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

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.

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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

Cancer Medicine ◽

10.1002/cam4.3265 ◽

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

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Diagnosis and quantification of bone marrow fibrosis are significantly biased by the pre-staining processing of bone marrow biopsies

Histopathology ◽

10.1111/j.1365-2559.2005.02302.x ◽

2006 ◽

Vol 48 (2) ◽

pp. 133-148 ◽

Cited By ~ 10

Author(s):

G Buesche ◽

A Georgii ◽

H-H Kreipe

Keyword(s):

Bone Marrow ◽

Bone Marrow Fibrosis ◽

Bone Marrow Biopsies ◽

Marrow Fibrosis

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Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

Case Reports in Hematology ◽

10.1155/2020/4360926 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Ricardo D. Parrondo ◽

Vivek Roy ◽

Taimur Sher ◽

Victoria Alegria ◽

Asher A. Chanan-Khan ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Poor Prognosis ◽

Proteasome Inhibitors ◽

Salvage Chemotherapy ◽

First Line ◽

Immunomodulatory Agents ◽

Resistance To Therapy ◽

Line Setting ◽

Novel Agent

Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.

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

American Journal of Clinical Pathology ◽

10.1309/ajcpt5y2jriuucub ◽

2012 ◽

Vol 137 (6) ◽

pp. 870-878 ◽

Cited By ~ 12

Author(s):

Emina Babarović ◽

Toni Valković ◽

Sanja Štifter ◽

Ivana Budisavljević ◽

Irena Seili-Bekafigo ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis

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Selinexor: a first-in-class SINE compound for treatment of relapsed refractory multiple myeloma

Future Oncology ◽

10.2217/fon-2020-0054 ◽

2020 ◽

Vol 16 (19) ◽

pp. 1331-1350 ◽

Cited By ~ 3

Author(s):

Shambavi Richard ◽

Joshua Richter ◽

Sundar Jagannath

Keyword(s):

Multiple Myeloma ◽

Poor Prognosis ◽

Proteasome Inhibitors ◽

Resistance Mechanisms ◽

Mechanisms Of Action ◽

Epigenetic Alterations ◽

Oral Agent ◽

Immunomodulatory Agents ◽

Tumor Suppressor Proteins ◽

Functional Inactivation

The progression of multiple myeloma is accompanied by complex cytogenetic and epigenetic alterations that include mutation or functional inactivation of tumor suppressor proteins and overexpression of oncoproteins. Patients whose myeloma is refractory to the three major classes of drugs including immunomodulatory agents, proteasome inhibitors and anti-CD38 monoclonal antibodies have a very poor prognosis. Drugs with novel mechanisms of action that can bypass resistance mechanisms are sorely needed for this group of patients. Selinexor represents a novel, oral agent with an innovative mechanism of action that offers a significant therapeutic advance in this group of heavily treated patients. Moreover, this novel mechanism may provide additional options for patients with less refractory disease.

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PHF19 Promotes Drug Resistance through EZH2 Inactivation in Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4495.4495 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4495-4495 ◽

Cited By ~ 1

Author(s):

