A longitudinal analysis of chromosomal abnormalities in disease progression from MGUS/SMM to newly diagnosed and relapsed multiple myeloma

Abstract Abstract 1811 The presence of chromosomal aberrations is a characteristic feature of multiple myeloma (MM). Recently, Avet-Loiseau et al reported that amp5q31.3 and del12p13.31, detected by high-density, single-nucleotide polymorphism arrays analysis correlate with prognosis in MM patients who were treated upfront with conventional chemotherapy (JCO 2009; 27:4585–90). The aim of our study was to evaluate the effect of these chromosomal abberations on survival of patients with newly diagnosed MM or with relapsed/refractory myeloma who were treated with novel agent-based regimens. We studied 172 MM patients who were treated in a single center in Athens (Greece) during a 4-year period (2007–2011); 76 were newly-diagnosed and were treated upfront with either bortezomib- or IMiD-based regimens and 96 had relapsed or refractory MM and were treated with the combination of lenalidomide and dexamethasone with or without bortezomib (RD vs. VRD) based on the presence of previous peripheral neuropathy (Dimopoulos et al, Leukemia 2010;24:1769–78). A combined methodological approach of G-banding karyotypic analysis and interphase fluorescence in situ hybridization (FISH) was performed in all patients. G-banding analysis was performed according to the European Cytogenetic Guidelines and Quality Assurance (ECA, 2006). The clonality criteria and the karyotypic description followed the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN, 2009). FISH was performed according to the Recommendations for FISH in MM (European Myeloma Network) on uncultured BM, either on cytoplasmic immunoglobulin-enhanced cells (cIg-FISH) or on nuclei from purified CD138+ plasma cells. Commercially available DNA probes (Abott-VYSIS) were used for the detection of del17p, del13q, add1q21, t(4;14) and t(14;16). The probes RP11-96J7 and RP11-578N7 (labeled by Empire Genomics, NY, USA) were used to detect amp5q31 and del12p13. The frequency of the studied chromosomal abnormalities is depicted in the table. There was a strong correlation between the presence of amp5q31 with hyperdiploidy (p=0.012) but amp5q31 did not correlate with the presence of any other of the studied chromosomal aberrations. The presence of del12p13 was correlated with the presence of del13q (p=0.001), t(4;14) (p=0.009) and del17p (p=0.005). Add1q21 also correlated with del13q (p<0.001), t(4;14) (p<0.001) and del17p (p=0.007). In patients with relapsed/refractory MM, who received either RD or VRD, the median overall survival was 19 months. Patients with amp5q31 had a median survival of 18 months (95% CI: 13–23 months) vs. 21 months of the others (95% CI: 8–35 months; p=0.737), while patients with del12p13 had a median survival of 27 months (95% CI: 0–57 months) vs. 19 months of the others (95% CI: 10–27 months; p=0.767). Of the other studied cytogenetic abnormalities, the presence of del17p (11 vs. 26 months; p=0.001), amp1q21 (12 vs. 26 months; p=0.001) and del13q by FISH (11 vs. 26 months; p=0.025), but not of t(4;14) (p=0.521), were associated with inferior overall survival. In patients with newly-diagnosed MM, the median overall survival was 57 months. The median survival of patients with amp5q31 was 46 months vs. 57 months of all others (p=0.315) and for patients with del12p13 has not been reached vs. 57 months of all others (p=0.379). In conclusion, amp5q31 and del12p13 are recurrent chromosomal abnormalities in MM. Amp5q31 is not associated with the presence of other genetic features, except hyperdiploidy. αmp5q31 or 12p13 was not predictive of survival ιn our series. However, further studies are needed in patients with newly diagnosed MM who receive novel agents upfront to validate the prognostic importance of amp5q31 and del12p13.TableCytogenetic abnormalityPatients at diagnosis (n=76)Relpased/refractory patients (n=96)p-valueamp5q3112 (15.7%)20 (20.8%)0.271amp5q31 as sole anomaly5 (6.5%)7 (7.2%)0.674del12p138 (10.5%)16 (16.6%)0.171del13q28 (36.8%)28 (29.1%)0.279del17p13 (17.1%)15 (15.6%)0.765add1q2115 (19.7%)26 (27%)0.303t(14;16)1 (1.3%)1 (1%)0.832t(4;14)4 (5.2%)10 (10.4%)0.221Hyperdiploidy/hypodiploidy10 (13.1%)/6 (7.8%)11 (11.4%)/13 (13.5%)0.301 Disclosures: No relevant conflicts of interest to declare.

