scholarly journals Structure and signifi cance of cytogenetic abnormalities in patients with multiple myeloma

2021 ◽  
Vol 66 (1) ◽  
pp. 54-67
Author(s):  
T. V. Abramova ◽  
T. N. Obukhova ◽  
E. O. Gribanova ◽  
M. V. Solovev ◽  
M. V. Firsova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chromosomal Abnormality ◽  
Chromosomal Abnormalities ◽  
Negative Impact ◽  
Progression Free Survival ◽  
Β2 Microglobulin ◽  
Bone Marrow Trephine Biopsy ◽  
Ldh Activity ◽  
Pre Treatment

Introduction. Cytogenetic and genomic traits of tumour cells are considered the key mediating factors in multiple myeloma (MM). Selected chromosomal abnormalities are prognostic of therapeutic response and patient survival in MM.Aim — to assess of the diversity and rate of chromosomal abnormalities in MM patients and their association with the disease course.Materials and methods. The study enrolled 134 MM patients with pre-treatment bone marrow FISH assay screening for chromosomal abnormalities: t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), hyperdiploidy, del13q14/-13, del17p13/TP53, amp1q21, t(8q24)/cMYC. The studied criteria at the MM onset were: hemogram, lactate dehydrogenase (LDH) activity, calcium, β2-microglobulin and creatinine concentrations, punctate cytology, bone marrow trephine biopsy and/or soft tissue biopsy histology, bone X-ray, immunochemical variant of MM, disease staging. A median follow-up was 20 months (3.2–77.4).Results. The primary chromosomal abnormality rate was 82.9  %, among them t(14q32)/IGH  — 29.1  %, multiple trisomies — 46.3 % and their combination — 7.5 %. The rates of particular t(14q32)/IGH): t(11;14) — 16.4 %, t(4;14) — 12.7 %, t(14;16) and t(14;20) — 3.7 and 2.2 %, respectively. The secondary chromosomal abnormality rate was 69.4 %, among them del13q14/-13 — 40.3 %, amp1q21 — 39.6 %, t(8q24)/cMYC — 17.2 %, del17p13/TP53 — 12.7 %, del1p32 — 2.2 %. Analyses of the primary–secondary abnormality combinations showed that del13q14/-13 is more frequently combined with t(4;14) and less frequently with trisomies (p < 0.05). Amp1q21 occurs more frequently with t(4;14) and less — with t(11;14) (p<0.05). Patients with t(4;14) more frequently (p < 0.05) had anemia at a hemoglobin level<100 g/L, and the presence of amp1q21 and del17p13/TP53-enhanced serum LDH activity (p < 0.05). Abnormality t(8q24)/cMYC more often co-occurred with higher serum β2-microglobulin concentrations (p < 0.05). A three-year overall survival (OS) in del17p13/TP53-positive patients was 35.5 vs. 71.3 % in the negative (p = 0.002) and 50.8 vs. 67 % — in t(8q24)/cMYC-positive and negative patients, respectively (p = 0.001). Patients without amp1q21, with one, with two or more additional 1q21 copies had a five-year OS 79.4, 67.3 and 20.9 %, respectively (p = 0.0016), and a two-year progression-free survival (PFS) 83, 50 and 0 %, respectively (p = 0.005).Conclusion. We establish a negative impact of del17p13/TP53 and t(8q24)/cMYC on patients’ OS in MM, as well as unfavourable effect of amp1q21 on OS and PFS in the presence of two or more additional copies of 1q21 loci.

scholarly journals Chromosomal Abnormalities in Multiple Myeloma

Blood ◽  
1967 ◽  
Vol 30 (6) ◽  
pp. 738-748 ◽  
Author(s):  
K. C. DAS ◽  
B. K. AIKAT
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chromosomal Aberrations ◽  
Chromosomal Abnormality ◽  
Chromosomal Abnormalities ◽  
Acute Leukemias ◽  
Leukocyte Culture ◽  
Peripheral Leukocyte ◽  
Direct Preparation ◽  
Chromosomal Changes