Tengteng Yu ◽

Lanting Liu ◽

Shuaishuai Zhang ◽

Mu Hao ◽

Lugui Qiu

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Proliferation ◽

Drug Resistance ◽

Western Blotting ◽

Poor Prognosis ◽

Post Treatment ◽

Bone Lesions ◽

Newly Diagnosed ◽

Polycomb Repressive Complex

Abstract Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by mass growth of clonal plasma cells in the bone marrow, the secretion of abnormal monoclonal immunoglobulins and lytic bone lesions. Although current therapies have improved the outcome of patients, MM remains an incurable disease with a high rate of relapse and refractory. The survival of MM patients ranged from less than one month to more than 10 years. MM cells survival are more dependent on bone marrow microenvironment which induced drug-resistance of anti-MM agents. Cytogenetic aberrations of MM cell, such as chromosomal translocation, deletion and amplification induced oncogenes activation and tumor suppressor genes inactivation. Furthermore, epigenetic changes, such as histone methylation, have been suggested as a mediation of chemotherapy resistance in several cancer types, including MM. PcG (Polycomb group) proteins are conserved transcriptional repressors and essential to regulate cell fate.There were two main families of chromatin-modifying complexes, PRC1 (Polycomb repressive complex 1) and PRC2-4. In Drosophila, PRC2 contains the H3K27 histone methytransferase E (Z) whose trimethylation activity towards PcG target genes is stimulated by PCL (polycomb-like) protein. Three PCL paralogues have been identified: PHF1, MTF2 and PHF19. In this study, we found out that PHF19 is overexpressed and was related with relapse and drug resistance in multiple myeloma. Materials and methods: Gene Expression Profile Assay (GEP) was conducted in sequential patient samples including newly diagnosed, post-treatment and relapsed. 51 newly diagnosed and relapsed paired samples, 19 newly diagnosed and post-treatment paired specimens, 9 patients have newly diagnosed, post-treatment and relapsed samples at different time points were elucidated in this study. MM relapsed and drug-resistance highly correlated genes were screened and the prognosis and survival analysis were conducted. Real time quantitative PCR (RQ-PCR) and Western blotting were used to analysis the expression of the gene in MM cell lines and MM patients. The candidate gene was overexpressed in MM cells by lentiviral infection. The cell proliferation and drug sensitivity of MM cells and proteins in correlated signaling pathways were detected. Results: GEP assay showed that 56 genes expression in MM resistant clones after treatment and relapse have significantly increased, with 20 genes closely associated with the poor prognosis. Among them, PHF19, a component of the Polycomb repressive complex 2 (PRC2) family,significantly increased in relapsed and refactory patients and myeloma cell lines.The progression-free survival (PFS) and overall survival (OS) were significantly shortened in MM patients with overexpressed PHF19. PHF19 overexpression (OE) promoted the proliferation and inhibited apoptosis of MM cells. The sensitivity to doxorubicin and vincristine was significantly reduced in the PHF19 OE cells. Western blotting showed that the phosphorylation of EZH2 was significantly increased in PHF19 OE cells, while H3K27me3 level was significantly down-regulated. Overexpressed PHF19 through activating NF-κB signaling pathway induced persistent expression of EZH2 and their downstream anti-apoptotic gene, such as IGF1, BCL2 and HIF1α, which induced cell proliferation and drug resistance. Thus targeting PHF19, inhibiting the phosphorylation of EZH2 and sustaining histone H3K27 methylation level may be a potential therapeutic target in relapsed or refractory myeloma patients. Conclusion s: PHF19 expression was obviously increased in MM relapse and drug resistance patients with poor prognosis. Inhibition PHF19 and counteraction EZH2 phosphorylation should be combined to improve chemotherapy induced hypermethylation of H3K27, which may be a new therapeutic strategies in relapsed or refractory myeloma. Disclosures No relevant conflicts of interest to declare.

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Incidental Discovery of Multiorgan Extramedullary Plasmacytomas in the Setting of Newly Diagnosed Multiple Myeloma and Delayed Hemolytic Transfusion Reaction

Case Reports in Hematology ◽

10.1155/2017/4531858 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4

Author(s):

Joselle Cook ◽

Steven Song ◽

Anthony Ventimiglia ◽

Carol Luhrs

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Proliferation ◽

Poor Prognosis ◽

Transfusion Reaction ◽

Newly Diagnosed ◽

Hemolytic Transfusion Reaction ◽

Delayed Hemolytic Transfusion Reaction ◽

Incidental Discovery ◽

Extramedullary Plasmacytomas

Extramedullary plasmacytomas (EMPs) are defined by the presence of clonal plasma cell proliferation outside of the bone marrow, portending an overall poor prognosis. This case highlights extramedullary plasmacytomas as an unusual presenting manifestation of multiple myeloma. Through incidental discovery during a delayed hemolytic transfusion reaction workup, EMPs were found in the liver, spleen, and possibly the lung. Though rare at presentation, this case emphasizes that the presence of EMPs should be considered at the outset as it not only impacts the treatment regimen for such patients but also considerably affects prognosis.