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Melphalan, Prednisone and Lenalidomide Followed by Lenalidomide Maintenance Improves Health-Related Quality of Life (HRQoL), with Newly Diagnosed Multiple Myeloma (NDMM) Patients ≥ 65 Years Benefiting From Delays in Disease Progression

Blood ◽

10.1182/blood.v118.21.3157.3157 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3157-3157 ◽

Cited By ~ 1

Author(s):

Meletios Athanasios Dimopoulos ◽

Michel Delforge ◽

Roman Hajek ◽

Martin Kropff ◽

Maria Teresa Petrucci ◽

...

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Disease Progression ◽

Physical Functioning ◽

The Other ◽

Newly Diagnosed ◽

Employment Equity ◽

Disease Symptoms ◽

End Of Treatment ◽

Equity Ownership

Abstract Abstract 3157 Background: Lenalidomide maintenance following induction with melphalan, prednisone, and lenalidomide has been shown to provide sustained disease control by significantly decreasing the relative risk of progression in NDMM patients [Palumbo, 2010]. HRQoL analyses, alongside efficacy and safety considerations, may help establish a more complete picture of an overall treatment profile. Initial findings on HRQOL have shown a well-balanced profile of MPR-R in terms of efficacy, safety and tolerability, with HRQoL improving both during MPR induction and lenalidomide maintenance [Dimopoulos, 2011]. Alternative findings on novel NDMM treatment have shown efficacy of melphalan, prednisone and bortezomib (VMP) treatment to be associated with an intermittent deterioration in patients' HRQoL [Dhawan, 2009]. Methods: This analysis considers the impact on HRQoL of ending treatment due to progressive disease (PD) or discontinuation due to other reasons (DC) for both MPR-R and MP patients. HRQoL scores were assessed for six domains, pre-selected based on clinical relevance: Global QoL, Physical Functioning, Fatigue and Pain (from EORTC QLQ-C30), and Disease Symptoms and Side Effects of Treatment (from EORTC MY20). Mean HRQoL scores measured at PD/DC, PD alone and DC alone were compared to mean HRQoL scores at baseline. In a second analysis, HRQoL observations during treatment (excluding baseline) were compared to HRQoL at end of treatment, analyzing observations for patients experiencing PD/DC, PD and DC via a mixed effects model that adjusted for time of observation as a fixed effect and patient as a random effect. Results: With a May 2010 follow-up, mean HRQoL at PD/DC had significantly improved from baseline for 3 of 6 domains with MPR-R - Global QoL (55.9 vs. 46.8; p=.021), Pain (30.4 vs. 42.6; p=.044) and Disease Symptoms (21.6 vs. 28.6; p=.031)(a) with non-significant changes in the other 3 domains. When assessing MPR-R patients experiencing PD, Global QoL (48.0 vs. 37.3; p=.029) and Pain (38.9 vs. 54.6; p=.046) also significantly improved from baseline, with no significant changes in the other 4 scales. MPR-R patients with DC experienced one significant improvement for Disease Symptoms (16.0 vs. 26.9; p=.007), with non-significant changes in the other domains. No significant HRQoL changes at end of treatment vs. baseline were observed for MP in any comparisons of the six domains considered. HRQoL during treatment was better in 33 of 36 comparisons when compared to HRQoL at end of treatment (assessment for six HRQoL domains; MPR-R and MP; PD/DC, PD and DC, i.e. 6×2×3), with significantly better HRQoL during treatment in 14 out of 36 observations. PD/DC significantly reduced HRQoL in terms of Physical Functioning (56.9 vs. 67.5, p =.003) and Fatigue (46.4 vs. 37.8, p=.026) for MPR-R and Global QoL (48.7 vs. 59.4, p <.001), Physical Functioning (61.6 vs. 70.3, p =.001) and Fatigue (46.7 vs. 39.3, p =.021) for MP. All significant differences involved PD, with no significant differences observed for DC. 9 of 12 (=6×2) HRQoL comparisons (see Figure 1) showed significantly higher HRQoL during treatment vs. PD; 2 of 3 non-significant HRQoL differences related to Side Effects of Treatment. HRQoL was clinically meaningfully higher during treatment than at progression in all 5 statistically significant MPR-R comparisons, but only in two MP comparisons (Global QoL and Physical Functioning), as determined by Minimal Important Differences (MIDs) [Dimopoulos, 2011]. The results indicate that delaying progression through continued MPR-R treatment is of key importance in strengthening NDMM patients' HRQoL. Conclusions: Continuous lenalidomide significantly prolongs progression-free survival in NDMM patients. The underlying analysis documented higher HRQoL especially during MPR-R treatment compared to HRQoL at disease progression. Patients continuing on lenalidomide treatment experienced an elevated level of HRQoL, often reporting higher HRQoL levels at the end of MPR-R treatment vs. baseline. These findings further highlight the favourable balance between efficacy, tolerability and HRQoL with MPR-R. Disclosures: Dimopoulos: Celgene: Consultancy, Honoraria. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria. Petrucci:Celgene: Honoraria. Lewis:Celgene: Employment, Equity Ownership. Millar:Celgene: Consultancy. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Ortho-Biotech: Honoraria.

