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BIOMARKER:

Chr t(14;16)

7d
Irradiated Donor Cells Following Stem Cell Transplant in Controlling Cancer in Patients With Hematologic Malignancies (clinicaltrials.gov)
P1, N=4, Active, not recruiting, Rutgers, The State University of New Jersey | Recruiting --> Active, not recruiting | N=40 --> 4
Enrollment closed • Enrollment change
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TP53 (Tumor protein P53) • NPM1 (Nucleophosmin 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1)
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TP53 mutation • FLT3-ITD mutation • RUNX1 mutation • ASXL1 mutation • RAS mutation • Chr t(4;14) • Chr t(14;16) • JAK2 mutation
2ms
Carfilzomib, Pomalidomide, and Dexamethasone in Treating Patients With High-Risk Multiple Myeloma (clinicaltrials.gov)
P2, N=29, Active, not recruiting, Emory University | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2022 --> Aug 2023
Enrollment closed • Trial primary completion date
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Chr t(4;14) • Chr t(14;16)
|
clonoSEQ
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carfilzomib • pomalidomide • Decadron (dexamethasone)
2ms
Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma (clinicaltrials.gov)
P2, N=83, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2022 --> Feb 2023 | Trial primary completion date: Aug 2022 --> Feb 2023
Trial completion date • Trial primary completion date
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ERN1 (Endoplasmic Reticulum To Nucleus Signaling 1) • XBP1 (X-box-binding protein 1)
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Chr t(4;14) • Chr t(14;16)
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gemcitabine • Farydak (panobinostat) • melphalan • busulfan • peripheral blood stem cell transplantation
4ms
Selinexor Plus VRd in High Risk Newly Diagnosed Multiple Myeloma (clinicaltrials.gov)
P1/2, N=42, Recruiting, Xia Zhongjun | Not yet recruiting --> Recruiting
Enrollment open
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TP53 (Tumor protein P53)
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TP53 mutation • Chr t(4;14) • Chr t(14;16)
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lenalidomide • bortezomib • Xpovio (selinexor)
4ms
D-VTd as induction therapy in newly diagnosed multiple myeloma (NDMM) patients who are candidates for transplantation: a real-life experience in a single center (IMW 2022)
Introduction: D-VTd (Daratumumab, Velcade, Thalidomide, Dexamethasone) is approved by EMA/FDA and is recommended by the Therapeutic Guidelines ESMO/NCCN (IA evidence) as standard induction and consolidation therapy in transplant-eligible NDMM patients, according to the Cassiopeia clinical trial, which demonstrated a significant improvement in progression-free survival compared to VTd (HR: 0.47) (Moreau P et al, Lancet 2019; 394: 29–38)...In maintenance (Daratumumab or Lenalidomide or DRd, 13 evaluable patients): PR: 7%, VGPR: 7%, sCR 69%...Mobilization and collection of peripheral blood hematopoietic progenitor cells (PBPCs):It was carried out with G-CSF (10 ug/kg/12 hours x 4 days), requiring the association of Plerixafor in 6 patients (23%)... D-VTd as induction therapy in NDMM transplant-eligible patients is feasible in real-life practice with a very high response rate and acceptable toxicity. Our results are in line with those of the Cassiopeia clinical trial, highlighting the rapid response and the high rate of negative minimal residual disease (MRD).