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Bone Marrow Biopsy and Aspirate Evaluation in 90 Patients with Essential Thrombocythemia Treated with PEG Interferon alpha-2b. Preliminary Results.

Blood ◽

10.1182/blood.v104.11.1523.1523 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1523-1523 ◽

Cited By ~ 4

Author(s):

L. Gugliotta ◽

S. Bulgarelli ◽

A. Tieghi ◽

S. Asioli ◽

G. Gardini ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Bone Marrow Biopsy ◽

Essential Thrombocythemia ◽

Bone Marrow Fibrosis ◽

Minor Response ◽

Bone Marrow Biopsies ◽

Hematological Response ◽

Second Year ◽

Marrow Fibrosis

Abstract Ninety patients with Essential Thrombocythemia (ET) where object of a phase II prospective multicentre study designed to evaluate efficacy, safety and tolerability of a two years treatment with PEG Interferon α-2b (PEG Intron, Schering Plough). The patients, 30 M and 60 F, 18–72 years old (median 45), observed in 16 Hematological Institutions of the Gruppo Italiano Malattie Mieloproliferative Croniche (GIMMC), received the ET diagnosis according to the PVSG criteria. At PEG Intron treatment start the patients showed: previous cytoreduction 97% (IFN α 31%), platelet count >1000 x 109/L 81%, splenomegaly 22%. At the end of the first year The PEG Intron starting dose of 25 μg/week resulted increased to a mean value of 55 μg/week and the Hematological Response (HR = Plts <500x109/L) was registered in 79% of the patients still on treatment. At the end of second year 65 patient still receiving PEG Intron (mean dose 31 μg/week) showed a maintenance of the HR (66%), a Partial Response (17%) and a Minor Response (17%). By utilizing the data included in the study CRFs we preliminarily evaluated the bone marrow biopsy and aspirate both performed at baseline, after 1 and 2 years in 89 and 86, 79 and 67, 57 and 50 patients, respectively. Data concerning the bone marrow biopsies after 1 year of treatment are reported: BONE MARROW BIOPSY BASELINE % 1 YR % 2 YRS % Cellularity increased 56 51 48 Granulopoiesis increased 51 54 39 Erytropoiesis increased 29 24 23 MK number increased 99 90 84 MK size increased 78 69 62 MK ploidy 54 51 42 MK dystrophy 52 56 59 Fibrosis mild 40 37 46 Fibrosis moderate 7 25 26 The increase of bone marrow fibrosis registered after one year (representative also of second year data) resulted not related to patient gender, age >45 years, platelet count >1000 x109/L, Hb <12 g/dL, splenomegaly, previous IFN treatment, PEG Intron dose >50 μg/week. In conclusion, the present study shows that in ET patients a two years PEG Intron treatment, able to induce and to maintain the Hematological Response in the majority of cases, is associated to a decrease of bone marrow cellularity, granulopoiesis, erytropoiesis, MK number, size and ploidy and, moreover, with an increase of MK dystrophy and of bone marrow fibrosis. These preliminary data on bone biopsy and aspirate will be object of a planned centralized reevaluation by a Panel of Pathologists and Clinicians.

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Evidence for Reduced Angiogenesis in Bone Marrow of Systemic Sclerosis Patients Immunohistochemetry and Computerized Imagine Analysis.

Blood ◽

10.1182/blood.v114.22.5126.5126 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5126-5126

Author(s):

Valentina Carrai ◽

Renato Alterini ◽

Riccardo Saccardi ◽

Irene Miniati ◽

Luigi Rigacci ◽

...