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Bortezomib-Based Therapy without Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma Patients with t(4;14): A Canadian National Trial,

Blood ◽

10.1182/blood.v118.21.3982.3982 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3982-3982

Author(s):

Donna E. Reece ◽

Giovanni Piza Rodriguez ◽

David Szwajcer ◽

Leonard A Minuk ◽

Mariela Pantoja ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stem Cell ◽

Maintenance Therapy ◽

Disease Progression ◽

Induction Therapy ◽

Research Funding ◽

Pegylated Liposomal Doxorubicin ◽

Progression Free Survival ◽

Newly Diagnosed

Abstract Abstract 3982 Newly diagnosed multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who undergo a single ASCT after older induction regimens have a median progression-free survival (PFS) of only 8–9 months (mos) and median overall survival (OS) of 18 mos (Chang H, et al. Bone Marrow Transplan t 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Given the efficacy of bortezomib in t(4;14) disease, we designed a phase II study based on this agent in which ASCT was not performed as part of first-line therapy. Pts received induction therapy with four 21-day cycles of pegylated liposomal doxorubicin 30 mg/m2on day 4, bortezomib 1.3 mg/m2on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1–4, 8–11, 15–18 of cycle 1 and on days 1–4 and 11–14 of cycles 2–4 (DBD), followed by post-induction therapy with eight 28-day cycles of oral cyclophosphamide 300 mg/m2on days 1, 8, 15, 22, bortezomib 1.5 mg/m2 on days 1,8,15 and prednisone 100 mg q 2 days (CyBor-P). Maintenance therapy with dexamethasone 40 mg/weekly was then administered until disease progression. Although elective stem cell collection was recommended after induction therapy, routine ASCT was not performed in the absence of disease progression. Between February 2008-May 2011, 383 newly diagnosed MM pts were screened for t(4;14) in 8 Canadian centers, and 43 (11.2%) were found to be positive by FISH. Five did not meet the CRAB criteria for symptomatic MM, 7 were ineligible, 3 declined participation and 28 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4, but not t(4;14), and underwent ASCT after induction therapy; this pt is included in the safety analysis only. The median age was 60 years (range 42–69) and 63% were male. The median percent of nuclei positive for t(4;14) by FISH in the initial bone marrow (unpurified) was 26% (range 2–62), serum β2-microglobulin 239 nmol/L (range 43–1695) and albumin 36 g/L (range 28–48); ten pts had ISS stage 1,10 had stage 2 and 7 had stage 3 MM. Immunoglobulin subtype included IgGκ in 7, IgAκ in 6, IgAλ in 6, IgGλ in 5 and IgMλ in 1. Using modified uniform criteria, the best response in 23 evaluable pts includes: sCR in 6 (26%), CR in 4 (17%), VGPR in 9 (39%), PR in 2 (9%) and SD in 2 (9%). Median F/U is 13.5 mos (range 1.2–35); 6 have progressed at median of 3 mos on study (range 1–11). Four pts have died (due to progression in 3 and complex medical problems/consent withdrawal in 1 in VGPR). SAEs were reported in 7 pts; only 6 pts (21%) developed grade 2 peripheral neuropathy, which necessitated dose reductions of bortezomib in 4. The actuarial 2-yr PFS is 47.7% (95%CI 25.9–87.9%), median PFS is 23. 2 months and 2-yr OS is 76.8% (95%CI 58.3–100%); the median OS has not yet been reached. We conclude: 1) the incidence of t(4;14) by FISH in newly-diagnosed MM pts is 11.2%; which appears to be lower than the 15% anticipated 2) 11.6% of these are asymptomatic; 3) this bortezomib-based regimen is well-tolerated; 4) the overall response rate (sCR + CR + VGPR + PR) is 91% with 82% achieving ≥ VGPR and 43% ≥ CR; 5) the PFS and OS with this approach compare favorably with those seen with older studies of single or double ASCT, and even with some recently reported trials using more modern induction regimens before ASCT, in pts with t(4;14); and 6) the use of more effective maintenance therapy, including agents targeting the aberrations associated with t(4;14), would be of interest in future trials. Disclosures: Reece: Millennium: Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol, Meyers, Squibb: Honoraria, Research Funding; Amgen: Honoraria. Off Label Use: Bortezomib regimens other than VMP (boretzomib, melphalan and prednisone)for initial therapy of myeloma. Piza Rodriguez:Celgene: Unrestricted educational grant; Otsuka: Honoraria. Belch:Ortho/Janssen: Honoraria; Celgene: Honoraria. White:Celgene: Consultancy, Honoraria, Research Funding; Ortho/Janssen: Honoraria, Research Funding. Chen:Celgene: Research Funding. Kukreti:Celgene: Honoraria.

