Extramedullary Disease In Patients Research Articles

Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes.

The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.

Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease.

Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.

S2556 Not Your Everyday Duodenal Ulcer: Massive GI Bleed Secondary to Extramedullary Plasma Cell Myeloma

Introduction: Plasma cell neoplasms are defined by a monoclonal proliferation of a single clone of immunoglobulin producing plasma cells. Extramedullary plasmacytomas are rare plasma cell dyscrasias that arise outside of the bone marrow, most commonly in the head or neck. Extramedullary multiple myeloma (MM) involves the gastrointestinal (GI) tract in < 5% of cases, and often presents with non-specific symptoms. Here we discuss one such case of uncommon GI involvement of a plasma cell tumor. Case Description/Methods: A 62-year-old male with active lambda light chain MM presented with global fatigue, melena, and hematemesis. Initial vitals included blood pressure 90/62 mmHg and heart rate 95 bpm, with labs revealing normocytic, normochromic anemia with hemoglobin (Hgb) 3.9 g/dL. He was transfused 4 units of packed red blood cells with an appropriate Hgb response to 8.6 g/dL. Immediate esophagogastroduodenoscopy (EGD) found a nonbleeding cratered duodenal ulcer with adherent clot, not amenable to endoscopic intervention (Figure a). He remained hemodynamically stable, and given the lack of continued evidence for GI bleed over the following days, vascular interventional radiology (VIR) embolization was deferred. Prior to discharge, patient was having light brown stools with no active signs of bleeding. He was discharged on pantoprazole, with plan for repeat Hgb within 1 week and repeat EGD in 1 month. Unfortunately, patient was readmitted in cardiac arrest within 24 hours of discharge, with oropharyngeal blood and melena. Resuscitation attempts were unsuccessful. Autopsy determined cause of death to be extramedullary GI disease, with plasma cell infiltration and resultant transmural duodenal ulceration involving the gastroduodenal artery having caused acute hemorrhage (Figureb-c). Discussion: While incredibly rare, due to high mortality and swift progression it is crucial for providers to consider GI extramedullary disease in patients with a history of plasma cell neoplasm who present with upper GI bleed. This holds especially true in cases where the identified lesion is not amenable to endoscopic therapy. Though our patient underwent appropriate resuscitation and evaluation with apparent resolution of symptoms, he died within a day of discharge. Further workup including advanced imaging studies, such as positron emission tomography/computed tomography (PET-CT), or consideration of VIR embolization (deferred here given clinical cessation of bleeding) could be lifesaving.Figure 1.: (a) Ulcer at the duodenal bulb, completely obstructing duodenum. (b) Gastroduodenal ulcer (brackets) with eroded gastroduodenal artery (arrow). (c) H&E, 2X: artery with overlying fibrin cap (1), and surrounding pancreatic parenchyma (2) with plasma cell infiltrate (3).

Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease.

Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.

Diagnostic role of 11C-methionine PET/CT in patients with multiple myeloma and other plasma cell malignancy: a literature review

In patients with plasma cell malignancy (multiple myeloma and plasmacytoma), whole-body low-dose computed tomography, magnetic resonance imaging, and 18F-FDG PET/CT are widely applied and suggested by international guidelines to assess the disease extension. Recently, 11C-methionine PET/CT has proven to be promising in those patients compared to other diagnostic techniques. We aimed to review current literature on the state of the art of 11C-methionine PET/CT in patients with plasma cell malignancy. PubMed/MEDLINE database was screened to find articles regarding the role of 11C-methionine PET/CT in plasma cell malignancy. Terms (PET OR positron emission tomography) AND methionine AND myeloma were used. Among 23 studies initially retrieved, 7 (overall 258 patients) were included. In all except two studies, 11C-methionine PET/CT was related to 18F-FDG PET/CT (of whom one also with 11C-4′-thiothymidine PET/CT), one study to 11C-choline PET/CT and one compared multiple myeloma and control patients, both having 11C-methionine scan. Overall, 11C-methionine PET/CT resulted able to detect a higher number of positive patients as well as more bone lesions than 18F-FDG and 11C-choline (detection rate: 75.6–90.7%, 55.0–76.7%, and 73.7%, respectively). A stronger correlation with bone marrow histological results was found for 11C-methionine than for 18F-FDG and 11C-choline PET/CT scans. Although additional studies are needed to validate the role of 11C-methionine PET/CT, it seems to be a safety and effective tool in identification of medullary and extramedullary disease in patients with plasma cell malignancy.

Implications of detecting serum monoclonal protein by MASS-fix following stem cell transplantation in multiple myeloma.

