Comparison of Survival and Clinical Features In Different Age Cohorts of Patients with Multiple Myeloma: A Single Center Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4997-4997
Author(s):  
Jae Ho Jeong ◽  
Shinkyo Yoon ◽  
Dalyong Kim ◽  
Jeong Eun Kim ◽  
Dok Hyun Yoon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Features ◽  
Bone Lesion ◽  
Elevated Serum ◽  
High Serum ◽  
Single Center ◽  
Age Cohorts ◽  
Β2 Microglobulin ◽  
The Impact

Abstract Abstract 4997 Purpose This analysis was aimed to compare clinical features in different age cohorts of multiple myeloma (MM) patients and to identify the impact of the clinical characteristics on survival in the patients in a single center. Patients and Methods We retrospectively analyzed data from 513 patients between Sep 1995 and Feb 2010 in the Asan Medical Center. Correlation of baseline characteristics with survival was made by the following age strata: <45, 45–54, 55–64, and ≥65 years of age. Results Median observed overall survival (OS) in the entire cohort was 3.20 years (95% confidence interval: 2.71–3.68). Observed survival decreased steadily with ages from 4.56 years in patients younger than age 45 years to 2.50 years in patients ≥65 years (P=0.003). The patients in the oldest group (age 65 years or older) were more likely to have International Staging System (ISS) stage II or III than others (P=0.007). There were no significant differences in hypercalcemia (≥10 mg/dL), elevated serum creatinine (≥2 mg/dL), anemia (Hb <10 g/dL) and osteolytic bone lesion, so called CRAB among the different age cohorts. Prognostic factors including elevated C-reactive protein (CRP) (≥ 0.8mg/dL), lactate dehydrogenase (LDH), bone marrow plasma cell infiltration also did not differ significantly among 10-year age cohorts. However, hypoalbuminemia (<3.5 g/dL) and high serum β2-microglobulin (≥3.5 mg/dL) level were more frequent in patients ≥65 years of age (P=0.001 and P=0.046, respectively). Furthermore, higher proportion of patients underwent ASCT in the younger 10-year age cohorts (71.4%, 53.7%, 43.4%, 2.5% in < 45, 45–54, 55–64, and ≥ 65 years of age, respectively, P<0.001). Conclusion No significant differences in the myeloma related organ or tissue impairment and prognostic markers including CRP, LDH and bone marrow infiltration of myeloma cells were noted among different age groups. However, survival significantly declined in the higher age group, which might be related to higher ISS stage associated with hypoalbuminemia, high serum β2-microglobulin level and lower proportion of patients receiving ASCT. Disclosures: No relevant conflicts of interest to declare.

Clinicopathological and Prognostic Characteristics of CD33-Positive Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3409-3409
Author(s):  
Naohi Sahara ◽  
Kazunori Ohnishi ◽  
Takaaki Ono ◽  
Yuya Sugimoto ◽  
Miki Kobaysahi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Level ◽  
Bone Marrow Cells ◽  
Bone Lesion ◽  
Prognostic Significance ◽  
Clinical Information ◽  
Prognostic Indicators ◽  
Newly Diagnosed ◽  
Β2 Microglobulin