Clinical
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TP53 (Tumor protein P53) • CD34 (CD34 molecule)
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Chr t(4;14) • Chr t(14;16)
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lenalidomide • bortezomib • Darzalex (daratumumab) • thalidomide • dexamethasone • Mozobil (plerixafor)
4ms
Immuno-PRISM (PRecision Intervention Smoldering Myeloma) (clinicaltrials.gov)
P2, N=51, Recruiting, Irene Ghobrial, MD | Not yet recruiting --> Recruiting
Enrollment open • IO biomarker
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TP53 (Tumor protein P53) • CORIN (Corin, Serine Peptidase)
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TP53 mutation • Chr t(4;14) • Chr t(14;16)
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lenalidomide • dexamethasone • Tecvayli (teclistamab)
5ms
New P2 trial • IO biomarker
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TP53 (Tumor protein P53) • CORIN (Corin, Serine Peptidase)
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TP53 mutation • Chr t(4;14) • Chr t(14;16)
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lenalidomide • dexamethasone • Tecvayli (teclistamab)
5ms
Belantamab Mafodotin, Pomalidomide and Dexamethasone for the Treatment of High-Risk Myeloma (clinicaltrials.gov)
P2, N=34, Recruiting, Emory University | Not yet recruiting --> Recruiting
Enrollment open
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CD4 (CD4 Molecule)
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Chr t(4;14) • Chr t(14;16)
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pomalidomide • Blenrep (belantamab mafodotin) • Hemady (dexamethasone tablets) • Decadron (dexamethasone)
5ms
Haploidentical Stem Cell Transplant With Prophylactic Natural Killer DLI for Lymphoma, Multiple Myeloma, and CLL (clinicaltrials.gov)
P1, N=30, Active, not recruiting, Noah Merin | Trial primary completion date: May 2022 --> Oct 2022
Trial primary completion date
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CD20 (Membrane Spanning 4-Domains A1) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • CD4 (CD4 Molecule) • HLA-DQB1 (Major Histocompatibility Complex, Class II, DQ Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B)
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Chr del(17p) • Chr del(11q) • Chr t(4;14) • Chr t(14;16) • CD20 expression
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Rituxan (rituximab) • bendamustine • fludarabine IV
5ms
Multiple Myeloma: 2022 update on Diagnosis, Risk-stratification and Management. (PubMed, Am J Hematol)
In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Standard risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high-risk myeloma. A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse.
Journal
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TP53 (Tumor protein P53)
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TP53 mutation • Chr t(4;14) • Chr t(14;16)
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lenalidomide • bortezomib • Darzalex (daratumumab) • dexamethasone
6ms
Bone metabolism parameters and their relation to cytogenetics in multiple myeloma. (PubMed, Eur J Haematol)
Our analysis has shown, some cytogenetic changes, especially delRB1, t(14;16) and 1q21gain, which affect the components of the cytokine network in multiple myeloma.
Journal
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IL6 (Interleukin 6) • HGF (Hepatocyte growth factor) • B2M (Beta-2-microglobulin) • DKK1 (dickkopf WNT signaling pathway inhibitor 1) • ICAM1 (Intercellular adhesion molecule 1) • SDC1 (Syndecan 1) • TNFRSF11B (Tumor necrosis factor receptor superfamily member 11B)
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Chr t(14;16)
7ms
CHARACTERIZATION OF MULTIPLE MYELOMA CELL LINES WITH ACQUIRED-RESISTANCE TO PROTEASOME INHIBITORS HIGHLIGHTS A LINK BETWEEN RESISTANCE AND METABOLIC DEREGULATION (EHA 2022)
Methods For that purpose, we have derived and characterized 6 Bortezomib (Btz)-resistant human myeloma cells lines (BR-HMCLs) from different molecular subgroups and still dependent on the addition of IL-6 including XG1BR t(11;14), XG2BR t(12;14), XG7BR, XG20BR, XG24BR t(4;14) and XG19BR t(14;16)...In addition, these BR-HMCLs also showed significant cross-resistance to Carfilzomib (Cfz) and Ixazomib (Ixa) PIs (p<0.05 for Cfz or Ixa). Finally, no significant cross-resistance was observed with other therapeutic agents (melphalan, dexamethasone or IMIDs), indicating that the observed drug resistance mechanisms are especially related to PIs...Conclusion Altogether, we developed acquired PIs resistant HMCLs that exhibit PSMB5 mutation as observed in patients, and we identified pathways linked to metabolism deregulation in these cell lines. These results make our PI-resistant models, an attractive preclinical model to test new therapeutic strategies to overcome PI resistance in MM.
