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  • American Society of Hematology  (8)
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  • American Society of Hematology  (8)
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  • 1
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 1-3
    Kurzfassung: Purpose: Most data on the prognostic impact of cytogenetic abnormalities come from the setting of newly diagnosed multiple myeloma, it remains unclear whether the dynamic changes of cytogenetic aberrations affect the prognostic evaluation in multiple myeloma. Methods: We analyzed the prognostic impact of dynamic changes of cytogenetic abnormalities with a cohort consisting of 80 paired patients with consecutive cytogenetic data both at diagnosis and recurrence among 568 patients with newly diagnosed multiple myeloma. Results : Three patterns of recurrence were established from 80 paired patients: Pattern A (40%) consisted of 32 patients without new cytogenetic abnormalities at the time of progression. Pattern B (15%) consisted of 12 patients harboring new standard risk (SR) cytogenetic aberrations. Pattern C (45%) consisted of 36 patients with new high-risk (HR) cytogenetic abnormalities. The median overall survival (mOS; P & lt;0.001) and median progression-free survival (mPFS; P =0.013) differed significantly among three patterns. Four groups including 60 paired patients were further established according to genetic risk stratification changes. There were 15 patients who kept SR in group 1 (25%); 12 SR patients who evolved into HR group in group 2 (20%); 17 HR patients without new HR cytogenetic abnormalities in group 3 (28%); and 16 HR patients harboring new HR cytogenetic aberrations in group 4 (27%). The mOS (P=0.001) also differed significantly among these four groups. Conclusions: Dynamic cytogenetic changes significantly affected prognostic evaluation in multiple myeloma. Patients harboring new HR cytogenetic abnormalities and escalated genetic risk stratification at relapse had worse outcomes. Figure 1 Disclosures Anderson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2020
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4343-4343
    Kurzfassung: In the era of bortezomib, traditional prognostic markers in multiple myeloma (MM) may be suspect. The outcome of patients with t(4;14) is largely improved by bortezomib based treatment. Whether the outcome of patients with t(4;14) is still homogeneously inferior remains unknown. In this long follow-up non-randomized clinical trial, we observed no significant difference in the PFS and OS of t(4;14) positive or negative patients in the bortezomib arm. Interestingly, t(4;14) was highly correlated with the presence of 1q21 gain. In t(4;14)-positive patients, the median OS of patients with and without 1q21 gain was 38.8 and 57.2 months (P=0.034), respectively. In t(4;14)-negative patients, the median OS of the two subgroups was 43.0 and 89.4 months (P 〈 0.001), respectively. In contrast, no statistical difference in PFS or OS was observed in 1q21 gain patients with versus without t(4;14) aberration. We then discovered that 1q21 gain facilitated the acquisition of new chromosome abnormalities and contributed to the genomic instability, evidenced by the strong correlation between 1q21 gain and complex karyotypes or the acquisition of more than two cytogenetic aberrations. Moreover, 1q21 gain and/or del(17p) were powerful enough to discriminate the high-risk patients. The combination of 1q21 gain with International Staging System (ISS) was useful to divide MM patients with respect to their survival. Finally, although bortezomib might benefit patients with 1q21 gain, it could not completely overcome its adverse effects, suggesting the necessity of more effective therapies for these patients. Figure Disclosures Zhan: BIPHARM LLC: Consultancy, Other: % Allocation of Profit. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; OncoPep: Other: Scientific founder ; Sanofi-Aventis: Other: Advisory Board; C4 Therapeutics: Other: Scientific founder .
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2019
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4405-4405
    Kurzfassung: Background: Recent attempts have focused on identifying fewer magnitude of minimal residual disease (MRD) rather than exploring the biological and genetic features of the residual plasma cells (PCs). Interphase fluorescence in situ hybridization (iFISH) analyses in sequential samples provide a simple and reliable method to longitudinal track the dynamic changes in clonal architecture and speculate the possible evolutionary pattern. Here, we report for the first time the incidence and prognostic significance of cytogenetic abnormalities (CA) existed in the PCs of patients achieving at least partial remission. Methods: A cohort of 193 patients with at least one CA at diagnosis were analyzed using data from the prospective, non-randomized clinical trial (BDH 2008/02), and iFISH analyses were performed in patient-paired diagnostic and post-therapy samples. Results: Persistent CA in residual tumor cells were observed for the majority of patients (63%), even detectable in 28/63 (44%) patients with MRD negativity ( 〈 10-4). The absence of CA in residual PCs was associated with prolonged survival regardless of MRD status. It was noted that MRD-positive but FISH-negative patients experienced similar survival to MRD-negative patients (m-TTP 4.5 vs. 5.1 years, P=0.983). According to the change of the clonal size of specific CA, patients were clustered into five groups, reflecting five patterns of clone selection under therapy pressure. 1) Pattern A were observed in 36 (19%) patients where a minor subpopulation or undetectable subclone in the pre-treatment sample became dominant after therapy. 