Bone marrow microvascular density and angiogenic growth factors in multiple myeloma

2004 ◽  
Vol 42 (10) ◽  
Author(s):  
Michael G. Alexandrakis ◽  
Freda J. Passam ◽  
Emmanuel Ganotakis ◽  
Evgenios Dafnis ◽  
Constantina Dambaki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Levels ◽  
Microvascular Density ◽  
Newly Diagnosed ◽  
Plateau Phase ◽  
Angiogenic Growth Factors ◽  
Bone Marrow Biopsies ◽  
Tnf Α ◽  
Pre Treatment

AbstractThere is evidence that angiogenesis plays an important role in the progression of multiple myeloma (MM). Hepatocyte growth factor (HGF) and tumor necrosis factor-α (TNF-α) are cytokines that potently stimulate angiogenesis. We evaluated the microvascular density (MVD) of bone marrow biopsies (after immunostaining with anti-CD34 antibodies) and serum levels of HGF and TNF-α in 43 patients with newly diagnosed MM. Twenty-four of these patients reached a plateau phase after treatment and were reevaluated for MVD, HGF and TNF-α. MVD values and serum levels of HGF and TNF-α were elevated in newly diagnosed MM patients in comparison with healthy controls. Pre-treatment MVD, HGF and TNF-α increased with advancing stage of MM disease. In patients reaching the plateau phase, a significant reduction in MVD, HGF and TNF-α levels occurred. A positive correlation was noted between pre-treatment MVD and serum levels of TNF-α and lactic dehydrogenase but not with HGF. However, HGF strongly correlated with β

scholarly journals Angiogenesis-Related Cytokines, RANKL, and Osteoprotegerin in Multiple Myeloma Patients in relation to Clinical Features and Response to Treatment

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
K. Sfiridaki ◽  
C. A. Pappa ◽  
G. Tsirakis ◽  
P. Kanellou ◽  
M. Kaparou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Serum Levels ◽  
Response To Treatment ◽  
Disease Stage ◽  
Vascular Endothelial ◽  
Newly Diagnosed ◽  
Plateau Phase ◽  
Endothelial Growth Factor ◽  
Hepatocyte Growth

An essential cytokine system for the osteoclast biology in multiple myeloma (MM) consists of the receptor of activator of NF-κB ligand (RANKL), its receptor (RANK), and the soluble decoy receptor, osteoprotegerin (OPG). Myeloma cells cause imbalance in OPG/RANKL interactions. We measured serum levels of OPG, soluble (s) RANKL, sRANKL/OPG ratio, markers of disease activity [LDH, CRP, interleukin-6 (IL-6),β2-microglobulin (B2M)], and angiogenic factors [hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], in 54 newly diagnosed MM patients and in 25 of them in plateau phase. All the above values were higher in MM patients compared to controls and decreased in plateau phase. sRANKL and RANKL/OPG were higher with advancing disease stage and skeletal grade. Significant correlations were found among RANKL and RANKL/OPG with HGF, LDH, VEGF, IL-6, and B2M. In conclusion, RANKL and OPG play significant roles in MM pathophysiology, as regulators of bone turnover and mediators of angiogenesis.

Circulating Levels of the Wnt Inhibitors Dickkopf-1 and Sclerostin In Different Phases of Multiple Myeloma: Alterations Post-Therapy with Lenalidomide and Dexamethasone with or without Bortezomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2963-2963 ◽  
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Maria Gkotzamanidou ◽  
Cornelia Bratengeier ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Bone Resorption Marker ◽  
Newly Diagnosed ◽  
Plateau Phase ◽  
Median Increase ◽  
Asymptomatic Patients ◽  
Circulating Levels ◽  
Dickkopf 1