Abstract Chromosome studies were carried out in five cases of multiple myeloma by peripheral leukocyte culture and direct preparation from bonemarrow cells. No chromosomal abnormality was detected by leukocyte culture in any of these cases. Analysis of bone marrow metaphase plates revealed abnormalities in four out of five cases. Chromosomal changes were characterized by their variability from case to case, as well as among different groups of cells in individual cases. Both numerical and structural anomalies were encountered. The chromosome series more frequently involved were C, A, G and B in decreasing order. The diverse chromosomal aberrations encountered in these four cases of multiple myeloma are reminiscent of those described in acute leukemias.

scholarly journals Genetic program activity delineates risk, relapse, and therapy responsiveness in multiple myeloma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Matthew A. Wall ◽  
Serdar Turkarslan ◽  
Wei-Ju Wu ◽  
Samuel A. Danziger ◽  
David J. Reiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Abnormalities ◽  
Transcriptional Regulatory Network ◽  
Progression Free Survival ◽  
Cross Sectional ◽  
Free Survival ◽  
Extreme Risk ◽  
Transcriptional Regulatory ◽  
Transcription Regulators ◽  
Immunosuppressive Microenvironment

AbstractDespite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to multiple lines of therapies. Therefore, we not only need the ability to predict which patients are at high risk for disease progression but also a means to understand the mechanisms underlying their risk. Here, we report a transcriptional regulatory network (TRN) for MM inferred from cross-sectional multi-omics data from 881 patients that predicts how 124 chromosomal abnormalities and somatic mutations causally perturb 392 transcription regulators of 8549 genes to manifest in distinct clinical phenotypes and outcomes. We identified 141 genetic programs whose activity profiles stratify patients into 25 distinct transcriptional states and proved to be more predictive of outcomes than did mutations. The coherence of these programs and accuracy of our network-based risk prediction was validated in two independent datasets. We observed subtype-specific vulnerabilities to interventions with existing drugs and revealed plausible mechanisms for relapse, including the establishment of an immunosuppressive microenvironment. Investigation of the t(4;14) clinical subtype using the TRN revealed that 16% of these patients exhibit an extreme-risk combination of genetic programs (median progression-free survival of 5 months) that create a distinct phenotype with targetable genes and pathways.

scholarly journals Is the platelet-to-lymphocyte ratio a new prognostic marker in multiple myeloma?

2018 ◽  
Vol 10 (04) ◽  
pp. 363-369 ◽  
Author(s):  
Serife Solmaz ◽  
Ozcan Uzun ◽  
Celal Acar ◽  
Omur Gokmen Sevindik ◽  
Ozden Piskin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Negative Impact ◽  
Progression Free Survival ◽  
Cost Effective ◽  
P Value ◽  
Platelet To Lymphocyte Ratio ◽  
Cox Models ◽  
Lymphocyte Ratio ◽  
Kaplan Meier ◽  
The Cost

ABSTRACT BACKGROUND: Recent reports showed neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), as a predictor of progression-free survival (PFS) and overall survival (OS) in various malignancies. MATERIALS AND METHODS: We retrospectively examined the PLR, NLR, and MLR in a cohort of 186 newly diagnosed multiple myeloma (MM) patients. This study investigated the prognostic relevance of NLR, PLR, and MLR in MM patients. NLR, PLR, and MLR were calculated from whole blood counts before therapy. The Kaplan–Meier curves and multivariate Cox models were used for the evaluation of survival. RESULTS: Applying cutoff of 1.9 (NLR), 120.00 (PLR), and 0.27 (MLR), decreased PLR showed a negative impact on the outcome. Decreased PLR is an independent predictor for PFS and OS. There were no significant differences in median survival between the high and low NLR (P = 0.80) and MLR (P = 0.87) groups. CONCLUSIONS: In this study, thrombocytopenia and low PLR are associated with poor survival in MM patients does this P value apply to thrombocytopenia or low PLR and may serve as the cost-effective prognostic biomarker.