Abstract In multiple myeloma (MM), there have been few reports about the CD33 expression on MM cells so far, showing that a part (6.5–12 %) of patients expressed CD33 on their MM cells. However in these reports, neither detailed clinical information nor its prognostic significance was described. Therefore, we analyzed the CD33 expression on MM cells from newly diagnosed patients by flow cytometry and the correlation with other clinical parameters to determine the clinicopathological significance of this molecule in MM. The CD33 expression on MM cells was studied in the bone marrow from newly diagnosed 63 patients with MM. The median age of the patients was 69 years (range 43–91). The monoclonal component was: IgG in 46%, IgA in 27%, and Bence Jones protein (BJP) in 22% of patients. The patients were distributed according to Durie-Salmon stage, as follows: stage I, 15%; II, 35%; III, 50%. Fifty-five of these patients were treated with either melphalan-prednisolone (n=23) or VMMD with (n=7), or without (n=20) interferon (IFN) a. Four patients were treated with VAD followed by auto-PBSCT. Heparinized bone marrow cells were obtained at diagnosis. Cells were incubated with FITC-labelled anti-CD38, PE-anti-CD13, anti-CD33, anti-CD49e, anti-CD56, Per CP-anti-CD45 or APC-anti-CD19 monoclonal antibody. Cells were gated by their forward and side scatter characteristics and strong CD38 expression (CD38++). An antigen was defined as positive when more than 20 % of MM cells expressed it. Of 63 patients evaluated for CD33 expression, 14 (22%) were positive and 49 (78%) were negative. Of 14 patients with CD33+ MM, more than 80% of MM cells were positive in 6 (9.5%). No significant differences were found between the two groups in terms of age, sex, bone lesion extension, presence of extramedullary involvement, or Durie-Salmon stage. In addition, several prognostic indicators such as the serum level of calcium, creatinine, WBC counts, prevalence of BJP in urine, and chromosomal aberrancies such as del(13q), t(4;14), or t(11;14) were similar in both groups of patients. On the other hand, the serum level of β2 microglobulin and LDH in the CD33+ patients were significantly higher than in the CD33− patients (P=0.002 and 0.001, respectively). In addition, the CD33+ patients had a higher incidence of anemia and thrombocytopenia (P=0.01 and 0.02, respectively). With a median follow up of 18 months, the estimated over all survival was significantly shorter in the CD33+ patients than the CD33− patients (median survival; 18 vs. 38 months, P=0.04). Especially, mortality within a year from diagnosis in the CD33+ patients was significantly higher than the CD33− patients(43 vs. 10 %, respectively, P=0.005). No correlation between CD33 and other surface markers such as CD13, CD45, CD49e, and CD56 was observed. We here found that CD33+ MM patients showed higher serum β2 microglobulin and LDH level and a higher incidence of anemia or thrombocytopenia with poor prognosis. These results suggest that CD33+ MM might be a discrete entity and CD33 might be a useful therapeutic target for these patients.

Hepatocyte Growth Factor-Producing Multiple Myeloma (HGF myeloma) Is a Distinct Clinical Entity and Needs for Molecular Targeted Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1717-1717
Author(s):  
Yutaka Hattori ◽  
Shin-ichiro Okamoto ◽  
Wenlin Du ◽  
Taketo Yamada ◽  
Naoki Shimada ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Molecular Targeted Therapy ◽  
Bone Lesion ◽  
Elevated Serum ◽  
Lytic Bone Lesion ◽  
Hepatocyte Growth