2) Pattern B was identified in 29 (15%) patients whose fractions of PCs harboring different CA were decreased with inconsistent extent. 3) Identical CA fraction in residual PCs were found in 22 (11%) patients as Pattern C. 4) Pattern D. The fractions of PCs harboring specific CA in 35 patients (18%) were uniformly declined. 5) 71 patients lost their abnormal cytogenetic clone after therapy (less than cut-off level) were classified as Pattern E. The cytogenetic dynamics of pattern A and B can be interpreted as a therapy-induced selection process with comparable inferior survival (m-TTP 1.2 vs. 1.6 years, respectively). Patients with pattern E experienced the most favorable outcome (m-TTP 5.0 years), following those with pattern D and C (m-TTP 3.5 and 2.5 years). Among the 65 patients with clonal selection, 24 underwent upfront auto-transplantation that experienced significantly improved survival. However, upfront transplant failed to completely reverse the inferior outcome caused by therapy-induced clonal selection. Longitudinal cytogenetic studies at relapse were available in 43 patients. The results suggested that sequential cytogenetic dynamics were observed in most patients, and the cytogenetic architecture of residual cells could to some extent predict the evolutional pattern at relapse. Conclusions: The repeat cytogenetic evaluation in residual cells could not only serves as a good complementary tool for MRD detection, but also provides a better understanding of clinical response and clonal evolution. Therapy-induced clonal selection was associated with inferior outcome regardless of the baseline cytogenetic profiles. The early identification of resistant clone may contribute to guide better tailored therapy strategies based on the feature of the residual tumor cells. Figure Disclosures Munshi: Celgene: Consultancy; Adaptive: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2019
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 47-48
    Kurzfassung: Background: Current definition of multi-hit multiple myeloma (MM) is based upon the number of high-risk cytogenetic abnormalities (CA). But we may overlook the influence of standard-risk CA and different concurrent patterns. In fact, standard-risk t(11;14) and del(13q) may bring extra danger when concurrent with other CA. And the concurrency of two secondary CA may do more harm to patients than that of one secondary CA with one primary CA. This study is to answer whether CA number or pattern exert an impact on outcomes of MM patients. Methods: This study was carried out based on the prospective, non-randomized clinical trial BDH 2008/02. 537 MM patients with complete cytogenetic data were enrolled, of whom 64% (341/537) patients were treated with bortezomib-based three-drug induction therapy, and the remaining patients with thalidomide-based therapy. Autologous stem cell transplantation (ASCT) was recommended post induction therapy in transplant-eligible patients, and all patients received maintenance therapy for two years. CA were divided into primary CA [pCA: any type of IgH breakage], and secondary CA [sCA: del(17p), del(13q), gain(1q) (≥3 copies)] Results: In the era of novel agents, patients with pCA only did not have outcomes different from those patients without any FISH abnormality. Patients with s1 CA or s1+p CA had hazard ratio for PFS or OS of 1.5-2.0. Patients with s2 CA or s2+p CA had hazard ratio for PFS or OS of 2.0-3.0. Patients with concurrent del(13q), del(17p) and gain(1q) (s3 CA) had hazard ratio for PFS of 3.11 and for OS of 3.00. Patients with s3+p CA had hazard ratio for PFS of 4.65 and for OS of 6.16. Based on these results, we divided patients into four subgroups: no CA or only pCA, s1 CA in the presence or absence of pCA, s2 CA in the presence or absence of pCA, and s3 CA in the presence or absence of pCA. Both the PFS and OS decreased in a stepwise fashion with the accumulation of CA (Figure 1). Therefore, we defined double-hit MM as any one sCA in the presence or absence of pCA. Triple-hit MM referred to two sCA plus pCA or not, and quadra-hit MM referred to three sCA plus pCA or not. Furthermore, we confirmed the prognostic independence of CA pattern in the multivariant analysis with International Staging System (ISS) and LDH (Table 1). Conclusion: In this study, we found that the primary CA as a whole lost its adverse effect when treated by bortezomib-based regimens. CA subtype conferred a prognostic value. In details, secondary CA imposed an accumulative risk to patients. For the first time, we indicated that double-hit or triple-hit MM should be defined upon the number of secondary CA. This definition coincides with the "Two-Hit" theory of cancer causation and fits well with MM evolution model. The prognostic significance of CA pattern needs validation in further prospective trials. Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2020
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5491-5491
    Kurzfassung: Background Chemotherapy resistance remains a significant hurdle in the treatment of multiple myeloma (MM). However, it is difficult to discriminate the potential refractory patients from the very early stage. Flow cytometry is a convenient tool to detect the residual myeloma cell tiding, indicating therapeutic response sensitively. Methods From June, 2014 to December, 2016, 172 sequential patients with newly diagnosed multiple myeloma were enrolled in the BDH2008/02 clinical trial. Patient informed consent was obtained in accordance with the Declaration of Helsinki. 