma and 17p Deletion (ASH 2022)
Key eligibility criteria included: relapsed or relapsed/refractory disease; up to 3 prior lines of therapy, del(17p) observed by fluorescence in situ hybridization (FISH) in at least 10% of plasma cells at any time of MM history, previous exposure to lenalidomide (Len), absence of refractoriness or intolerance to pomalidomide, and previous exposure to an anti-CD38 monoclonal antibody. Pts received continuous treatment with daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter; oral pomalidomide (4 mg, once daily on days 1–21); and oral or intravenous dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle...Conclusion. In this difficult-to-treat population, DPd is a therapeutic option for pts of all ages and can be considered as a bridge to other immunotherapies.
Clinical • P2 data • IO biomarker
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TP53 (Tumor protein P53)
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TP53 mutation • Chr del(17p) • Chr del(1p)
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lenalidomide • Darzalex (daratumumab) • pomalidomide • dexamethasone injection
over1year
Risk-Adapted Therapy Directed According to Response (RADAR, UK-MRA Myeloma XV) – Comparing MRD-Guided Treatment Escalation and De-Escalation Strategies in Patients with Newly Diagnosed Myeloma Suitable for Stem Cell Transplantation (ASH 2022)
Eligible patients receive induction with 4 cycles of RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue...The amended question for the high-risk pathway is: does induction, consolidation and maintenance incorporating isatuximab, show activity of prolonging disease control?...Recruitment is on target and outcomes will provide RCT-level evidence for the adaptive use of MRD in treatment allocation. Finally, the platform design enabled adaptation, in this case, to include CD38 antibody for high-risk patients, ensuring up-to-date treatment based on latest evidence, keeping pace with evolving standard of care in the UK, and without altering the scientific MRD-related questions.
Clinical • IO biomarker
|
LY9 (Lymphocyte Antigen 9) • SLAMF7 (SLAM Family Member 7)
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Chr del(1p)
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lenalidomide • bortezomib • cyclophosphamide • Sarclisa (isatuximab-irfc) • melphalan
over1year
Targeting Autophagy to Overcome Resistance to Immunogenic Chemotherapy in High-Risk Multiple Myeloma (ASH 2022)
Bortezomib (BTZ) can induce immunogenic cell death (ICD), which stimulates anti-cancer immunity and improves clinical response...Interestingly, combining BTZ with autophagy inducers, including rapamycin and venetoclax, restored vesicular transport of CALR to the cell surface and MM phagocytosis by DCs. Altogether, our work identifies a unique mechanism of immune escape that may contribute to the poor clinical outcome observed in del17p HR-MM patients. It further suggests that combining an ICD inducer BTZ with an autophagy inducer, such as venetoclax, in this subset of patients may restore ICD and improve the outcome of HR-MM patients.
IO biomarker
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CALR (Calreticulin) • PPP1R15A (Protein Phosphatase 1 Regulatory Subunit 15A) • GABARAP (GABA Type A Receptor-Associated Protein)
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Chr del(17p) • Chr del(1p)
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Venclexta (venetoclax) • bortezomib • sirolimus
over2years
A Clinically Validated Targeted Capture Panel to Identify Translocations, Copy Number Abnormalities, and Mutations in Multiple Myeloma (ASH 2021)
We have developed a targeted sequencing panel for MM patient samples that is as robust or better than both FISH and WGS. A full protocol for sample processing and analysis is available, and has been used in a clinical diagnostic laboratory.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • SDC1 (Syndecan 1) • CDKN2C (Cyclin Dependent Kinase Inhibitor 2C)
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BRAF mutation • NRAS mutation • Chr t(4;14) • MYC translocation • IGH translocation • Chr del(1p)
over2years
High-Risk Gene Expression Subtype Provides Molecular Basis for Different Clinical Presentation of Primary and Secondary Plasma Cell Leukemia (ASH 2021)
In summary, this study supports using a lower percent CPC cutoff to clinically define PCL and highlights the importance of repeated CPC measurements in prognosticating pPCL patients. Further, PR RNA subtype emerged as a predictor of risk in pPCL and, given that the majority of sPCL patients were in the PR subtype, provides a molecular basis for the different clinical features observed between pPCL and sPCL patients.
Clinical
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RB1 (RB Transcriptional Corepressor 1) • B2M (Beta-2-microglobulin) • CDKN2C (Cyclin Dependent Kinase Inhibitor 2C)
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Chr t(11;14) • RB1 deletion • PGR expression • Chr del(1p)
over2years
FISH and WGS in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma – WGS Will Affect Future Treatment Decisions (ASH 2021)
FISH is the preferred approach in pts with BM PCI <10% and for the detection of clones <15% or variant ploidy levels. WGS is superior to FISH regarding the identification of biallelic events and rearrangements with heterogeneous breakpoints and rare partners. But even more, WGS can address various questions in follow up in terms of increase of complexity, target specific therapy, therapy failure and relapse.
IO biomarker
|
BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • CRBN (Cereblon) • SDC1 (Syndecan 1) • IRF1 (Interferon Regulatory Factor 1) • FOXO3 (Forkhead box O3) • MAFB (MAF BZIP Transcription Factor B) • TENT5C (Terminal Nucleotidyltransferase 5C)
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TP53 mutation • BRAF V600E • BRAF V600 • Chr t(11;14) • TP53 deletion • TP53 mutation + Chr del(17p) • Chr t(4;14) • Chr t(14;16) • MYC rearrangement • IRF1 expression • Chr del(1p) • MAFB expression • CRBN mutation
over2years
[VIRTUAL] TRIM33 loss in Multiple Myeloma is associated with defective DNA repair and sensitivity to PARP inhibition (IMW 2021)
Here, we show that a subgroup of MM patients have TRIM33 loss and these patients have high-risk disease and poor outcome. We show that TRIM33 is recruited to damaged chromatin where it regulates ALC1 activity. Therefore, TRIM33 loss results in a DDR defect leading to chromosomal abnormalities.
BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • TRIM33 (Tripartite Motif Containing 33) • TP53BP1 (Tumor Protein P53 Binding Protein 1)
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BRCA2 mutation • BRCA1 mutation • Chr del(1p)
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Lynparza (olaparib)
almost3years
[VIRTUAL] Impact of age and genetics on outcomes of multiple myeloma treated with autologous stem cell transplant: single centre retrospective review, 2002-2019 (BSH 2021)
Importantly, this also provides real-world validation of clin- ical trial data indicating poor outcomes with two or more high-risk abnormalities and the need to evaluate alternate strategies such as tandem ASCT or those explored in clinical trials such as MUK9. However, a single adverse genetic marker may not be sufficient rea- son to change treatment strategy.
Retrospective data • Review
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SDC1 (Syndecan 1)
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Chr t(4;14) • Chr t(14;16) • IGH translocation • Chr del(1p)
3years
The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma. (PubMed, Nat Commun)
In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.
Journal
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
KRAS mutation • NRAS mutation • Chr del(1p)