Abstract Background and Objective: Disease control of refractory or relapsed multiple myeloma (MM) remains a therapeutic challenge. Classification of the patients in the molecular basis and development of targeted therapy are crucial to overcome the situation. We previously reported that 20–30% of MM cells produce hepatocyte growth factor (HGF), and its serum concentration was specifically elevated in symptomatic MM patients. The purpose of this study is to elucidate the clinical characteristics of HGF-producing MM (HGF myeloma) and to explore a novel therapy. Patients & Methods: Serum concentrations of HGF obtained from 76 patients with MM were measured by ELIZA. Less than 0.3μg/L was considered as a normal range. Association of serum HGF levels with various clinical parameters for disease activity was examined, including age, ISS stage, type of M protein, hemoglobin level, serum creatinine, Ca, β2M, albumin, LDH, CRP, bone marrow MM cell %, chromosomal abnormality, presence of lytic bone lesion and extramedullar plasmacytoma. Phase 2 thalidomide monotherapy was also conducted in 56 patients with refractory MM. HGF-specific competitive inhibitor, NK4 protein, was used for in vitro experiments such as growth inhibition by MTT assay, induction of apoptosis by flow cytometer and activation of intracellular signaling molecules by Western blot analysis. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was intramuscularly injected into lcr/scid-mice bearing tumors derived from HGFproducing KMS11 and 34 cells. Results: Elevated serum HGF level was significantly associated with the presence of anemia (p=0.03) and lytic bone lesion (p=0.009). Seven out of eight patients with high CRP levels without infection and five out of nine patients with extramedullar plasmacytoma also demonstrated elevated serum HGF level. Furthermore, in thalidomide monotherapy for refractory MM, increase in pre- and posttreatment serum HGF level was significant poor prognostic factors for overall survival (OS) in univariate analyses, p=0.025 and 0.01, respectively. Elevation of post-treatment HGF level was also independent poor prognostic factor for OS in multivariate analysis. We next examined the possibility of molecular targeted therapy of HGF using NK4. NK4 protein stabilized the growth of HGF-producing MM cell lines and primary bone marrow MM cells in vitro. NK4 also increased in annexin V+ apoptotic cell fraction and regulated the activation of c-Met, ERK1/2, STAT3, and AKT-1. AdCMV.NK4 significantly delayed growth of KMS 11 and 34-derived tumors in vivo. Histological examination revealed that AdCMV.NK4 induced apoptosis of the tumor cells, accompanied by a reduction in neovascularization in the tumors. AdCMV.NK4 injection prolonged survival of KMS 11 tumor-bearing mice. Conclusion: HGF myeloma is characterized by increased disease activity such as anemia, bone lesion, high CRP level and extramedullar plasmacytoma and also by shorter survival by conventional therapy including thalidomide, and it should be recognized as a distinct clinical entity. Since NK4 showed direct anti-myeloma effect as well as anti-angiogenic activity against HGF-producing MM cells, molecular targeted therapy, for example using NK4, is to be established to improve the therapeutic outcome of HGF myloma.

Retrospective analysis of cytogenetic and clinical characteristics on 65 patients with multiple myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5075-5075
Author(s):  
Li Yang ◽  
Jingsong He ◽  
Xiaojian Meng ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Retrospective Analysis ◽  
Clinical Features ◽  
Elevated Serum ◽  
Serum Levels ◽  
Fish Analysis ◽  
Molecular Cytogenetic ◽  
Cytogenetic Aberrations ◽  
Conventional Cytogenetics