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Risk of Progression and Survival in Newly Diagnosed Multiple Myeloma Patients Non-Responsive to Bortezomib-Based Induction Therapy: an Observational Multicenter International Study

Blood ◽

10.1182/blood.v124.21.3488.3488 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3488-3488

Author(s):

Yael C Cohen ◽

Erel Joffe ◽

Noam Benyamini ◽

Meletios A. Dimopoulos ◽

Svetlana Trestman ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Disease Progression ◽

Line Treatment ◽

Second Line ◽

Newly Diagnosed ◽

Inclusion Criteria ◽

First Line ◽

Line Therapy ◽

Induction Regimen

Abstract INTRODUCTION Botezomib-based induction is widely used and highly effective for the treatment of patients with newly diagnosed multiple myeloma (NDMM), with an overall response rate (ORR) of 75-80%. However, the outcomes of patients who fail to respond to this treatment remain unclear. The goal of this study was to investigate the outcome of patients with NDMM who failed to respond to bortezomib-based induction as compared to induction-responsive patients. METHODS We reviewed consecutive patients with NDMM between 1-JAN-2007 and 31-JAN-2014 in three participating centers in Greece and Israel. Inclusion criteria were measurable disease and an induction regimen containing bortezomib in combination with alkylators and/or corticosteroids. Patients who failed to achieve at least partial response in accordance with IMWG criteria after 4 cycles of therapy were classified as non-responsive and their baseline characteristics, next treatment, overall survival and progression following second-line treatment (2ndPFS) were assessed and compared to responsive patients. 2ndPFS was defined as the time from 2nd line treatment to disease progression, death or censoring. In the non-responsive group we limited this analysis to patients advancing to 2nd line within six months of initiation of induction. RESULTS Two hundred and ninety five patients met inclusion criteria and 74 (25%) were non-responsive to bortezomib-containing induction. Non-responsive patients were older, more anemic and had more often ISS-3, del17p and ECOG performance status 2-4 (table 1). Notably, these patients received less often a bi-weekly bortezomib schedule, a triple-drug regimen and high dose melphalan treatment at first line. Of the non-responsive patients 57% (n=42) received salvage treatment immediately following induction non-response, with an ORR of 59% (25/42); 12/31(39%) of those treated with salvage 2nd line and 13/15(87%) of those who underwent HDM at first line, responded. Failure to respond to bortezomib induction was associated with increased mortality (HR 5.06, 95% CI 2.80 – 9.16) (Fig. a), which remained significant in multivariate analysis. One- and 3-years OS in responsive vs. non-responsive patients were 97% vs 76% and 88% vs 53%, respectively (p<0.0001). 2ndPFS in patients who received salvage second line therapy immediately following induction failure was similar to that measured in bortezomib-responsive patients receiving 2nd-line therapy for disease progression, approaching 14 months. However, survival from time of salvage 2nd-line treatment was significantly lower among patients non-responsive to bortezomib-based induction compared to that measured in responsive patients (25 months vs. not reached, respectively, p=0.024; Fig. b). CONCLUSIONS Failure to respond to a bortezomib-based induction was found to be an independent risk factor for mortality. Despite the non-inferior 2ndPFS reported in these patients as compared with their bortezomib-responsive counterparts, survival remained significantly inferior. Possibly this difference is because non-responsive patients are less