Preclinical
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IL6 (Interleukin 6)
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Chr t(11;14) • Chr t(4;14) • Chr t(14;16)
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bortezomib • Ninlaro (ixazomib) • carfilzomib • dexamethasone • melphalan
7ms
YOUNG ADULTS WITH MULTIPLE MYELOMA – A SINGLE CENTER EXPERIENCE (EHA 2022)
On the other hand, in our population, ISS, CRAB symptoms, cytogenetic data, immunophenotypic features and treatment was not shown to have an impact on clinical course of the disease or survival. This study has limitations, particularly attributable to its retrospective nature, small number of patients within a single institution and lack of detailed information regarding imaging techniques, and comorbidities.
Clinical
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TP53 (Tumor protein P53)
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TP53 mutation • Chr t(11;14) • Chr t(4;14) • Chr t(14;16) • Chr t(14;20)
7ms
COEXISTENCE OF ≥2 HIGH-RISK MOLECULAR ABNORMALITIES SUPERVENES THE PROGNOSTIC VALUE OF THE REVISED INTERNATIONAL STAGING SYSTEM FOR MYELOMA: REAL-WORLD DATA ANALYSIS FROM THE GREEK MYELOMA STUDY GROUP (EHA 2022)
Conclusion According to our analysis of a large cohort of newly diagnosed MM patients UHR myeloma, was the strongest independent predictor for OS, supervening the prognostic value of R-ISS. Moreover, UHR status could serve as an additional prognostic marker for R-ISS2 patients, helping thus to optimize therapeutic approach of MM patients.
Clinical • Real-world evidence
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B2M (Beta-2-microglobulin)
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Chr t(4;14) • Chr t(14;16)
7ms
ISATUXIMAB, LENALIDOMIDE, BORTEZOMIB AND DEXAMETHASONE AS INDUCTION THERAPY FOR NEWLY-DIAGNOSED MULTIPLE MYELOMA PATIENTS WITH HIGH-RISK CYTOGENETICS: A SUBGROUP ANALYSIS FROM THE GMMG-HD7 TRIAL (EHA 2022)
MRD negativity rates for Isa-RVd vs. RVd were 49.7% (86/173) vs. 36.7% (54/147; OR=1.70, 95% CI: 1.09-2.68) in standard risk patients, 46.7% (35/75) vs. 34.7% (35/101; OR=1.65, 95% CI: 0.90-3.05) in high-risk patients and 56.3% (27/48) vs. 44.1% (15/34; OR=1.63, 95% CI: 0.67-3.99) in ultra high-risk patients. Conclusion Isa-RVd induction therapy is superior to RVd in patients with transplant-eligible NDMM and high-risk or ultra high-risk cytogenetics, consistent with the benefit observed in the overall trial population.
Clinical
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SDC1 (Syndecan 1)
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Chr t(4;14) • Chr t(14;16)
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lenalidomide • bortezomib • Sarclisa (isatuximab-irfc) • dexamethasone
7ms
The impact of bortezomib-based induction in newly diagnosed multiple myeloma with chromosome 1q21 gain. (PubMed, Ther Adv Hematol)
+1q is an adverse factor for OS in MM uniformly treated with bortezomib-based induction but was partially mitigated by ASCT. A risk scoring system comprising +1q, LDH, high-risk FISH, and ISS is a potential tool for risk stratification in MM.
Journal
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SDC1 (Syndecan 1)
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Chr t(4;14) • Chr t(14;16) • Chr del(13)(q14)
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bortezomib
8ms
Circulating Serum MiRNA-8074 as a Novel Prognostic Biomarker for Multiple Myeloma. (PubMed, Cells)
In total, 105 newly diagnosed MM patients treated with thalidomide (n = 27), bortezomib (n = 41) and bortezomib with thalidomide (n = 37) were studied. In addition to the known prognostic factors, such as ECOG > 1, Durie-Salmon stage III, diagnosis of light chain disease or non-secreting MM, renal failure, hypoalbuminemia, hypercalcemia, high β2-microglobulin, elevated LDH, and t(14;16), a high expression of miRNA-8074 was significantly associated with a higher risk of death (HR = 4.12, 95% CI: 2.20-7.70; p = 0.0009). In summary, miRNA-8074 may be a useful diagnostic tool to assess the prognosis in MM patients.