Abstract Abstract 5075 Multiple myeloma (MM) is a malignant disorder characterized by abnormal proliferation of monoclonal, immunoglobulin producing plasma cells in the bone marrow. Studies with large samples have shown that molecular cytogenetic changes play an important role in the prognosis of MM. Based upon these findings, we tested cytogenetic aberrations of 65 patients with MM by conventional cytogenetics analysis and FISH technique in this study. Retrospective study was done on these cases for clinical features. Methods: This is a retrospective analysis of 65 patients with MM diagnosed between June 2007 and May 2010 including 13 relapsed cases and 52 newly diagnosed patients. Patients received bortezomib-based combination chemotherapy including bortezomib plus dexamethasone (BD) and the triplet combinations (bortezomib, adriamycin, dexamethasone (BAD), bortezomib, cytoxan, dexamethasone (BCD) and bortezomib, melphalan, prednisone (BMP) or traditional chemotherapy including doxorubicin, vincristine plus dexamethasone (VAD), melphalan plus dexamethasone (MP), melphalan, dexamethasone plus thalidomide (MPT)). To further clarify the correlation between cytogenetic and clinical features on patients with multiple myeloma, we used conventional cytogenetics analysis with R-banding technique and interphase fluorescence in situ hybridization (FISH) to describe the molecular cytogenetic characterization of bone marrow nucleated cells from 65 patients. SPSS (version 18.0) software was used for data analysis, χ2 tests or Fisher's exact test was used for betweengroup comparison of the discrete variables and Log- Rank was used for survival analysis. p<0.05 reflects the remarkable significance. Results: 16.9% of patients (11/65) showed abnormal cytogenetic aberrations including 90.9% (10/11) cases with ultra complex aberration and complex aberration via conventional cytogenetics. In addition, we were able to show aberrations in 49.2% (32/65) of patients by interphase FISH analysis. Abnormalities of 13q14, 1q21, 14q32 and 17p13 were detected in 27.7% (18/65), 13.8% (9/65), 16.9% (11/65), and 29.2% (19/65) by FISH, respectively. 1q21 amplification is strongly associated with 13q14 mutation (P=0.008), demonstrating significant correlation between two. Abnormality of 13q14 deletion or 1q21 amplification were associated with lower levels of albumin (P<0.05). Patients with 13q14 deletion frequently had stage III disease by DS and ISS staging, and compared with patients not detected on FISH analysis, they tended to have elevated serum levels of β2-microglobulin at diagnosis (P<0.05). 17p13 deletion coexistent with 13q14 deletion frequently correlate with elevated serum levels of β2-microglobulin and advanced clinical staging. The median progression-free survival (PFS) of patients with 17p13 deletion or 17p13/13q14 aberrations were both 11.0m, significantly lower than patients with no detected abnormality (median PFS 19.0m) (P<0.05). The median overall survival (OS) of patients with FISH negtive results was 38.0m, significantly higher than those with 13q14, 14q32 or 1q21 abnormality and 17p13/13q14 or more than three abnormalities (P<0.05). Conclusions: This study validates myeloma cells are prone to show complex aberration and FISH is superior in the detection of cytogenetic aberrations to conventional cytogenetics analysis for patients with multiple myeloma. 1q21 had significant correlation to 13q abnormality. 17p13 deletion coexist with 13q14 deletion and 14q32 rearrangeent were used to associate with poor prognosis. 17p13 deletion or 17p13/13q14 deletion was associated with poorer PFS while abnormality of 13q14, 1q21,14q32, 17p13/13q14 or more than 3 abnormalities were correlate with poorer OS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4696-4700 ◽  
Author(s):  
Nikhil C. Munshi ◽  
Kenneth C. Anderson ◽  
P. Leif Bergsagel ◽  
John Shaughnessy ◽  
Antonio Palumbo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
In Situ Hybridization ◽  
High Risk ◽  
Risk Stratification ◽  
Fluorescence In Situ Hybridization ◽  
High Serum ◽  
Β2 Microglobulin ◽  
Poor Outcome ◽  
13Q Deletion

Abstract A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β2-microglobulin level and International Staging System stages II and III, incorporating high β2-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.

Poorer Survival in Multiple Myeloma Correlates with Patients’ Age and Is Linked to a Higher Stage at Presentation but Prognostic Parameters Reflecting the Biology of the Myeloma Clone Are Not Associated with Age.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1491-1491 ◽  
Author(s):  
Heinz Ludwig ◽  
Brian G.M. Durie ◽  
Erik Rasmussen ◽  
John Crowley
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Serum Albumin ◽  
Prognostic Parameters ◽  
Age Cohorts ◽  
Number Of Patients ◽  
Age Cohort ◽  
The Impact ◽  
Tumor Clone ◽  
Low Serum