Measurable residual disease (MRD) assessment by marrow-based next-generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false-negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MASS-FIX). Of all 61 complete responders who were NGF-negative for MRD, around day-100 post ASCT, 59% were MASS-FIX-positive. At median follow-up of 26months, 69% of MASS-FIX(+)/NGF(-) patients were alive and progression-free versus 96% of MASS-FIX(-)/NGF(-) patients, P=0·02. MASS-FIX, a simple peripheral blood-based assay complements marrow-based NGF to accurately prognosticate patients with myeloma.

Utility and prognostic value of 18F-FDG PET/CT scan in patients with newly diagnosed multiple myeloma.

8023Background: Positron emission tomography–Computed tomography (PET/CT) can identify bony lesions, assess disease burden and detect extramedullary disease in patients with newly diagnosed multipl...

Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT

We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (≥2; P<0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: P=0.86, and extramedullary organ: P=0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival (P=0.07) while single organ involvement was significantly worse (P=0.001). Multiple organ sites were associated with worse outcome (P<0.001 and P=0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (P=0.13 for both).

IL17A and IL23R gene polymorphisms affect the clinical features and prognosis of patients with multiple myeloma.

Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A -197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A -197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A -197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL-17 and IL-23R polymorphisms may affect severity, bone lesions, and extra-medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.

Extramedullary disease in patients with acute myeloid leukemia assessed by (18)F‐FDG PET

Prevalence of extramedullary disease (EMD) in acute myeloid leukemia (AML) at the time of diagnosis is unknown. Previous estimates range from 2.5% to 30.5% and are usually based on clinical examination. This may cause an under diagnosis of EMD as not all extramedullary manifestations are easily detectable. Few recent studies have used positron emission tomography (PET) scans for diagnosing EMD in patients AML. During a 9-month period, newly diagnosed patients with AML who were candidates for intensive chemotherapy were 18F-Fluoro-deoxy-glucose (FDG) PET-scanned prior to induction treatment. We compared the prevalence of EMD diagnosed by PET scans and by clinical examination. Subsequent PET scans following induction chemotherapy were performed for response evaluation of EMD. Twenty-six patients were included in the study. 18-F-FDG PET scans revealed more than twice as many patients with EMD than found by clinical examination (65% vs. 31%). PET demonstrated 55 EMD lesions compared with 15 diagnosed by clinical examination. In general, the responses of EMD detected by PET scans were concordant with the bone marrow responses assessed by pathology examination. 18-F-FDG PET is a useful tool for diagnosing EMD in AML and for assessing treatment responses of EMD in AML.

Cytogenetics of extramedullary manifestations in multiple myeloma

Extramedullary disease in patients with multiple myeloma is a rare event, occurring mostly in advanced disease or relapse. Outcome is poor and prognostic factors predicting the development of extramedullary disease have not been defined. We investigated cytogenetic alterations of myeloma cells in different extramedullary manifestations by adapting the fluorescence in situ hybridization (FISH) technique in combination with cytoplasmic immunoglobulin staining to study the cytogenetics of plasma cell tumours on paraffin embedded material. Thirty six patients were investigated: 19 with extramedullary disease, 11 with skeletal extramedullary disease and six with solitary extramedullary plasmacytoma. The first two groups showed the following results: del(17p13) 32% vs. 27%, del(13q14) 35% vs. 27%, MYC-overrepresentation 28% vs. 18% and t(4;14) 37% vs. 18%. We detected an overall higher incidence of del(17p13) in both groups compared to data from bone marrow samples of multiple myeloma reported to date (range 7-16%). The solitary extramedullary plasmacytomas presented overall less cytogenetic aberrations than the other groups. Most important, three patients with extramedullary disease and one with skeletal extramedullary disease presented different FISH findings in the extramedullary tumour compared to their bone marrow plasma cells. del(17p13), occurring additional in three of four cases, seems a strong marker for extramedullary progression of myeloma.

Lenalidomide Is Effective for the Treatment of Bortezomib-Resistant Extramedullary Disease in Patients With Multiple Myeloma: Report of 2 Cases

Introduction Extramedullary (EM) disease of multiple myeloma (MM) may occur either at diagnosis or during the course of the disease. The presence of EM disease at any time in the course of disease is associated with significantly shorter overall survival and progression-free survival. There are few studies focusing on the treatment of patients with MM and EM disease. Bortezomib has been reported to be the preferred choice of treatment for MM with EM disease. Lenalidomide is a more potent immunomodulatory drug (IMiD) that has made significant impact in the management of patients with relapsed/refractory MM. However there is little information regarding the effect of lenalidomide on EM disease in patients with MM. Here we report 2 cases of MM with bortezomib-resistant EM disease that were successfully treated with lenalidomide and dexamethasone.