Journal
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TP53 (Tumor protein P53) • B2M (Beta-2-microglobulin) • MAPK1 (Mitogen-activated protein kinase 1)
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Chr t(11;14) • LDH elevation • Chr t(14;16)
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bortezomib • thalidomide
8ms
Current Approaches to Management of Newly Diagnosed Multiple Myeloma. (PubMed, Am J Hematol)
Among transplant ineligible patients, those with standard risk MM should receive DRd continued until disease progression, while bortezomib containing regimens (VRd or VRd lite) can be considered for high-risk patients. Finally, standard risk patients should receive lenalidomide maintenance after induction/ASCT, while a proteasome inhibitor-IMiD combinations should be used for high risk patients.
Review • Journal
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TP53 (Tumor protein P53)
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TP53 mutation • Chr t(4;14) • Chr t(14;16) • TP53 mutation + Chr del(17p)
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lenalidomide • bortezomib
9ms
Single-cell RNA sequencing of rare circulating tumor cells in precursor myeloma patients reveals molecular underpinnings of tumor cell circulation (AACR 2022)
This study highlights the utility of scRNA-seq for molecular profiling of CTCs, even in asymptomatic low tumor burden disease. Additional analyses are ongoing in the expanded cohort of 40 patients with paired samples to help gain further insight into CTC heterogeneity. Overall, this study will help enable the design of new molecular liquid biopsy-based approaches to diagnosis, disease monitoring, and biological insights to improve treatment strategies for precursor myeloma patients.
Clinical • Circulating Tumor Cells
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CCND1 (Cyclin D1) • TNFA (Tumor Necrosis Factor-Alpha)
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Chr t(11;14) • Chr t(14;16)
9ms
The Cytogenetic Profile of Primary and Secondary Plasma Cell Leukemia: Etiopathogenetic Perspectives, Prognostic Impact and Clinical Relevance to Newly Diagnosed Multiple Myeloma with Differential Circulating Clonal Plasma Cells. (PubMed, Biomedicines)
These observations proved relevant in the NDMM setting, where higher levels of circulating plasma cells (CPCs) were strongly associated with high-risk cytogenetics (median frequency of CPCs: 0.11% of peripheral blood nucleated cells for high-risk vs. 0.007% for standard-risk NDMM, p < 0.0001). Most importantly, the combined evaluation of CPCs (higher or lower than a cut-off of 0.03%), together with patients' cytogenetic status, could be used for an improved prognostic stratification of NDMM patients.
Journal
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MYC (V-myc avian myelocytomatosis viral oncogene homolog)
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Chr t(11;14) • Chr t(4;14) • Chr t(14;16) • MYC translocation
10ms
Genomic characterization of functional high-risk multiple myeloma patients. (PubMed, Blood Cancer J)
This is also corroborated by the association with the mutational signature associated with abnormal DNA damage response. We have also developed a machine learning based classifier that can identify most of these patients at diagnosis.
Journal
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TP53 (Tumor protein P53) • IL6 (Interleukin 6)
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TP53 mutation • TP53 deletion • Chr t(4;14) • Chr t(14;16)
10ms
Diagnosis and Management of Multiple Myeloma: A Review. (PubMed, JAMA)
Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.
Review • Journal
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B2M (Beta-2-microglobulin)
|
Chr t(4;14) • Chr t(14;16)
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lenalidomide • bortezomib • dexamethasone
11ms
T Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation Conditioned With a Reduced Intensity Regimen in Patients With Hematologic Malignancies and Aplastic Anemia (clinicaltrials.gov)
P1, N=15, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2022 --> May 2023 | Trial primary completion date: May 2022 --> May 2023
Trial completion date • Trial primary completion date
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1)
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TP53 mutation • Chr del(17p) • FLT3 mutation • RUNX1 mutation • ASXL1 mutation • Chr t(4;14) • Chr t(14;16)
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Rituxan (rituximab) • cyclophosphamide • fludarabine IV • Thymoglobulin (anti-thymocyte globulin (rabbit))
11ms
Plasma Cells in the Cellular Product Impact Progression Free Survival (PFS) but Not Overall Survival (OS) after Autologous (Auto) Hematopoietic Cell Transplant (HCT) (TCT-ASTCT-CIBMTR 2022)
Pts were consented on the 1 st day of the apheresis collection after receiving G-CSF (10 mcg/kg/day) and plerixafor (0.24 mg/kg) mobilization...A 0.1% increase in tumor cell contamination by FC was associated with a hazard ratio of 1.025 (95% CI: 0.983-1.069) for OS. In the era of novel induction agents and maintenance therapy after Auto HCT, tumor cell contamination of the cellular product impacts PFS, but not OS.