likely to respond to further proteasome inhibitor therapy at following relapses. Randomized controlled trials are needed to test whether intensification of induction and/or of further treatment may improve the poor prognosis of patients who fail to respond to bortezomib-based induction. Table 1: All patients n = 295 Induction non-responsive n = 74 Induction - responsive n =221 P value Demographic Median Age (yrs) 62.0 66.8 61.0 0.004 Gender Male Female 148 (50%) 147 (50%) 42 (55%) 33 (45%) 107 (48%) 114 (52%) 0.347 Patient / Disease ECOG 0-1 2-4 182 (63%) 107 (37%) 33 (45%) 40 (55%) 149 (69%) 67 (31%) <0.0001 ISS I II III 74 (28%) 95 (36%) 95 (36%) 9 (14%) 20 (33%) 33 (53%) 65 (32%) 75 (37%) 62 (31%) 0.002 High risk Cytogenietics Del17p High risk (%) Elevated LDH (%) Extramedullary disease (%) Hb≤ 10 gr% Creatinine > 2mg% 23 (14%) 69 (34%) 66 (27%) 23 (9.5%) 114 (43%) 64 (23%) 10 (26%) 13 (28%) 21 (36%) 5 (8.1%) 35 (54%) 20 (30%) 13 (10%) 56 (36%) 45 (24%) 18 (9.7%) 79 (39) 44 (21%) 0.031 0.297 0.091 0.805 0.044 0.094 Therapy Induction regimen VCD Vd VMP PAD 204 (69%) 49 (17%) 11 (4%) 19 (6%) 52 (57%) 18 (24%) 3 (4%) 4 (5%) 162 (73%) 31 (14%) 8 (4%) 15 (7%) 0.007 Any triplet 243 (82%) 55 (74%) 188 (85%) 0.051 Bortezomib schedule Bi-weekly Weekly 239 (81%) 56 (19%) 52 (70%) 22 (30%) 187 (85%) 34 (15%) 0.010 HDM at first line 143 (48%) 15 (20%) 128 (58%) <0.0001 Figure 1 Figure 1. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria.

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The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis

Blood ◽

10.1182/blood.v66.2.380.380 ◽

1985 ◽

Vol 66 (2) ◽

pp. 380-390 ◽

Cited By ~ 283

Author(s):

GW Dewald ◽

RA Kyle ◽

GA Hicks ◽

PR Greipp

Keyword(s):

Multiple Myeloma ◽

Median Survival ◽

Plasma Cell ◽

Chromosomal Abnormalities ◽

Chromosome Analysis ◽

Plasma Cell Leukemia ◽

Newly Diagnosed ◽

Cell Leukemia ◽

Chromosome 11 ◽

Cytogenetic Studies

Abstract Chromosome studies were done on 82 patients with multiple myeloma, 11 with amyloidosis, 2 with multiple myeloma and amyloidosis, and 5 with plasma cell leukemia to investigate their chromosomal abnormalities and to determine the usefulness of cytogenetic studies. A chromosomally abnormal clone was found in 29 patients but was observed most often in those with active disease: in 18% of patients with newly diagnosed multiple myeloma, in 63% with aggressive disease, and in 40% with plasma cell leukemia. Survival among the newly diagnosed patients was significantly shorter (P = .0089) for those in whom an abnormal clone was identified (median survival, six months) than for those in whom only normal metaphases were observed (median survival, greater than 12 months). Among all of the patients, survival from the time of chromosome analysis was shorter for those in whom a chromosomally abnormal clone was found: the median survival was three months for patients with all abnormal metaphases and eight months for patients with normal and abnormal metaphases and has not yet been reached for patients with only normal metaphases. The most common anomalous chromosomes in patients with a plasma cell proliferative disorder were 1, 11, and 14: 11 patients had an abnormality involving chromosome 14q32 and nine patients had an anomalous chromosome 11. The single most common abnormality, a t(11;14)(q13;q32), occurred in three patients. Among the patients who developed preleukemia or acute nonlymphocytic leukemia, the most common anomaly involved chromosome 7. The results suggest that cytogenetic studies are useful for identifying patients who have a poor prognosis and can help distinguish patients with a cytopenia because of preleukemia from those with an aggressive plasma cell proliferative process.