Abstract Abstract 2963 Dickkopf-1 (Dkk-1) and sclerostin are inhibitors of the Wingless-type and integrase 1 (Wnt) signaling and they are implicated in the pathogenesis of multiple myeloma (MM) bone disease through inhibition of osteoblast function. There is very limited information for the circulating levels of Dkk-1 and sclerostin in different phases of MM and their alterations post therapies with novel agents. Therefore, we studied 284 MM patients (153M/131F, median age 66 years): 167 consecutive patients were newly-diagnosed (20 had asymptomatic MM and 147 symptomatic MM), 29 patients were at the plateau phase of MM and 88 patients had relapsed/refractory MM and received therapy with the combination of lenalidomide plus dexamethasone with or without bortezomib (VRD or RD; Dimopoulos et al, Leukemia 2010). For newly diagnosed patients, serum was stored at the time of diagnosis, while for patients at the plateau phase serum was collected at the time of confirmation of the plateau (at least 6 months with stable M-protein without criteria confirming progression) and for relapsed/refractory patients on day 1 of cycles 1, 4 and 7 of VRD or RD administration. Circulating levels of Dkk-1 and sclerostin were measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA and Biomedica Medizinprodukte, Vienna, Austria, respectively) in all patients and in 20 gender- and age- matched healthy controls. Circulating Dkk-1 and sclerostin concentrations of newly diagnosed symptomatic patients (median: 1383 pg/mL, range:274-32, 862 pg/mL and 415 pg/mL, 0–3,340 pg/mL respectively) were increased compared to controls (1069 pg/mL, 540-2, 709 pg/mL; p<0.001 and 250 pg/mL, 0–720 pg/mL; p=0.03, respectively) and to asymptomatic patients at diagnosis (1044 pg/mL, 480-2, 335 pg/mL; p<0.001 and 140 pg/mL, 0–1,100 pg/mL; p=0.001, respectively). Patients at plateau phase had increased circulating levels of sclerostin (704 pg/mL, 68–2000 pg/mL; p <0.001) compared to controls (p=0.002) as well as to MM patients at diagnosis (p=0.02). In contrast, they had lower serum levels of Dkk-1 (1013 pg/mL, 414–1729 pg/mL) compared to MM patients at diagnosis (p<0.001) and no difference compared to controls. Patients with ISS-3 myeloma at diagnosis had higher values of Dkk-1 and sclerostin than ISS-1 and ISS-2 patients [median Dkk-1 values for ISS-1, ISS-2 and ISS-3 were: 1059 pg/mL, 1290 pg/mL and 2649 pg/mL, respectively; p(ANOVA)=0.031; median sclerostin values for ISS-1, ISS-2 and ISS-3 were: 394 pg/mL, 392 pg/mL and 714 pg/mL, respectively; p(ANOVA)=0.001]. Patients with lytic disease at diagnosis (n=116) had increased levels of Dkk-1 compared with patients with no lytic disease (n=51): 1475 pg/mL, 327-32, 862 pg/mL vs. 840 pg/mL, 274–1112 pg/mL; p=0.002. There was no difference in sclerostin levels between these patients; however, patients with advanced bone disease (>3 lytic lesions and/or a fracture) had a borderline increase in their circulating sclerostin compared to all others (p=0.072). Dkk-1 circulating levels correlated weakly with sclerostin (r=0.201, p=0.05). Relapsed patients had increased Dkk-1 (1218 pg/mL, 161-19, 325 pg/mL) and sclerostin (886 pg/mL, 90-6, 272 pg/mL) levels compared to controls and to asymptomatic patients at diagnosis (p<0.001 for all comparisons). In patients who received RD, Dkk-1 was increased and sclerostin was decreased after 6 cycles of therapy. Responders to RD had a median increase of 9% in Dkk-1 serum levels after 6 cycles of therapy, while non-responders had a median increase of 91% compared to baseline values (p<0.01). Patients who did not respond to RD showed an increase in bone resorption marker CTX (p=0.021) after 6 cycles of therapy. VRD administration resulted in a significant reduction of sRANKL (p=0.024) and increase of bone formation marker, osteocalcin (p=0.01) after 6 cycles, but showed only minimal reduction of Dkk-1 (p=0.08) and no alterations on sclerostin. In conclusion our study suggests that Dkk-1 is elevated in active myeloma, while sclerostin is elevated even in the plateau phase of the disease. Both correlated with adverse disease features. The increase of Dkk-1 by RD seems to be balanced by a reduction effect of bortezomib on Dkk-1 in VRD. Furthermore, the reduction of sclerostin in RD patients may represent a modulatory effect of lenalidomide on marrow microenvironment. These results further support the rationale for the use of drugs targeting Dkk-1 and sclerostin in MM. Disclosures: No relevant conflicts of interest to declare.