Clinical
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CD38 (CD38 Molecule) • CD34 (CD34 molecule) • SDC1 (Syndecan 1)
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Chr t(4;14) • Chr t(14;16) • SDC1 positive
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Mozobil (plerixafor)
1year
Biologic Basis of the Impact of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Treated with Quadruplet Therapy (TCT-ASTCT-CIBMTR 2022)
Methods MASTER is a prospective, multi-center clinical trial utilizing daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, AHCT (Melphalan conditioning), followed by MRD response-adapted Dara-KRd consolidation with planned enrichment for pts with high-risk chromosome abnormalities (HRCA). The greatest impact is afforded to the highest risk disease subset elucidating the biologic underpinnings of the impact of AHCT in MM. At this time, AHCT should remain an integral part of therapy for fit, NDMM patients, particularly those with the high-risk disease and those who remain MRD positive after induction.
Chr del(17p) • Chr t(4;14) • Chr t(14;16) • Chr t(14;20)
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clonoSEQ
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lenalidomide • Darzalex (daratumumab) • carfilzomib • dexamethasone • melphalan
1year
S1702 Isatuximab in Treating Patients With Relapsed or Refractory Primary Amyloidosis (clinicaltrials.gov)
P2, N=43, Active, not recruiting, Southwest Oncology Group | Trial primary completion date: Oct 2021 --> Jun 2022
Clinical • Trial primary completion date
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NPPB (Natriuretic Peptide B)
|
Chr t(11;14) • Chr t(4;14) • Chr t(14;16)
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Sarclisa (isatuximab-irfc)
1year
Evaluation of Hematopoietic Stem Cell Product As a New Site for Minimal Residual Disease By Next Generation Flow in Multiple Myeloma (ASH 2021)
Aims- To compare MRD quantification of plasma cell between BM and HSC product after induction from Newly Diagnosed MM(NDMM) Transplant Eligible (TE) patients (pts) exposed to daratumumab, cyclophosphamide, thalidomide and dexamethasone (Dara-CTD) protocol. In this preliminary data the sample size did not allow to show a direct correlation between BM and HCS product. A larger sample would be needed to confirm the hypothesis.
IO biomarker • Minimal residual disease
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CD38 (CD38 Molecule) • SDC1 (Syndecan 1)
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Chr t(4;14) • Chr t(14;16)
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cyclophosphamide • Darzalex (daratumumab) • thalidomide • dexamethasone
1year
[VIRTUAL] Impact of Cytogenetic Aberrations on Clinical Characteristics and Treatment Response in Indian Multiple Myeloma Patients: A Single Tertiary Center Experience (AMP 2021)
This study aimed to evaluate the association between cytogenetic abnormalities and clinicohaematological characteristics at diagnosis, and retrospectively compare the overall response rate to 2 triple drug combinations comprised of bortezomib, cyclophosphamide, and dexamethasone (VCd) versus thalidomide, cyclophosphamide, and dexamethasone (VRd) in transplant eligible patients with untreated MM. The key differences in baseline characteristics at presentation compared to Western population could be attributed to ethnic diversity. Triplet induction therapy VRd was superior as regards to response rates compared to VCd arm.