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Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

10.1101/2020.04.01.012351 ◽

2020 ◽

Author(s):

Matthew A. Wall ◽

Serdar Turkarslan ◽

Wei-Ju Wu ◽

Samuel A. Danziger ◽

David J. Reiss ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Biological Networks ◽

Somatic Mutations ◽

Chromosomal Abnormalities ◽

Transcriptional Regulatory Network ◽

Transcriptional Regulators ◽

Activity Profile ◽

Downstream Effects ◽

Transcriptional Regulatory

AbstractDespite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to their previous therapies. Although many therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM biology across patients impacts the likelihood of success for existing therapies and those in the pipeline. 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. We hypothesized that knowledge of the biological networks that give rise to MM, specifically the transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene regulation, would enable improved predictions of disease progression and actionable insights for treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the generation of a MM TRN that links chromosomal abnormalities and somatic mutations to downstream effects on gene expression via perturbation of transcriptional regulators. We find that 141 genetic programs underlie the disease and that the activity profile of these programs fall into one of 25 distinct transcriptional states. These transcriptional signatures prove to be more predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-specific vulnerabilities to interventions with existing drugs and motivate the development of new targeted therapies that appear especially promising for relapsed refractory MM.

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Prognostic value of 1q21 amplification in multiple myeloma

Terapevticheskii arkhiv ◽

10.17116/terarkh201789732-38 ◽

2017 ◽

Vol 89 (7) ◽

pp. 32-38 ◽

Cited By ~ 4

Author(s):

T V Abramova ◽

T N Obukhova ◽

L P Mendeleeva ◽

O S Pokrovskaya ◽

E O Gribanova ◽

...

Keyword(s):

Multiple Myeloma ◽

Survival Rate ◽

Disease Progression ◽

Chromosomal Abnormalities ◽

Disease Onset ◽

Clinical Manifestations ◽

Diagnostic Study ◽

Extra Copy ◽

Course Of Disease

Aim. To determine the prevalence of amp1q21 and its relationship to the clinical manifestations of multiple myeloma (MM). Subjects and methods. In December 2009 to March 2016, a total 134 patients aged 30 to 81 years (median 57 years) underwent a pretreatment FISH-study of bone marrow (BM) with centromeric and locus-specific DNA probes to identify amp1q21, t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), trisomies of chromosomes 5, 9, 15, del13q14, del17p13/TP53, and t(8q24)/cMYC. Induction therapy with bortezomib-containing cycles was performed. Autologous stem cell transplantation was carried out in 48 patients. The median follow-up of patients was 19.3 months (3.2—77.4 months). Disease progression was diagnosed in 69 (51.5%) patients; 12 patients also underwent FISH study during disease progression. Results. At the onset of MM, amp1q21 was detected in 53 (39.6%) patients. The overall 5-year survival rate in patients with amp1q21 was almost 2 times lower than that in those without amp1q21 (43.5 and 79.4%, respectively; p=0.07). The overall 5-year survival rate in patients with one extra copy of 1q21 (only 3 copies) was 67.3%, that in those with 2 or more extra copies of 1q21 (only 4—7 copies) was 20.9% (p=0.0016). Nine (75%) of the 12 patients examined during disease progression were found to have amp1q21: 2 cases were detected in the period of progression to have amp1q21 in its absence at disease onset; 7 cases had amp1q21 both at MM onset and progression; however, the number of copies of 1q21 was unchanged. Conclusion. Аmp1q21 is one of the most common chromosomal abnormalities in patients with new-onset MM and may appear in the course of disease progression. The presence of аmp1q21 is an important prognostic factor and must have to be included in the diagnostic study both at disease onset and progression.