Durable Remission with Salvage Autotransplants in Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1227-1227
Author(s):  
Nina Shah ◽  
Khawaja Fraz Ahmed ◽  
Sofia Qureshi ◽  
Jatin Shah ◽  
Robert Z Orlowski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Median Time ◽  
Chromosomal Abnormalities ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Remission Duration

Abstract Abstract 1227 Poster Board I-249 Background In comparison with single autologous hematopoietic stem cell transplantation (auto HCT), tandem autologous HCT has resulted in longer event-free and overall survival in randomized trials for patients with newly diagnosed multiple myeloma (MM). Most myeloma patients, however, only receive a single auto HCT. Many of these patients are eligible for a second auto HCT as salvage at the time of relapse. We evaluated the outcome of salvage auto HCT for MM patients treated at our institution. Methods We performed a retrospective chart review and identified 62 MM patients (38 males, 24 females) who received a second auto HCT as salvage between 1/3/1992 and 11/4/2008.. Preparative regimen was high-dose melphalan alone or in combination with other chemotherapy agents, including busulfan, topotecan and bortezomib. Three patients received a combination of thiotepa, busulfan and cyclophosphamide. Results Median interval between the first and salvage auto HCT was 21 months (range 2-81). Median age at salvage HCT was 55 years (37-73) and median prior treatment regimens were 4 (range 2-16). Twelve patients had chromosomal abnormalities on conventional cytogenetic studies. Patients received a median CD34 cell dose of 4 ×106 / kg (range 2.3-11.2). Fourteen patients (22%) experienced grade 3 or higher toxicity after the salvage auto HCT. Two patients died within 100 days with a TRM of 3%. Median time to neutrophil engraftment was 10 days (8-38). Responses after salvage auto HCT were as follows: CR+ near CR 15%, PR 48%, with an overall response rate of 63%. Twenty-seven (44%) patients received post auto HCT maintenance therapy. Median follow-up from salvage HCT was 25 months. Kaplan-Meier estimates of median progression-free survival and overall survival (OS) were 15.5 and 43.3 months, respectively. Median time to progression after the first and salvage auto HCT was 20 and 12 months, respectively, with total remission duration of 32 months from two HCTs. Median OS from the time of diagnosis was 72 months, comparable to reported results with tandem auto HCT. At last follow up, 20 patients were alive and in remission. Conclusions In selected MM patients a second auto HCT for salvage therapy is well tolerated with acceptable toxicity. The combined remission duration and overall survival are comparable to outcomes with tandem autotransplants. Disclosures Qazilbash: Cephalon: Speakers Bureau.

Lenalidomide Consolidation Followed by Maintenance After Autologous Transplantation for Multiple Myeloma Decreases Thymic Output and Terminally Differentiated CD4 and CD8 T Cells but Increases Treg

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4046-4046 ◽  
Author(s):  
Emmanuel Clave ◽  
Corinne Douay ◽  
Tereza Coman ◽  
Marc Busson ◽  
Caroline Bompoint ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Autologous Transplantation ◽  
Immune Surveillance ◽  
Progression Free Survival ◽  
High Dose ◽  
Post Transplantation