Abstract Up to now no systematic analysis on the impact of different age categories on survival in patients with multiple myeloma has been reported. Information on possible correlations of host and tumor related prognostic factors with different age categories are lacking. We studied these parameters in a large cohort of patients with multiple myeloma (n=10.750) submitted by participating institutions and groups in the international staging system (ISS) project. Prognostic factors were recorded and age was calculated at start of initial chemotherapy. Patients were grouped into 6 age cohorts (<40, 40−<50, 50−<60, 60−<70, 70−<80 and ≥80 years). P values were calculated with the Jonckheere-Terpstra test and Spearman’s correlation coefficient was used where appropriate. The sequential median survivals constantly decreased by decade from 61 months to 60, 53, 40, 32 and 24 months in the 6 patient cohorts from age < 40 years to age >80 years examined, respectively, with a median value of 44 months (p<0.0001). The distribution of prognostic factors by age revealed a highly significant correlation between high serum ß2 microglobulin ( Sß2M, ≥3.5mg/dl) and age, ranging from 45% in patients in the youngest to 75% of patients in the oldest age cohort (r=0.17 (0.15–0.19), p<0.0001). A similar correlation was seen between low serum albumin (<3.5g/dl) and age: The proportion of patients with low serum albumin levels increased from 32% in patients at age < 40 years to 54% in patients > 80 years (r= −0.11(−0.13, −0.09), p<0.0001). Consequently, as Sß2M and serum albumin constitute the prognostic parameters of the ISS, a close correlation between ISS stage and age was found (p< 0.0001). The proportion of patients with ISS stage I (Sß2M < 3.5mg/dl and serum albumin ≥ 3.5 mg/dL) was 40% in patients aged <40 years and only 12% in those aged ≥80 years. In contrast, 44% of patients of the oldest and 31% of the youngest age cohort presented with ISS stage III. In addition, a similar, albeit lesser trend was noted for decreasing hemoglobin with age (r=−0.08 (−0.10, −0.07, p<0.0001) and increasing serum creatinine with age (r=0.08 (0.06, 0.10), p <0.0001). The parameters reflecting the biology of the myeloma clone did not vary between different age cohorts. Bone marrow plasma cell infiltration (BMPC) ≥33%, CRP levels ≥0.8 (mg/dL) and normal LDH was seen in similar frequencies in the different age categories. Similarly, no age dependent variation in cytogenetically defined prognostic variables was seen. The proportion of patients with Del 13 and of those with t (11; 14), t (4; 14) did not differ between the different age categories; these data were obtained in a limited number of patients only (616, 544 and 418 patients, respectively). In conclusion, age was identified as important prognostic factor in the six different age cohorts examined. Poorer survival with higher age is closely linked to higher ISS stage. In addition, creatinine and low hemoglobin correlate, albeit to a lesser degree, with increasing age, but not parameters reflecting adverse biologic features of the tumor clone (LDH, BMPC, CRP, del 13, t(11;14) t(4;14). Hence, an ailing host and not a more aggressive tumor clone seems to account for the inverse correlation between survival and age.

Multiplex Analysis of Serum Cytokine Levels in Waldenström Macroglobulinemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2616-2616
Author(s):  
Sherine F. Elsawa ◽  
Anne J. Novak ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Vincent Rajkumar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Elevated Serum ◽  
Fold Increase ◽  
Serum Levels ◽  
Healthy Controls ◽  
Β2 Microglobulin ◽  
Healthy Donors ◽  
Cytokine Levels

Abstract Waldenström macroglobulinemia (WM) is a monoclonal B cell disorder characterized by a circulating monoclonal IgM protein that may lead to serum hyperviscosity in association with an infiltration of lymphoplasmacytic cells into the bone marrow. Although proinflammatory and chemotactic cytokines can profoundly affect tumor cells and the tumor microenvironment, and many cytokines have been shown to have potent therapeutic efficacy in preclinical cancer models, the role of cytokine networks in WM is not fully understood. In this study, we used a high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) to simultaneously test 30 cytokines, chemokines, angiogenic factors as well as growth factors and soluble receptors in the sera of WM patients and compared them with other B cell malignancies including IgM monoclonal gammopathy of undetermined significance (MGUS), follicular lymphoma, chronic lymphocytic leukemia (CLL) as well as healthy controls. Using a Mann-Whitney U test to analyze the differences between the groups, 15 of the 30 cytokines tested had significantly different levels in WM compared to healthy controls. Of those 15 cytokines, 11 were elevated in WM patients and 4 were decreased. Cytokines were grouped into 3 groups; those with &lt; 2-fold difference, 2–8 fold difference and those having &gt; 8-fold difference in their cytokine levels compared to healthy donors. There was a greater than 8-fold increase in the serum levels of Rantes, G-CSF and IL-2R (p&lt;0.0001) in WM patients. Furthermore, 3 cytokines had between 2–8-fold increase in WM patients including IL-4 (p&lt;0.0001), IL-6 (p&lt;0.0019) and IP-10 (p&lt;0.0006). Five cytokines had statistically elevated levels in WM patients compared to healthy controls, however the fold increase was &lt; 2 including HGF (p&lt;0.0185), IL-10 (p&lt;0.0002), MIP-1α (P&lt;0.0484), IL-2 (P&lt;0.0130) and IL-12 (P&lt;0.0155). Of the cytokines that had significantly lower levels in the sera of WM patients, IL-8 (p&lt;0.0001) and EGF (p&lt;0.0001) were &gt; 8-fold decreased, MCP-1 (p&lt;0.0001) was 2–8 fold lower and Eotaxin (p&lt;0.0004) was &lt; 2-fold lower in WM patients. All of the cytokines that had the greatest fold difference (&gt; 8-fold) in WM patients compared to healthy donors also differed significantly from the MGUS patients. Rantes, G-CSF, IL-2R and EGF had significantly different levels compared to other B cell malignancies. We tested for a correlation between the cytokines that had &gt; 2-fold difference between the WM group and control group with clinical features of the disease and found the cytokines IL-6 and IL-2R had a significant correlation with β2-microglobulin levels (p&lt;0.01). We analyzed cytokine levels in the bone marrow plasma of the same patients and found that high levels of IL-2R in the bone marrow microenvironment significantly correlated with anemia and elevated serum β2-microglobulin (p&lt;0.01). In conclusion, we have simultaneously analyzed sera from WM patients for 30 cytokines and found the most significantly elevated cytokines are Rantes, G-CSF and IL-2R and the most significantly downregulated cytokines are IL-8 and EGF. Furthermore, we found that elevated serum levels of IL-6 and IL-2R correlated with β2-microglobulin levels, a measure of disease activity. Further analysis of the biological role of these cytokines in WM may offer insight into disease pathogenesis and provide a basis for novel targeted therapies.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