Clinical
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TP53 (Tumor protein P53) • FGFR3 (Fibroblast growth factor receptor 3) • CCND1 (Cyclin D1) • B2M (Beta-2-microglobulin)
|
Chr t(11;14) • TP53 deletion • Chr t(4;14) • Chr t(14;16) • Chr t(11;14)(q13;q32) • IGH translocation • Chr t(14;20)
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bortezomib • thalidomide
1year
Biologic Basis of the Impact of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Treated with Quadruplet Therapy (ASH 2021)
"Methods MASTER is a prospective, multi-center clinical trial utilizing daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, AHCT (Melphalan conditioning), followed by MRD response-adapted Dara-KRd consolidation with planned enrichment for patients with high-risk chromosome abnormalities (HRCA). At this time, AHCT should remain an integral part of therapy for fit, NDMM patients, particularly those with the high-risk disease and those who remain MRD positive after induction. Future studies exploring AHCT deferral in NDMM should be focused on patients who are MRD negative post optimal induction."
Chr del(17p) • Chr t(4;14) • Chr t(14;16) • Chr t(14;20)
|
clonoSEQ
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lenalidomide • Darzalex (daratumumab) • carfilzomib • dexamethasone • melphalan
1year
Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), Autologous Transplantation and MRD Response-Adapted Consolidation and Treatment Cessation. Final Primary Endpoint Analysis of the Master Trial (ASH 2021)
"Monoclonal antibody-based quadruplet therapy, AHCT and MRD response-adapted consolidation therapy leads to the highest rate of MRD negativity reported in NDMM. Near all patients with 0 or 1 HRCA and confirmed MRD negativity remain free of IMWG progression or MRD resurgence despite cessation of treatment. While most patients with ultra-high risk MM reach deep responses with this approach, novel consolidative strategies are needed."
Chr t(4;14) • Chr t(14;16)
|
clonoSEQ
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lenalidomide • Darzalex (daratumumab) • carfilzomib
1year
The Clinical Course and Life Expectancy of Patients with Multiple Myeloma Who Discontinue Their First Daratumumab-Containing Line of Therapy (ASH 2021)
Legends to Figure: A: Overall survival after T 0 ; B: Overall survival after T 0 by cytogenetic risk; C: Overall survival after T 0 by IR; D: Overall survival after T 0 by prior exposure. Abbreviations: T 0 =time of discontinuation of the first daratumumab-containing line of therapy; IR=index regimen; high-risk=t(4;14), t(14;16) or del17p by FISH; D-mono=daratumumab monotherapy; D-bor=daratumumab-bortezomib-dexamethasone; D-len=daratumumab-lenalidomide-dexamethasone; D-other=daratumumab in other combinations; Double_CE=exposed to daratumumab and another class of drugs; Triple_CE=exposed to daratumumab and two other classes of drugs; Quadruple_CE=exposed to daratumumab and three other classes of drugs; ABCDLP-exposed=exposed to daratumumab, bortezomib, carfilzomib, lenalidomide and pomalidomide
Clinical • IO biomarker
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CD38 (CD38 Molecule)
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Chr t(4;14) • Chr t(14;16)
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lenalidomide • bortezomib • Darzalex (daratumumab) • carfilzomib • pomalidomide • dexamethasone
1year
Phenotypic High-Risk Disease in the Context of Carfilzomib and Lenalidomide Combination Induction Therapy for Newly Diagnosed Transplant-Eligible Myeloma Patients (ASH 2021)
Methods The UK NCRI Myeloma XI trial is a phase III randomised controlled trial that recruited 2568 newly diagnosed transplant eligible patients, of which 526 were randomised to receive the induction combination KRdc comprising carfilzomib (K, 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2)), lenalidomide (R, 25mg PO d1-21), dexamethasone (d, 40mg PO d1-4,8-9,15-16) and cyclophosphamide (c, 500mg PO d1,8) as part of an adaptive trial design...401/526 (76%) of patients underwent high dose melphalan and ASCT on trial after KRdc induction...Discussion The combination of a second-generation immunomodulatory agent and proteasome inhibitor in the KRdc induction regimen is associated with deep responses and only a very small proportion of patients have primary refractory disease. Early relapse after KRdc and ASCT occurred in 9% of patients and was associated with high bone marrow disease burden and molecular high-risk features.
