scholarly journals The impact of bone marrow fibrosis and JAK2 expression on clinical outcomes in patients with newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors

2020 ◽  
Vol 9 (16) ◽  
pp. 5869-5880
Author(s):  
Barry Paul ◽  
Yue Zhao ◽  
Gavin Loitsch ◽  
Daniel Feinberg ◽  
Parker Mathews ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Outcomes ◽  
Proteasome Inhibitors ◽  
Newly Diagnosed ◽  
Bone Marrow Fibrosis ◽  
Immunomodulatory Agents ◽  
The Impact ◽  
Marrow Fibrosis

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.

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.

scholarly journals Assessment of Bone Marrow Fibrosis and Angiogenesis in Monitoring Patients With Multiple Myeloma

2012 ◽  
Vol 137 (6) ◽  
pp. 870-878 ◽  
Author(s):  
Emina Babarović ◽  
Toni Valković ◽  
Sanja Štifter ◽  
Ivana Budisavljević ◽  
Irena Seili-Bekafigo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

The Impact of Bone Marrow Fibrosis on the Outcome of Hematopoietic Stem Cell Transplantation

2010 ◽  
Vol 42 (7) ◽  
pp. 2713-2719 ◽  
Author(s):  
E. Suyanı ◽  
Ş.Z. Akı ◽  
Z.A. Yeǧin ◽  
Z.N. Özkurt ◽  
Ş. Altındal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Bone Marrow Fibrosis ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Marrow Fibrosis

Monitoring of multiple myeloma and bone marrow fibrosis with aminoterminal propeptide of type III collagen (PIIINP)

1992 ◽  
Vol 82 (1) ◽  
pp. 32-37 ◽  
Author(s):  
Taina Taube ◽  
Kaarle Franssila ◽  
Leila Risteli ◽  
Juha Risteli and ◽  
Inkeri Elomaa
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Type Iii Collagen ◽  
Bone Marrow Fibrosis ◽  
Type Iii ◽  
Marrow Fibrosis

Prognostic Implications and Clinical Characteristics Associated with Bone Marrow Fibrosis in Patients with Myelofibrosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2824-2824
Author(s):  
Aziz Nazha ◽  
Zeev Estrov ◽  
Jorge E. Cortes ◽  
Sherry Pierce ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
World Health ◽  
Cancer Center ◽  
Bone Marrow Fibrosis ◽  
Jak2 Mutation ◽  
Hematopoietic Stem ◽  
Md Anderson ◽  
The Impact ◽  
Marrow Fibrosis

Abstract Abstract 2824 Background: Myelofibrosis (MF) is a heterogeneous, hematopoietic stem cell malignancy characterized by abnormal proliferation of myeloid cells with varying maturity and function. Bone marrow fibrosis (BMF), which results from abnormal deposition of stromal reticulin and collagen fibers, plays a major role in the pathophysiology of MF. Objectives: To investigate the characteristics associated with the extent of BMF and its implications on the clinical manifestation, overall survival (OS), event-free survival (EFS), and transformation to acute leukemia in patients with primary or secondary myelofibrosis. Methods: We conducted a retrospective chart review analysis of 514 patients who were diagnosed with myelofibrosis according to World Health Organization criteria (353 patients with primary myelofibrosis, 82 with post polycythemia vera [Post-PV] MF, and 79 with post essential thrombocythemia [Post-ET] MF) and were referred to MD Anderson Cancer Center between February 2005 and December 2009. Results of the first bone marrow biopsy done at MD Anderson were reviewed. BMF was documented according to the European consensus grading system (MF 0–3), in which MF-3 is the most severe grade of fibrosis. Result: Of 514 patients, 7 (1%) had MF-0, 44 (9%) had MF-1, 171 (33%) had MF-2, and 292 (57%) had MF-3. Table 1 summarizes patient characteristics and outcomes by grade. Conclusion: Severe bone marrow fibrosis was associated with lower Hgb, lower WBC count, larger spleen and abnormal cytogenetics. There was no association between JAK2 mutation and the severity of BMF. The OS, EFS and transformation to leukemia were similar among patients with various degrees of fibrosis. Similar results were achieved in patients with primary, post-PV MF, and post-ET MF. This might explain the heterogeneity of the disease course and its prognosis. Longer follow-up is needed to further investigate the impact of BMF on OS, EFS and PFS. Disclosures: No relevant conflicts of interest to declare.