Association of PML Expression with Chemotherapy-Resistance In Multiple Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2959-2959
Author(s):  
Daisuke Ohgiya ◽  
Makoto Onizuka ◽  
Hiromichi Matsushita ◽  
Naoya Nakamura ◽  
Hiroshi Kawada ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Chemotherapy Resistance ◽  
Nuclear Body ◽  
Rank Test ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 2959 Background: Although several novel agents have improved the prognosis of patients with multiple myeloma (MM), it still remains an incurable disease because of the difficulty to eradicate MM cells by current therapeutic approaches. Recent studies have revealed that a subset of malignant cells, cancer stem cells, contribute to chemotherapy-resistance in cancer treatment. Promyelocytic leukemia gene product (PML), known as a tumor suppressor through a variety of cellular functions in a nuclear macromolecular structure called the PML nuclear body, has been reported to be responsible for the chemotherapy-resistance by regulating cell cycle in chronic myeloid leukemia. We therefore investigated the impact of PML expression on the cellular proliferation status of MM cells and patients' prognoses. Materials/Methods: Bone marrow clot sections from 48 patients with newly diagnosed MM from Jan 1998 to Dec 2009 before any therapy at diagnosis were obtained, and analyzed, according to appropriate procedure approved by IRB at the Tokai University School of Medicine (Kanagawa, Japan) with written informed consent. They were doubly-stained with a combination of anti-PML/anti-CD138 and anti-Ki67/anti-CD138. For evaluation of the relation between PML status and cellular proliferation, the positive rates of PML and Ki67 in CD138 positive cells were compared. For investigation of the impact of PML expression on the prognosis of MM, the patients were divided into 3 groups, according to the PML positive rates in the CD138 positive cells: negative/low (less than 25 percentile: 12 cases), intermediate (from 25 to 75 percentile: 24 cases) and high (more than 75 percentile: 12 cases). Their overall survivals were compared using log-rank test. Furthermore, the PML positive rates between before and after treatments were compared using paired t-test. Results: The median observation period of 48 cases was 915 days. The median age of the patients was 62.5 (38-76) at diagnosis. All the patients were underwent combination chemotherapies containing alkylating agents as initial therapies. Two and nine patients were underwent allogeneic and autologous stem cell transplantation during the clinical courses, respectively. The numbers of patients of international staging system (ISS) stage I, II and III were 17, 14 and 17 cases. The PML positive rates in each case ranged from 0% to 83.8%. They were not correlated with ISS stages (Spearman r = 0.083) and the Ki67 positive rates (Spearman r = -0.13). The PML positive rates in the negative/low, intermediate and the high groups were less than 22.1%, from 22.1 to 56.6% and more than 56.6%, respectively. No significant difference in overall survival was observed among the 3 groups (p>0.05). However, there were significant differences in two year survival rate when the 3 groups were compared (100%, 85.2% and 54.7%; p=0.015) (Fig. 1). In 13 patients whose bone marrow clot sections were sequentially collected, the PML positive rates after treatments were significantly higher than those at diagnosis (p=0.0042) (Fig. 2). Especially, PML positive rates in all the 3 patients from the negative/low group were progressively increased (0.3 to 82.6%, 14.1 to 100%, 19.0 to 37.5%), and 2 of them died due to disease progression. On the other hand, 2 patients whose PML positive rates decreased after treatment were alive more than 5 years without therapies. Conclusion: Our data indicated that the level of the PML expression at diagnosis was a possible prognostic factor for early course of the disease (2 years after diagnosis). Chemotherapies might induce PML expression in MM cells or select PML positive MM cells. These findings suggest that PML expression presumably reflect chemotherapy-resistance in MM cells. The molecular mechanism of the association is now under investigation. Disclosures: No relevant conflicts of interest to declare.