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The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis

Blood ◽

10.1182/blood.v66.2.380.bloodjournal662380 ◽

1985 ◽

Vol 66 (2) ◽

pp. 380-390 ◽

Cited By ~ 5

Author(s):

GW Dewald ◽

RA Kyle ◽

GA Hicks ◽

PR Greipp

Keyword(s):

Multiple Myeloma ◽

Median Survival ◽

Plasma Cell ◽

Chromosomal Abnormalities ◽

Chromosome Analysis ◽

Plasma Cell Leukemia ◽

Newly Diagnosed ◽

Cell Leukemia ◽

Chromosome 11 ◽

Cytogenetic Studies

Chromosome studies were done on 82 patients with multiple myeloma, 11 with amyloidosis, 2 with multiple myeloma and amyloidosis, and 5 with plasma cell leukemia to investigate their chromosomal abnormalities and to determine the usefulness of cytogenetic studies. A chromosomally abnormal clone was found in 29 patients but was observed most often in those with active disease: in 18% of patients with newly diagnosed multiple myeloma, in 63% with aggressive disease, and in 40% with plasma cell leukemia. Survival among the newly diagnosed patients was significantly shorter (P = .0089) for those in whom an abnormal clone was identified (median survival, six months) than for those in whom only normal metaphases were observed (median survival, greater than 12 months). Among all of the patients, survival from the time of chromosome analysis was shorter for those in whom a chromosomally abnormal clone was found: the median survival was three months for patients with all abnormal metaphases and eight months for patients with normal and abnormal metaphases and has not yet been reached for patients with only normal metaphases. The most common anomalous chromosomes in patients with a plasma cell proliferative disorder were 1, 11, and 14: 11 patients had an abnormality involving chromosome 14q32 and nine patients had an anomalous chromosome 11. The single most common abnormality, a t(11;14)(q13;q32), occurred in three patients. Among the patients who developed preleukemia or acute nonlymphocytic leukemia, the most common anomaly involved chromosome 7. The results suggest that cytogenetic studies are useful for identifying patients who have a poor prognosis and can help distinguish patients with a cytopenia because of preleukemia from those with an aggressive plasma cell proliferative process.

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Addition of daratumumab to multiple myeloma backbone regimens significantly improves clinical outcomes: a systematic review and meta-analysis of randomised controlled trials

Scientific Reports ◽

10.1038/s41598-021-01440-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Szabolcs Kiss ◽

Noémi Gede ◽

Péter Hegyi ◽

Bettina Nagy ◽

Rita Deák ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Randomised Controlled Trials ◽

Residual Disease ◽

Meta Analysis ◽

Complete Response ◽

Controlled Trials ◽

Newly Diagnosed ◽

Hazard Ratios ◽

Randomised Controlled

AbstractDaratumumab has shown clinical benefit in multiple myeloma. We aimed to evaluate the safety and efficacy of adding daratumumab to backbone anti-myeloma treatments. Systematic search was performed up to August 2021 to identify randomised controlled trials comparing the outcomes of backbone therapy with and without daratumumab in relapsed/refractory and newly diagnosed myeloma (RRMM and NDMM, respectively). Odds ratios (ORs) and hazard ratios (HRs) were calculated with 95% confidence intervals (CIs). Primary outcomes were death or disease progression, minimal residual disease (MRD) negativity, and stringent complete response (sCR). Secondary outcomes were complete response or better and safety endpoints prespecified in the study protocol: PROSPERO (CRD42020222904). In NDMM, MRD negativity [OR = 3.61 (CI 2.33–5.61)] and sCR [OR = 2.29 (CI 1.49–3.51)] were more likely and death or disease progression [HR = 0.47 (CI 0.39–0.57)] was less likely to occur with daratumumab compared to control. Regarding RRMM, MRD negativity [OR = 5.43 (CI 2.76–10.66)] and sCR [OR = 3.08 (CI 2.00–4.76)] were more likely and death or disease progression was less likely [HR = 0.50 (CI 0.37–0.67)] with daratumumab compared to control. The addition of daratumumab has shown high clinical efficacy and acceptable toxicity profile for the treatment of NDMM and RRMM regarding the endpoints examined.