144 patients with at least two flow cytometry detections were analyzed. Bone marrow samples were detected by an eight-color EuroFlow panel. CD20 negative and CD81 positive is defined as normal phenotype. Results We conducted a median of 3-time (2-8) flow cytometry detection on each patient. When newly diagnosed and achieved best response, CD20, CD81 expression rates were 29.9%, 9.7% and 14.9%, 64.4% (P=0.0091, P 〈 0.0001), respectively. According to the status variation of CD20 and CD81, all patients were divided into three groups: both markers were always normal (Group A), either CD20 or CD81 was abnormal at diagnosed and turned normal during therapy (Group B) and markers stayed abnormal (Group C). Patients with undetectable residual tumor cells were also classified as Group A. The overall response rate of the patients in Group C was inferior to Group B ( 〉 PR rate: 54.3% vs. 71.4%, P=0.021). And the OS of Group C was significantly worse than Group A and B (47.9 months vs. not reached vs. not reached, P=0.036). Conclusion CD20/CD81 switching to normal phenotype during therapy indicates therapeutic response and an improved outcome than that staying abnormal. The expression tiding of CD20 and CD81 may be a reasonable combination to dynamically stratify MM patients, directing the choice of maintenance therapy. Figure Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2019
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 10011-10012
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2022
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 26-27
    Kurzfassung: Background: Age is a pivotal prognostic factor for multiple myeloma (MM). The risk of evolving from MGUS and SMM to symptomatic MM steadily increases with age. And there are nuances in clinical manifestations and cytogenetic characteristics between young and old patients. The aim of this study is to delineate the clinical and laboratory features and determine the relative contribution of ISS, performance status and cytogenetic abnormalities in each age MM patients. Methods: In this study, 778 MM patients were enrolled in the prospective, non-randomized BDH2008/02 clinical trial between January, 2008 and December, 2016. Briefly, the patients accepted bortezomib or thalidomide-based induction therapy. Transplantation eligible patients accepted ASCT, otherwise they accepted the original regimen consolidation therapy. Subsequently, unless intolerance, patients received either thalidomide-based or lenalidomide-based maintenance therapy for two years. Conventional FISH panel included del(13q), del(17p), gain(1q), t(11;14), t(4;14), t(14;16), and t(14;20). The positive cut-off value for chromosome deletion or gain was 20%, and for chromosome translocation was 10%. A multivariate Cox proportional-hazards model was developed to assess the variables with significant effects on PFS and OS. Explained variation of variables was quantified by RD2. Statistical analysis was conducted by Stata/MP 16.0 (Stata Corp., TX, USA) and SPSS 26.0 (IBM Corp., Chicago, Illinois, USA). Results: Among 778 patients with complete data, 59.5% (463/778) were younger than 60 years old, 31.4% (244/778) were 61-70 years old, and only 9.1% (71/778) were over 71 years old. The median PFS of patients≤60, 61-70 and ≥71 years of age was 36.3, 32.6 and 23.1 months, respectively (P & lt;0.001). The median OS in each age group was 86.2, 60.7 and 34.9 months, respectively (P & lt;0.001) (Figure A-D). The median evaluated glomerular filtration rate of the three groups was 89.1, 74.0 and 66.4 ml/min (P & lt;0.001), respectively. The serum β2-microglobulin level gradually increased with age (P & lt;0.001), along with the proportion of patients with ISS 3 stage. Patients ≥71 years old had a higher proportion of ECOG performance status score 3-4, twice than that of patients ≤60 years old. The incidence of high-risk IgH translocation decreased with age, and was 25.4%, 21.3% and 14.3% across age groups. The incidence of gain(1q) increased with age, and was 43.9%, 47.1% and 54.8%, respectively. The incidence of del(17p) and del(13q) seldom changed with age (Figure E). With age, the risk of high-risk cytogenetic abnormalities did not change significantly, accounting for about 50% in each age group. The risk of ISS gradually decreased, accounting for 36%, 27%, and 14% in ≤60, 61-70 and ≥71 year subgroups, respectively. The risk of the ECOG performance status gradually increased with age, accounting for 10%, 17%, and 36% in the three subgroups (Figure F). The overall response rate of induction treatment gradually decreased with age, and were 90.2%, 81.9%, and 69.2%, respectively (P & lt;0.001). Elderly patients with impaired renal function or more than one high-risk cytogenetic abnormalities might benefit more from bortezomib based treatment than younger patients (Figure G). Conclusion: Age is an important prognostic factor in MM. With age, the risk of MM progression or death steadily grows. Cytogenetic abnormalities are equally important in every age group. The risk of poor performance status increases in elderly patients with a reduction risk in ISS. Elderly patients should focus on the status of frailty and molecular events to determine treatment. Figure Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2020
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    Online-Ressource
    Online-Ressource
    American Society of Hematology ; 2019
    In:  Blood Advances Vol. 3, No. 19 ( 2019-10-8), p. 2895-2904
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 19 ( 2019-10-8), p. 2895-2904
    Kurzfassung: Early responders with MM (TBR ≤3 months) are more likely to have higher lactate dehydrogenase levels and experience inferior outcomes. The kinetic pattern of response is a simple and powerful predictor for survival of patients with MM even in the era of novel agents.
    Materialart: Online-Ressource
    ISSN: 2473-9529 , 2473-9537
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2019
    ZDB Id: 2876449-3
    Standort Signatur Einschränkungen Verfügbarkeit
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