Correlation among DCE‐MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma

Correlation among DCE‐MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma

High Plasma Lysyloxidase Concentration Is Associated with Inferior Outcome and Extramedullary Disease in Patients with Acute Myeloid Leukemia

Abstract 935 Background:Previous work of our group led to the identification of several differentially regulated microRNAs in patients with acute myeloid Leukemia (AML) harboring a mutation of the Nucleophosmin 1 gene (NPM1) – amongst these was miR-149 which is reported to regulate Lysyloxidase (LOX). LOX is described as necessary for premetastatic niche formation in various epithelium-derived malignancies and its expression level correlates with distant metastasis free- and overall survival (OS). Animal models have demonstrated that inhibition of LOX sufficiently eliminates metastasis. Therefore, we were interested to investigate whether the LOX-concentration in AML plasma samples is of prognostic relevance and whether it is associated with certain characteristics such as extramedullary disease.Patients and methods: Plasma samples of 156 patients with AML (n=63 with reported extramedullary manifestation and n=93 without reported extramedullary manifestation; age 17–60 years) who were treated within the prospective AML2003 trial (NCT00180102) of the SAL study group were analyzed for LOX concentration using the Amplite Fluorimetric LOX Assay Kit (AAT Bioquest, Sunnyvale, CA, USA). All fluorescence reads were performed in triplicate with recombinant human LOXL2 (R&D Systems, Minneapolis, MN, USA) for standard curve estimation. Signals were read by a fluorescence microplate reader at Ex/Em 540/590 nm. Supernatant of the NPM1 mutated AML cell line OCI/AML3 served as internal control. LOX values were compared for statistical significance using the two tailed t test for continuous variables and chi-square test for dichotomized variables. The method of Kaplan-Meier was used to estimate OS and event-free survival (EFS). Survival distributions were compared using the log-rank test. Results:The mean LOX concentration for all patients was 58 ng/mL (standard error of the mean (SEM) 12). Dichotomizing at the mean LOX level (n=29 patients > mean = LOX-high; n=126 ≤ mean = LOX-low), survival comparing LOX-high and LOX-low patients in a univariate analysis revealed a 3-year OS of 22% (95% CI: 6–39%) and 53% (95% CI: 43–62%, p=.004), and 2-year EFS of 14% (95% CI: 2–28%) and 43% (95% CI: 34–52%, p=.001), respectively. In the Lox-high group 79% of patients exposed extramedullary AML compared to 32% in the Lox-low group, p<0.001. The mean LOX concentration in AML patients with extramedullary disease (n=63) was 131 ng/mL (SEM 26) as compared to 9 ng/mL (SEM 4) in patients without reported extramedullary AML manifestation (n=93), p<0.001. Conclusions:This analysis is the first study so far investigating the role of LOX in AML. High LOX levels are associated with statistically significant worse OS and EFS in AML patients. The positive correlation between high LOX levels and extramedullary AML suggests a potentially pathophysiological relevant mechanism involved in extramedullary homing and growth of AML and may offer further insights into AML biology. Future studies will need to address the functional modalities of how LOX is regulated and how it contributes to migratory and adhesion properties in AML. Disclosures:No relevant conflicts of interest to declare.

Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma

We studied 174 consecutive patients with relapsed refractory multiple myeloma (MM) enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone at Mayo Clinic. Extramedullary disease (EMD) was present at the time of trial entry in 7.5% (13 of 174 patients). The rate of EMD in the first 3 years following diagnosis of MM was 3%. The response of EMD to pomalidomide plus low-dose dexamethasone included two complete and two partial responses among the 13 patients (response rate, 31%). Overall survival measured from trial entry was significantly shorter for patients with treatment-emergent EMD compared with those who did not have EMD, (median 16 months versus not reached, P=0.002).

Incidence of extramedullary disease in patients with acute promyelocytic leukemia: a single-institution experience

Using current treatment regimens, over 90% of patients with acute promyelocytic leukemia will achieve complete remission (CR). However, approximately 30% of these patients will relapse, including a small proportion who will develop extramedullary disease (EMD). In this study, we investigated the incidence of EMD in 263 patients with APL who were treated at our institution from January 1990 to May 2008. With a median follow-up of 31 months (range 2 days-203 months), 8 (3%) patients developed EMD. The most commonly affected site was the central nervous system (n = 7). Before developing EMD, one patient had achieved CR with a chemotherapy-only regimen, six patients had achieved CR with all-trans-retinoic acid (ATRA)-based regimens, and one patient had achieved CR with an ATRA plus arsenic trioxide (ATO)-based regimen. The EMD conferred a poor prognosis; five patients died within 4 months of developing EMD. The molecular status did not predict EMD; four patients had a negative PCR for the PML-RARA transcripts prior to relapse with EMD. In conclusion, the incidence of EMD is low. We were unable to identify any specific factors that could predict the development of EMD.