Role of Serum Lactate Dehydrogenase (LDH) As a Prognostic Marker for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3115-3115
Author(s):  
Krina Patel ◽  
Robert Z. Orlowski ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
Simrit Parmar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Lactate Dehydrogenase ◽  
Hematopoietic Stem Cell Transplantation ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Abstract 3115 Background: The International Staging System (ISS), chromosomal abnormalities, and response to therapy are well recognized predictors of outcome in multiple myeloma (MM). However, the role of serum lactate dehydrogenase (LDH) as a prognostic marker for MM is not well established. Recently we showed that high LDH at diagnosis of MM is a predictor of shorter survival. Here we report the impact of the LDH level at the time of autologous hematopoietic stem cell transplantation (auto-HCT) on its outcome. Methods: We evaluated 1,658 patients with symptomatic myeloma who underwent auto-HCT from July 1988 to December 2010 at our institution. The primary objective was to determine the impact of high LDH (>1000 IU/L) level, obtained on the start day of the preparative regimen, on progression free survival (PFS) and overall survival (OS). Results: Patient characteristics according to LDH level at auto-HCT are summarized in Table 1. Patients in the 2 LDH groups (>1000 or ≤ 1000) were matched for age, gender, disease status, and response to prior therapy at the time of auto-HCT. Patients with LDH >1000 IU/L had a significantly higher beta-2 microglobulin (β2m) and bone marrow plasmacytosis at the time of auto-HCT. Median times to neutrophil (10 vs. 10 days: p=0.10) and platelet engraftment (11.3 vs.12.2 days: p=0.20) were not different in the 2 groups. Also, there was no significant difference in CR, VGPR, PR or overall response rates between the 2 groups. Median follow up was 35 months (1 to 244). Median OS in patients with LDH >1000 and ≤ 1000 were 49.2 and 68.0 months, respectively (p=0.03). Median PFS in patients with LDH >1000 and ≤ 1000 were 14.4 and 24.7 months, respectively (p=0.001). On univariate analyses, >10% plasma cells in bone marrow biopsy, relapsed disease, serum β2M ≥ 3.5 at auto-HCT, presence of any chromosomal abnormality, and < PR after auto-HCT were associated with significantly shorter PFS and OS. Conclusions: Having a serum LDH value of >1000 IU/L prior to auto-HCT is associated with shorter PFS and OS in patients with MM. These high risk patients may require aggressive post-transplant therapy, including consolidation, maintenance, tandem transplants or novel approaches like immunotherapy. Disclosures: Shah: Celgene: Membership on an entity's Board of Directors or advisory committees.

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