Abstract Abstract 4046 Treatment with lenalidomide, an immunomodulatory drug, increases the time to progression in relapsed/refractory multiple myeloma. However, due to its pleiotropic effect, it is not known whether the efficacy of this drug is due only to direct tumor toxicity or also to immunomodulatory effects. We assessed in vivo the changes in T-cell reconstitution induced by lenalidomide consolidation and maintenance treatment following autologous peripheral blood stem cell transplantation (ASCT) in a cohort of multiple myeloma patients. Twenty-nine newly diagnosed myeloma patients were treated with the induction combination bortezomib plus dex followed by high dose melphalan (140–200 mg/m2) and ASCT. A first group of 11 patients were treated with lenalidomide consolidation initiated 3 to 6 months post transplantation: 25 mg/day, days 1–21 of a 28 day cycle for 2 months, followed by maintenance (10 mg/day) until disease progression. This group was compared with the 18 patients who did not receive any treatment after ASCT. Blood samples were collected at diagnosis, before the transplant and 1, 3, 6, 9, 12 and 18 months after ASCT. Thymic function was assessed by real-time PCR quantification of T cell receptor excision circles (sjTREC) and percentages and absolute counts of T lymphocyte subpopulations were determined by multicolor flow cytometry. Statistics were performed using the Log-Rank or Mann-Whitney test. The two cohorts had similar baseline characteristics and all 29 patients were in remission after ASCT. With a median follow-up of 4 years, progression-free survival (PFS) was superior with lenalidomide treatment (69% vs 36%, p=0.05) while overall survival (OS) was similar (82% vs 75%, p=0.5). Lenalidomide treatment induced a progressive decrease in sjTREC (median at 18 months, 0.25/μL vs 1.61/μL, p<0.05) and a decrease in the percentages and absolute counts of CD4+ and CD8+ CD45RA+CCR7- effector terminal T cell subpopulations (median at 18 months, 3.2/μL vs 17.6/μL, p<0.05 for CD4+CD45RA+CCR7- and 109/μL vs 345/μL, p<0.05 for CD8+CD45RA+CCR7-). Conversely, lenalidomide treated patients displayed an increase in CD4+CD25+CD127-/low Treg populations, in both percentage and absolute count (median 13% vs 8 %, p<0.05 and 48.9/μL vs 29.3/μL, p<0.05, respectively). No correlation was found with documented infections, relapse or survival. We confirm an increase in PFS with lenalidomide consolidation/maintenance following ASCT. However, our data also suggest that in myeloma patients, the effect of lenalidomide on the myeloma tumor may not be T cell mediated and this treatment may have a negative impact on the T cell immune surveillance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma

2021 ◽  
Author(s):  
Meera Mohan ◽  
Samantha Kendrick ◽  
Aniko Szabo ◽  
Naveen K Yarlagadda ◽  
Dinesh Atwal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Clinical Relapse ◽  
Landmark Analyses ◽  
Minimal Residual

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next generation flow cytometry (sensitivity of 10-5 cells) at 3 to 6 months intervals. With a median follow up of 9.9 years from diagnosis (range, 0.4 - 30.9), 61% of patients maintained MRD negativity, while 39% experienced MRD conversion at a median of 6.3 years (range, 1.4 - 25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95%vs. 84%; P = 0.001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 year (range, 0 - 4.9). However, 27% of MRD conversion positive patients had not yet experienced a clinical relapse with a median follow-up of 9.3 years (range, 2.2 - 21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared to patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.

Longitudinal whole body MRI (wbMRI) in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8590-8590
Author(s):  
Maximilian Merz ◽  
Barbara Wagner-Gund ◽  
Kai Neben ◽  
Anthony D. Ho ◽  
Hartmut Goldschmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Whole Body ◽  
Rank Test ◽  
Focal Lesions ◽  
Patients At Risk ◽  
Initial Work