The presence of bone marrow fibrosis is associated with poorer prognosis in newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19514-e19514
Author(s):  
Barry Paul ◽  
Gavin Loitsch ◽  
Daniel Feinberg ◽  
Ian Barak ◽  
Zhiguo Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Bone Marrow Fibrosis ◽  
Bone Marrow Biopsies ◽  
Immunomodulatory Agents ◽  
Marrow Fibrosis

e19514 Background: The treatment of newly diagnosed multiple myeloma (NDMM) has evolved significantly with the advent of the immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs). While the presence of bone marrow fibrosis (BMF) has previously been associated with poor prognosis in multiple myeloma (MM), these studies were small and conducted prior to the widespread use of IMiDs and PIs. Here, we determined the incidence of BMF in NDMM patients and correlated the degree of BMF with prognosis in a population enriched for IMiD and/or PI exposure. Methods: Bone marrow biopsies from 306 MM patients seen at Duke between 2003 and 2013 were screened for BMF using a reticulin stain. Samples were scored as absent, mild, moderate, or severe fibrosis based on the degree and intensity of staining. The association between presence and degree of BMF to progression free survival (PFS) and overall survival (OS) was calculated using Kaplan-Meier analysis. Results: Of the 306 patients evaluated, 248 (81.0%) were treated with an IMiD, 241 (78.8%) were treated with a PI, and 217 (70.9%) received both. Additionally, 160 (52.3%) patients went on to receive an autologous stem cell transplant (HSCT). A total of 193 patients (63.1%) were evaluable for BMF. Of these, 96 (49.7%) had detectable BMF, while 97 (50.3%) had no BMF. The degree of BMF was mild in 60 patients (62.5%), and moderate or severe in 34 patients (35.4%). Median PFS in patients without BMF was 30.4 months, and 21.8 months in patients with BMF present (log-rank p = 0.02). Median OS was 61.1 months in patients without BMF, and 46.3 months in patients with BMF (log-rank p = 0.048). Patients with moderate or severe BMF had a particularly poor prognosis with a PFS of only 18.8 months and an OS of 32.7 months. Conclusions: Our study represents the largest dataset to date examining the incidence of BMF in MM patients, and is the only one to examine the association of BMF with prognosis in the era of novel therapies and widespread use of HSCT. Our data suggests that BMF is common in NDMM, and MM patients with BMF (particularly those with more extensive BMF) have a poorer prognosis even when treated with IMiDs and PIs. These data emphasize the importance of determining the presence and degree of BMF at time of MM diagnosis, and suggest a role for adjunctive therapies that target BMF in MM patients with co-existing BMF.

A Paracrine Circuit Regulates Vascular Endothelial Growth Factor Production By Bone Marrow Plasma Cells in Patients with POEMS Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1757-1757
Author(s):  
Chen Wang ◽  
Qian-qian Cai ◽  
Xin-xin Cao ◽  
Dao-bin Zhou ◽  
Jian Li
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Serum Levels ◽  
Poems Syndrome ◽  
Newly Diagnosed ◽  
Bone Marrow Biopsies ◽  
Fluorescent Intensity ◽  
Bone Marrow Plasma ◽  
Endothelial Growth Factor