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Dissecting the Epigenetic Landscape of Smoldering, Newly Diagnosed and Relapsed Multiple Myeloma Revealed IRAK3 As a Marker of Disease Progression

Blood ◽

10.1182/blood-2018-99-115046 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3896-3896

Author(s):

Mahshid Rahmat ◽

Nicholas Haradhvala ◽

Romanos Sklavenitis-Pistofidis ◽

Jihye Park ◽

Daisy Huynh ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Multiple Myeloma ◽

Disease Progression ◽

Plasma Cells ◽

Whole Genome ◽

Newly Diagnosed ◽

Promoter Regions ◽

Healthy Donors ◽

Precursor States

Abstract Introduction. Multiple myeloma (MM) is a complex and heterogeneous malignancy of plasma cells that has two precursor states: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). MGUS and SMM are asymptomatic states that eventually give rise to overt MM, with some patients progressing, while others do not. Recent studies in MM pathobiology have highlighted epigenetic alterations that contribute to the onset, progression and heterogeneity of MM. Global hypomethylation of DNA, including tumor suppressor genes, and hypermethylation of B-cell specific enhancers, abnormal histone methylation patterns due to the overexpression of histone methyltransferases such as MMSET, and deregulation of non-coding RNAs along with mutations in different classes of chromatin modulators underline a potential for epigenetic biomarkers in disease prognosis and treatment. This study aimed to define epigenetic pathways that lead to the dynamic regulation of gene expression in MM pathogenesis. Methods. We performed ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) and RNA-seq on 10 MM cell lines and CD138+ plasma cells isolated from bone marrow aspirates of 3 healthy donors, 9 SMM, 8 newly diagnosed MM (NDMM) and 9 relapsed (RRMM) patients. ATAC-seq reads were trimmed of adapters, aligned to hg19 using bowtie2, and filtered for mapping quality >=Q30 using the ENCODE ATAC-seq pipeline. Reads mapping to promoter regions, defined as -400 to +250 bases from a refseq transcription start site, were counted using bedtools for each sample. Promoter read counts were then normalized by the total number of reads in promoters in the sample, scaled to 1 million total reads, and converted to log10(x+1) space. Results. To characterize the epigenetic contribution to disease progression in MM, we first identified accessible promoter regions in normal plasma cells (NPC), SMM, NDMM and RRMM patients and found regions displaying differential accessibility in MM progression. Next, we intersected the list of differential accessible regions (DARs) with matched transcriptome data and observed two main clusters: genes with unaltered transcription profiles and genes in which the dynamics of open chromatin regions (OCRs) correlated with gene expression. Transcriptomic analysis revealed that a large portion of the differentially expressed (DE) genes in SMM remain DE in NDMM as compared to NPCs (882 genes out of 1642 and 1150 DE genes in SMM and NDMM, respectively). Those genes were significantly enriched for pathways like epithelial mesenchymal transition, cell cycle checkpoints and mitosis, KRAS signaling and interleukin-JAK-STAT pathways. To investigate the genes that behaved differently among the stages of disease, we looked at differential accessibility and expression in NDMM and SMM samples, and integrated them with Whole-Genome Bisulfite-Sequencing and 450K DNA-methylation data from MM patients and healthy donors (BLUEPRINT). This analysis led to the identification of novel genes in MM progression, such as the transcriptional repressor ZNF254 and IRAK3, a negative regulator of the TLR/IL1R signaling pathway. Although gene expression data for these genes showed comparable mRNA levels in SMM and NPCs, followed by a significant decrease in NDMM/ RRMM, ATAC-seq revealed a striking drop in promoter accessibility in SMM, NDMM and RRMM cases. Comparison of ATAC-seq peaks to DNA methylation and ChIP-seq data revealed that the altered OCR of IRAK3 is actually hypermethylated in MM patients and marked by H3K4me3, a marker of active promoters, in MM cell lines. Hypermethylation of IRAK3 has been described in hepatocellular carcinoma, where it is associated with poor prognosis. Together, our data suggest that the identified IRAK3 OCR may act as a bivalent domain that loses accessibility in the precursor states and gains DNA methylation in MM progression. Hence, IRAK3 methylation could be a novel prognostic marker in MM. Conclusion. We have generated a global epigenetic map of primary tumors from patients at the smoldering, newly diagnosed and relapsed/refractory stage of multiple myeloma. Integrative analysis of ATAC-seq data with DNA methylome, transcriptome and whole-genome map of active and repressive histone marks in our study led to the identification of IRAK3 as a novel epigenetic biomarker of disease progression. Disclosures Licht: Celgene: Research Funding. Ghobrial:Takeda: Consultancy; BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy.

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