8590 Background: The detection of bone marrow focal lesions (FLs) by MRI at the initial work up has prognostic significance in multiple myeloma (MM), smoldering MM as well as MGUS. Currently, there are no data available on the predictive relevance of new FLs or FLs increasing in size in longitudinally performed wbMRIs for the follow-up of sMM and MGUS. Methods: We retrospectively analyzed 87 patients (sMM n=65; MGUS n=22) that received at least 2 (up to 5) wbMRIs for follow-up. The date of progression into MM requiring systemic therapy was defined as event for the analysis of progression free survival (PFS). Radiological progressive disease (rPD) was defined as the appearance of novel FLs or increase in size of preexisting FLs. Kaplan-Meier plots of PFS for patients with rPD and patients without rPD were analyzed using the log-rank test for significant differences. Results: Median follow-up was 61 months (9.8-101) with a median time between follow-up wbMRIs of 15.8 months (1-73). Progression from sMM/MGUS into MM was found in 28 patients (sMM 40%; MGUS 9%). Using wbMRI, rPD was found in 21 patients (sMM 32%; MGUS 0%). Of all patients, 76% (n=16) with rPD and 16% (n= 9) without rPD progressed into MM during the observation period. Analysis of Kaplan Meyer plots for PFS revealed a highly significant shorter PFS for patients with rPD (32 months) compared to patients with radiological stable disease in wbMRI (PFS not reached; p<0.0001). New appearance or progression of diffuse bone marrow infiltration was not associated with a shorter PFS (not reached; p>0.05). Conclusions: In our study, the appearance of novel FLs or progression of preexisting FLs was highly predictive for progression from sMM into MM requiring systemic treatment. We conclude that wbMRI is effective for the longitudinal follow-up of patients with sMM and MGUS and identifies a group of patients at risk for progression into MM.

Measurable residual disease (MRD) assessed by mass spectrometry (MS) in peripheral blood versus next generation sequencing (NGS) in bone marrow in multiple myeloma treated on phase II trial of KRd+ASCT.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8513-8513 ◽  
Author(s):  
Benjamin Avi Derman ◽  
Andrew T Stefka ◽  
Amanda McIver ◽  
Ken Jiang ◽  
Tadeusz Kubicki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Phase Ii ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Limit Of Detection ◽  
Progression Free Survival ◽  
Maldi Tof ◽  
Next Generation Sequencing Ngs

8513 Background: MRD-negativity in multiple myeloma (MM) assessed by NGS in bone marrow (BM) aspirate is associated with longer progression free survival (PFS) and overall survival. MS can detect monoclonal protein at a heightened sensitivity in peripheral blood (PB). We sought to assess the concordance of MS in PB and NGS in BM, comparing outcomes by MRD status. Methods: MRD was tested on paired PB and BM samples from transplant (ASCT)-eligible pts with newly diagnosed secretory MM who received treatment on a phase II clinical trial (NCT01816971) with KRd for 4 cycles, ASCT, KRd for 14 cycles, and lenalidomide maintenance (LM). Both NGS and MS were evaluable in 36 pts after a total of 18 cycles of KRd (C18) and in 24 pts after 1 year of LM. MS signatures were identified in pretreatment PB samples. C18 and after 1 year of LM PB samples were evaluated using both MALDI-TOF and liquid-chromatography-MS (LCMS) by the Binding Site Group. Paired MRD by NGS was performed by ClonoSEQ. 20/60 samples reached the limit of detection for 10−6 and 40/60 for 10−5. Results: There was substantial concordance between NGS and MALDI-TOF among the 60 samples ( κ= 0.667, 83% agreement) and fair concordance between NGS and LCMS ( κ= 0.348, 63% agreement). However, all 22 discordant samples (8 with NGS depth 10−6, 14 with NGS depth 10−5) were NGS−/LCMS+. 4/16 (25%) of these pts converted to NGS+, and 3/16 (19%) clinically progressed. There was stronger concordance between LCMS and NGS 10−6( κ= 0.615) than with NGS 10−5( κ= 0.375). At a median follow-up of 56 months, C18 LCMS−(n = 9) was associated with superior PFS vs all LCMS+(n = 27; p = 0.03) and independently vs NGS—/LCMS+ (n = 14; p = 0.04). There were 10 events (including 4 deaths) in the C18 LCMS+ group vs 0 in the LCMS− group. Conclusions: MRD assessment by LCMS in PB appears to reach and possibly exceed the sensitivity of MRD by NGS in BM at a depth of 10−5-10−6. LCMS positivity predicted conversion from NGS— to NGS+ in 25% of discordant cases, and LCMS negativity was a better predictor of superior PFS than MRD negativity by NGS. These observations need confirmation in larger prospective studies.

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