Bone Marrow Fibrosis In Patients With Multiple Myeloma: A New Prognostic Factor For Survival?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1946-1946 ◽  
Author(s):  
Tinna Hallgrimsdottir ◽  
Anna Porwit ◽  
Magnus Björkholm ◽  
Eva Rossmann ◽  
Hlif Steingrimsdottir ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
University Hospital ◽  
Bone Marrow Fibrosis ◽  
Significant Difference ◽  
The Difference ◽  
Marrow Fibrosis

Abstract Introduction Multiple myeloma (MM) is characterized by the proliferation of plasma cells in the bone marrow and a secretion of monoclonal immunoglobulins. Survival in MM is very variable and multiple factors are known to influence prognosis such as age, ISS stage, and genetic abnormalities. Fibrosis can be found in the bone marrow of MM patients but the literature reporting the incidence of fibrosis and its effect on prognosis is very limited. The purpose of this study was to estimate the incidence of bone marrow fibrosis in MM patients and its effect on survival. Materials and methods Data was collected at the Karolinska University Hospital in Solna, Sweden and information obtained from the hospital's records. We gathered information on all patients diagnosed with MM between 2003 and 2011. All bone marrow reports were reviewed and the presence of bone marrow fibrosis (evaluated using reticulin staining) at diagnosis was recorded. Fibrosis was graded as 1 (mild), 2 (significant) and 3 (advanced), in accordance with WHO 2008 criteria. Patients with fibrosis were paired with patients without fibrosis (matched by sex, birth year, and year of diagnosis). Survival comparing MM patients with and without fibrosis was evaluated using Kaplan-Meier estimate and Cox regression model. Results A total of 586 individuals, 327 males and 259 females, were diagnosed with MM at the Karolinska University Hospital, Solna during 2003 – 2011. Evidence of bone marrow fibrosis was noted in 223 (38%) patients at diagnosis, and 175 had fibrosis grade 1, 33 grade 2, and 15 grade 3. No significant difference was observed between males (N = 135) and females (N = 88) (p = 0.085). Mean age at diagnosis was significantly lower for patients with fibrosis (67.1 years) than in patients without fibrosis (69.7 years) (p = 0.013). Compared with paired patients without fibrosis (N = 217), patients with fibrosis had significantly worse survival (Figure), being 5.0 years vs. 4.4 years, respectively (relative risk (RR)=1.3, 95% confidence interval (CI) 1.00-1.70; p= 0.049). The difference was greatest in male patients and patients younger than 65 years at diagnosis. Survival was worse in patients with advanced fibrosis, 4.5 (95% CI 3.6-6.4) years for grade 1 fibrosis, and 3.0 (95% CI 1.6-NA) years for higher degree of fibrosis. Conclusion In this study, based on almost 600 patients with MM we show that bone marrow fibrosis is common at diagnosis (38%). Importantly, our findings show that the presence of fibrosis was associated with inferior survival. More studies are needed regarding the underlying causes for these findings, including treatment response, treatment-related complications and relation to other known prognostic factors. Disclosures: No relevant conflicts of interest to declare.

Significance of bone marrow fibrosis in multiple myeloma

Pathology ◽  
2007 ◽  
Vol 39 (5) ◽  
pp. 512-515 ◽  
Author(s):  
Rajiv Subramanian ◽  
Debdatta Basu ◽  
Tarun K. Dutta
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

Bone Marrow Fibrosis in Multiple Myeloma

1988 ◽  
Vol 90 (6) ◽  
pp. 753-753 ◽  
Author(s):  
A. Riccardi ◽  
G. Ucci ◽  
A. Coci ◽  
E. Ascari
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis
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