Abstract Background : POEMS syndrome is a rare paraneoplastic disorder, characterized by polyneuropathy, organomegaly, osteosclerosis and extravascular volume overload, due to an underlying plasma cell dyscrasia. Vascular endothelial growth factor (VEGF), a potent angiogenic cytokine that can increase vascular permeability, plays a critical role in its pathogenesis. Despite extensive VEGF studies concerning its role in disease diagnosis, monitoring and response assessment, little is known about its cellular source and mechanisms governing the production of VEGF in POEMS patients. Methods and Materials : Patients with POEMS syndrome, 62 newly diagnosed and 46 of them after lenalidomide-dexamethasone (LenDex) treatment, admitted to Peking Union Medical College Hospital between February 2014 and April 2015, were included in the current study. Clinical information, serum and bone marrow samples were collected with the Institutional approval. Serum levels of VEGF were measured by ELISA. VEGF levels in bone marrow plasma cells were quantified via real-time quantitative PCR and multiparameter flow cytometry, respectively. In addition, the phenotype, clonality and intracellular interleukin-6 (IL-6) expression of bone marrow plasma cells were also analyzed by flow cytometry. Furthermore, immunohistochemical staining was performed to study the plasma cell distribution, clonality and expression of VEGF, IL-6 and hypoxia-inducible factor-1α (HIF-1α) in bone marrow biopsies. Statistical analyses were conducted using SPSS 22, and a p < 0.05 was considered as significant. Results : Serum levels of VEGF were dramatically elevated in patients with newly diagnosed POEMS syndrome (median 5958 pg/mL), significantly higher than both disease and healthy controls (p < 0.001), and can be used as a diagnostic marker (area under curve 0.988, p < 0.001). A cut-off value of 2000 pg/mL had a specificity of 97.7% with a sensitivity of 91.9% in support of the diagnosis. After treatment, VEGF levels decreased gradually (6-cycle after LenDex, median 1184 pg/mL, p < 0.001; 12-cycle after LenDex, median 832 pg/mL, p < 0.001). Bone marrow plasma cells showed remarkable VEGF expression, validated in both mRNA and protein levels, which also decreased in response to LenDex therapy. More importantly, a statistically linear correlation was observed between serum and bone marrow plasma cell VEGF levels (newly diagnosed patients, rho = 0.33, p = 0.01; post-therapeutic patients, rho = 0.53, p < 0.001), supporting that bone marrow plasma cells were the source of circulating VEGF. Intriguingly, immunophenotying revealed that bone marrow plasma cells were polyclonal in most newly diagnosed cases. Monoclonal population, co-existing with polyclonal plasma cells, was observed only in 11 patients (18%). Further analyses showed that the relative amounts of these two populations were similar (41% vs. 59%) and they also had comparable intracellular VEGF expression (mean fluorescent intensity, 2009 vs. 2367, p = 0.594). However, monoclonal plasma cells had significantly higher intracellular IL-6 expression (mean fluorescent intensity, 1635 vs. 865, p = 0.006). In 46 newly diagnosed cases with bone marrow biopsies available, immunohistochemical staining was performed, and plasma cells were typically distributed in a scattered manner, with focal aggregates observed in 21 cases (46%). Intracellular κ and λ light chain staining demonstrated that the background scattered plasma cells were polyclonal, while both monoclonal and polyclonal fractions were observed in the focal area, which showed similar nuclear and intracellular staining of HIF-1α and VEGF, respectively. In contrast, IL-6 was mainly expressed in λ-restricted plasma cells. Conclusion : Bone marrow plasma cells are the potential source of VEGF production in patients with POEMS syndrome. Monoclonal plasma cells, aggregates focally in the bone marrow, may secret IL-6 to stimulate polyclonal plasma cells proliferation, and consequent VEGF production in a paracrine circuit. Disclosures Off Label Use: Lenalidomide for POEMS syndrome.

scholarly journals PD-L1/PD-1 Pattern of Expression Within the Bone Marrow Immune Microenvironment in Smoldering Myeloma and Active Multiple Myeloma Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Federica Costa ◽  
Rosanna Vescovini ◽  
Valentina Marchica ◽  
Paola Storti ◽  
Laura Notarfranchi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Unmet Need ◽  
Serum Levels ◽  
Newly Diagnosed ◽  
Effector Cells ◽  
Monoclonal Gammopathies ◽  
Total Cohort ◽  
Significant Difference ◽  
Smoldering Myeloma

BackgroundThe PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies.MethodsThe PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients.ResultsFirst, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16− cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells.ConclusionsOur data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment.