Keyword(s):

Bone Marrow ◽

Systemic Sclerosis ◽

Substantial Reduction ◽

Bone Marrow Fibrosis ◽

Bone Marrow Biopsies ◽

Angiogenic Potential ◽

Fibrotic Process ◽

The Mean ◽

Median Rate ◽

Marrow Fibrosis

Abstract Abstract 5126 Introdution Systemic sclerosis (SSc) involves the microcirculation, the immune system, and the connective tissue eventually leading to fibrosis. Vascular dysfunction is one of the earliest events in SSc pathogenesis: endothelial damage leads to a dysregulation of angiogenesis and a loss of capillaries. The consequent chronic ischemia provokes a diffuse sufference of the tissues with formation of ulcers. We analyzed BM biopsies in a series of patients undergoing HSCT in our Centre for severe, progressive SSc in order to clarify the association between modification bone marrow angiogenesis and clinical features of this disease. Materials and Methods The main clinical feature of the patients are following: modified Rodnan Skin Score was more than 8 in four patients; nailfold videocapillaroscopy was active in three patients; pulmonary arterial hypertension was upper limit only in two patients; carbon monoxide diffusing capacity was more than 40% in all the patients; high resolution computed tomography showed fibrosis or ground glass lesions in all the patients; topoisomerase I and antinuclear antibody was positive in all the patients. Only one patient showed arrhythmia. Eight SSc bone marrow biopsies were studied, compared with five bone marrow biopsies of non malignant controls. To evaluate angiogenesis, following monoclonal antibodies (MoAb) were used: VEGF, KDR, MMP-9, CD34. Bone marrow fibrosis was evaluated by silver impregnation for reticulum. To identify BM microvessel, anti-CD34 was used. Sections were observed at 400x magnification by two different blinded observers. To calculate the number of vessels, vascular mean area expressed in mm2, vascular percent mean area, perimeter and MVD, a multiparametric, semi-automatic computerized imagine analysis was employed. For each section, we evaluated eight consecutive areas and each area was 16001,92 mm2 (total area was 128015,36 mm2). The VEGF, MMP-9, KDR expression was evaluated as percentage of positive cells in a total of eight consecutive areas at 400x magnification. Results All patients showed a mean cellularity of 40% (SD 5.24, range 30-45%). In four patients bone marrow fibrosis was detected: two patients were classified as I° grade and two as II°grade. The bone marrow biopsy specimens from patients with SSc show a substantial reduction in vascularity. A multiparametric computerized analysis demonstrated significantly reduction of MVD in SSc cases. The mean MVD in SSc bone marrow was 712,63 (SD 392.03, range 124,98-1312,34) whereas in control specimens it was 1364,58 (SD 44.20, range 1312,34-1402,14). The mean number of vessels (p0.004) and percent vascular mean area are lower in sclerosis than controls (p0.0009). A significant increased expression of VEGF was observed. The median VEGF rate was 48,75 (range 30-85%) with expression ≥ 50% in half patients and in two patients with advanced SSc this expression was more than 70%. KDR expression was significantly lower in SSc bone marrow than in controls (p=0,003). The median KDR rate was 13,25% (range 1-40%) and 42% (range 40-45%) in sclerosis and controls respectively. In all cases the expression of MMP-9 was significantly lower than controls (p=0,0009) with median rate of 13,06% (range 1-25%) while median expression in controls was 30% (range 20-40%). Discussion We demonstrated in patient with SSc a reduction of bone marrow vascularity despite the stricking increase of a number of angiogenic factors. VEGF expression in SSc bone marrow is high in all cases with a double median rate compared to controls (48,75% vs 4,25%) while MVD is lower in sclerosis than controls (712,63 vs 1364,58). In regard to these alterations in our study we have observed a reduction of KDR and MMP-9. The overproduction of VEGF can generate a negative feedback to KDR while the low levels of MMP9 found in SSc bone marrow may be due to a hyperproduction of MMP inhibitors contributing to the reduction of bone marrow vascularity. In conclusion, our data demonstrate that in SSc the angiogenic potential of bone marrow is reduced, mirroring the systemic microvascular condition characterised by loss of capillaries and desertification despite the increase of VEGF. The amount of reticular fibers, detected in bone marrow, suggests that the fibrotic process may affect also the bone marrow contributing further to the reduction of angiogenic potential. Disclosures No relevant conflicts of interest to declare.

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