Clinical
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B2M (Beta-2-microglobulin)
|
Chr t(4;14) • Chr t(14;16)
|
lenalidomide • cyclophosphamide • carfilzomib • dexamethasone • melphalan
1year
Post-Induction Undetectable Minimal Residual Disease at 10-5 Sensitivity Level within Marrow and/or Stem Cell Graft Overrides Cytogenetic High Risk (ASH 2021)
Induction regimen consisted of bortezomib without or with immunomodulatory drug (IMID) 78.8%, 2.8% (prior to 2017) and 74.1%, 22.9% (after 2017)... Our real-world triplet drug induction-based experience shows for the first-time post-induction mMRD and MRD to be correlated with each other and with PFS. PFS with MRD(-) at 10 -5 results have displayed a better outcome compared to 10 -4 . MVA showed MRD and age to determine PFS, independent from post-induction CR, ISS and cytogenetic risk.
IO biomarker • Minimal residual disease
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD19 (CD19 Molecule) • CD27 • NCAM1 (Neural cell adhesion molecule 1) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • SDC1 (Syndecan 1)
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Chr t(11;14) • Chr t(4;14) • Chr t(14;16)
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bortezomib
1year
Genomic Characterization of in Vitro Acquired-Resistance to Proteasome Inhibitors (ASH 2021)
These cell lines were cultured continuously with escalating concentrations of Bortezomib (Btz) during 12 months and showed a significant resistance to Bortezomib compared to their parental cell lines (mean IC50: Btz-resistant HMCLs =5.5nM vs parental HMCLs=2.5nM, p<0.05). Of interest, we demonstrated that Btz-resistant HMCLs are also significantly more resistant to Carfilzomib (Cfz) and Ixazomib (Ixa) PIs (mean IC50: Btz-resistant HMCLs =6nM for Cfz and =70nM for Ixa vs parental HMCLs=3nM, for Cfz, p<0.05 ; and =21nM for Ixa, p<0.05. No significant cross-resistance was observed with other therapeutic agents including melphalan, dexamethasone and IMIDs indicating that the observed drug resistance mechanisms are specifically related to PIs...Metabolomic analyzes are currently ongoing for functional validation. Altogether, drug-resistant cell lines represent an attractive preclinical model to test molecules targeting these pathways in order to identify new therapeutic strategies to overcome PI resistance in MM.
Preclinical
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ERCC1 (Excision repair cross-complementation group 1) • POLD1 (DNA Polymerase Delta 1) • NQO1 (NAD(P)H dehydrogenase, quinone 1) • ERCC5 (ERCC Excision Repair 5 Endonuclease 2) • MCT1 (SLC16A1) • LRIG1 (Leucine Rich Repeats And Immunoglobulin Like Domains 1) • PDPK1 (3-Phosphoinositide dependent protein kinase 1)
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Chr t(11;14) • Chr t(4;14) • Chr t(14;16) • ERCC1 expression
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bortezomib • Ninlaro (ixazomib) • carfilzomib • dexamethasone • melphalan
1year
Clinical Outcomes and Treatment Strategies for Relapsed/Refractory Myeloma Patients after Relapse on BCMA-Targeted CAR T (ASH 2021)
Patients were refractory to various treatments: thalidomide (6% refractory), lenalidomide (74%), pomalidomide (84%), bortezomib (61%), carfilzomib (87%), ixazomib (23%), CD38-mAb (97%), alkylating agents (54%), venetoclax (19%) and selinexor (19%)...Information on additional MM treatment was available for 28 patients (90%); 1 patient was treated with cytarabine for MDS, 1 received no treatment, and 1 was lost to follow-up... RRMM patients relapsing after T cell engager therapy are a challenging population. Studying the prognosis of these patients including response to subsequent therapy will provide important clinical insights, especially as CAR T moves to an earlier treatment setting. Even though, due to selection, our cohort might be biased towards subjects with early CAR T failure, we show that novel agents, including bispecific Abs can cause durable responses in post-CAR T relapse.
Clinical • Clinical data
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TP53 (Tumor protein P53)
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Chr t(4;14) • Chr t(14;16)
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Venclexta (venetoclax) • lenalidomide • cytarabine • bortezomib • Xpovio (selinexor) • Ninlaro (ixazomib) • carfilzomib • thalidomide • pomalidomide