Asymptomatic Amyloidosis at the Time of Diagnostic Bone Marrow Biopsy in Newly Diagnosed Patients with Multiple Myeloma and Smoldering Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2803-2803
Author(s):  
Sergio Siragusa ◽  
William Morice ◽  
Morie A Gertz ◽  
Robert Kyle ◽  
Philip R. Greipp ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Congo Red ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Bone Marrow Biopsies ◽  
Smoldering Multiple Myeloma ◽  
High Level

Abstract Abstract 2803 Poster Board II-779 Background. The rate of asymptomatic amyloidosis (asym-amyloidosis) detected in patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. This topic is significant because unrecognized AL may be associated with increased mortality may change the patient's management. The objective of the present investigation was to evaluate the number and clinical significance of asym-amyloidosis in MM and SM patients at the time of the diagnostic bone marrow (BM) biopsy for MM. Materials and Methods. The study population was selected from the Mayo Clinic Dysproteinemia database and consisted of consecutive patients with an established diagnosis of MM or SMM without recognition of symptomatic AL. Bone marrow biopsies at diagnosis of MM or SMM were retrospectively stained with Congo Red and reviewed by a single pathologist. A patient was considered to have asym-amyloid if Congo Red staining with apple green birefringence was found. Results. Biopsies from 144 (M 84, F 59) patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26-84) years. No differences were found regarding hemoglobin, platelets, prothrombin time, serum and urine proteins, serum albumin, alkaline phosphate, creatinine and β2-microglobulin among MM and SMM patients. At a median follow-up 76 months (range 0-216), 32% patients were alive, 65% dead and 2.7% lost to follow-up. Immunoglobulin isotypes were as follows: 96/144 (67%) had IgG 23/144 (16%) IgA, 12/144 (8%) had light chain only, 1/77 (1%) had IgD, none had IgM and 12/144 (8%) had biclonal or indeterminate; 84/144 (58%) were κ restricted. The presence of amyloid was found in only 2 cases (1%, 95% CI – 0.6 to 3.2), 1 in MM and 1 in SMM group. Neither of these patients had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, 1 (0.7%, 95% CI -0.6 to 2.0) developed symptomatic AL after 119 months of follow-up. Characteristics of these three patients are shown in table 1. Conclusions. We found only 2 cases (1%) of amyloidosis in the 144 cases of MM or SMM. Our estimates are lower than the rates which have been reported by others, perhaps because of our high level of suspicion for amyloid at our Amyloidosis Center. These data do not support the need for searching for asym-amyloidosis in patients with newly diagnosed MM or SMM as long as they have no clinical features of AL. Disclosures: Off Label Use: Hydroxyurea use in myelofibrosis. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Witzig:Novartis: Research Funding. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

2012 ◽  
Vol 87 (7) ◽  
pp. 734-736 ◽  
Author(s):  
Anna Tasidou ◽  
Maria Roussou ◽  
Evangelos Terpos ◽  
Efstathios Kastritis ◽  
Maria Gkotzamanidou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Cyclin D1 ◽  
Novel Agents ◽  
Bone Marrow Biopsies

Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8010-8010
Author(s):  
Noemi Puig ◽  
Bruno Paiva ◽  
Teresa Contreras ◽  
M. Teresa Cedena ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Prognostic Value ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Time Points ◽  
Minimal Residual

8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to <10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to <10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to <10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p<0,0001), 94% (p=0,034); post-ASCT 86% (p<0,0001), 90% (p=0,022); post-Cons 89% (p<0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]

scholarly journals Prognostic Implications of Metabolic Total Volume and Total Lesion Glycolysis Assessed By PET/CT Combined with High Levels of Bone Marrow Plasma Cells Percentages As a Potential Risk Model in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3193-3193
Author(s):  
Toshiki Terao ◽  
Yoichi Machida ◽  
Takafumi Tsushima ◽  
Akihiro Kitadate ◽  
Daisuke Miura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Risk Stratification ◽  
Tumor Volume ◽  
Mononuclear Cells ◽  
Total Lesion Glycolysis ◽  
Whole Body ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Pet Ct

Introduction: Multiple myeloma (MM) is a heterogeneous malignant plasma cell (PC) disorder and the survival ranges from several months to > 10-years. Several risk stratification systems such as the Revised International Staging System (R-ISS) have been developed. PET/CT allows the direct assessment of metabolic tumor burden in various malignancies. Therefore, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), which are volumetric parameters applicable to PET/CT, are emerging tools for MM prognostication. This study was aimed to determine the value of MTV and TLG using PET/CT in the prognostication and in combination with various hematologic parameters such as bone marrow PC (BMPC) percentages and circulating tumorous PCs (CPCs) to identify the patients with high-risk features. Methods: A total of 196 consecutive patients with newly diagnosed MM (NDMM) who underwent baseline whole-body PET/CT between January 2009 and June 2019 at Kameda Medical Center, Kamogawa-shi, Japan, were retrospectively analyzed. PET/CT was performed using dedicated PET/CT scanners (Discovery ST Elite Performance; GE Healthcare, Milwaukee, USA). The standard uptake value (SUV) was normalized according to the injected dose and lean body mass. The baseline SUVmax of all lesions was recorded, and the highest value was considered as the SUVmax of the patient. MTV was defined as the myeloma lesions volume visualized on PET/CT scans with SUV greater than or equal to the fixed absolute threshold of SUV = 2.5. TLG was calculated as the sum of the product of average SUV (SUVmean) and MTV of all lesions. Computer‐aided analysis of PET-CT images for MTV and TLG calculations was performed using an open-source software application of Metavol (Hokkaido University, Sapporo, Japan). The CPCs were measured using an 8-color flowcytometry and reported as the percentage per total mononuclear cells using the monoclonal antibodies of CD19, 38, 45, 56, 117, 200, κ, λ, and CD138. The BMPC was calculated by counting the percentages of CD138-stained PCs among the all nucleated cells on bone marrow biopsy samples. Eleven patients (13.8%) were excluded because the MTV data could not be retrieved. Ultimately, 185 patients were included in our analysis. Written informed consent was obtained from all patients. Results: Among the 185 patients, 28 patients (15.1%) were negative for avid lesion on PET/CT. Whole-body MTV and TLG ranged from 0 to 2440.7 mL, with a median of 34.2 mL and from 0 to 12582.4 g, with a median of 97.0 g, respectively. The best cut-off values of MTV and TLG that discriminate the survival using a receiver-operating-characteristic curve analysis were 56.4 mL and 166.4 g, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with a lower cut-off value of MTV (≤56.4 mL) had better survival with not reached (NR) and 37.3 months as compared to those with a higher cut-off value (>56.4 mL) that reached 52.9 and 23.8 months, respectively (p=0.003 and 0.019). Similarly, the OS and PFS of patients with a lower cut-off value of TLG (≤166.4 g) showed better survivals with NR and 37.3 months as compared to those with a higher cut-off value (>166.4 g) that reached 54.3 and 28.8 months, respectively (p=0.0047 and 0.012). Next, we explored the prognostic impact of the clinical variables including MTV or TLG, CPCs, and BMPC. High levels of CPCs and BMPCs levels were defined as ≥0.018% of the total mononuclear cells and BMPCs of ≥57%, respectively. Univariate analysis showed that age≥70, serum creatinine≥2.0 mg/dL, R-ISS stage 3, higher cut-off value of MTV, and higher cut-off value of TLG were the associated with shorter OS. To measure the tumor volume with accuracy, we combined BMPC or CPCs and MTV or TLG. On multivariate analysis, age≥70 and the combination of higher cut-off value of MTV or TLG and high level of BMPC percentage were significantly associated with shorter OS [Hazard Ratio (HR) 2.12, p=0.038, HR 2.66, p=0.027 and HR 2.57, p=0.029, respectively] and PFS (Not assessed, HR 2.52, p=0.018 and HR 2.7, p= 0.011, respectively) (Figure 1). Conclusion: Our findings demonstrated that MTV and TLG calculated from pretreatment PET/CT were useful for risk stratification in patients with NDMM when combined with BMPC. The prognostic performance of the combined high-burden of TLG or MTV and high levels of BMPC were independent of the established risk factors. Disclosures Matsue: Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria.

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