Soft-Tissue Plasmacytomas in Multiple Myeloma: Incidence, Mechanisms of Extramedullary Spread, and Treatment Approach

2011 ◽  
Vol 29 (28) ◽  
pp. 3805-3812 ◽  
Author(s):  
Joan Bladé ◽  
Carlos Fernández de Larrea ◽  
Laura Rosiñol ◽  
María Teresa Cibeira ◽  
Raquel Jiménez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Soft Tissue ◽  
Chemokine Receptors ◽  
Experimental Studies ◽  
Disease Recurrence ◽  
Myeloma Cell ◽  
Response To Therapy ◽  
High Dose ◽  
Prognostic Impact

We provide an overview on soft-tissue extramedullary plasmacytomas (EMPs) in multiple myeloma (MM). We reviewed the incidence of EMPs in MM, myeloma bone marrow homing, possible mechanisms of extramedullary spread, and prognosis and response to therapy. The incidence of EMPs is 7% to 18% at MM diagnosis and up to 20% at relapse. The current notion that EMPs are more frequent after treatment with novel agents remains to be proven, especially considering that different patterns of disease recurrence can emerge as patients live longer in the era of novel drugs. Bone marrow genetic abnormalities are not associated with extramedullary spread per se, which also suggests that microenvironmental interactions are key. Possible mechanisms of extramedullary spread include decreased adhesion molecule expression and downregulation of chemokine receptors. EMPs usually show plasmablastic morphology with negative CD56 expression. High-dose therapy with autologous stem-cell transplantation (ASCT) can overcome the negative prognostic impact of extramedullary disease in younger selected patients. EMPs do not typically respond to thalidomide alone, but in contrast, responses to bortezomib have been reported. The incidence of EMPs in patients with MM is high and is associated with poor outcome in patients treated conventionally. A potential first-line treatment option seems to be a bortezomib-containing regimen followed by ASCT, whenever possible. Experimental studies on the mechanisms of myeloma cell adhesion, myeloma growth at extramedullary sites, and drug sensitivity are priorities for this area of continuing therapeutic challenge.

scholarly journals Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4914-4923 ◽  
Author(s):  
Karène Mahtouk ◽  
Dirk Hose ◽  
Pierre Raynaud ◽  
Michael Hundemer ◽  
Michel Jourdan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Myeloma Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Polymorphonuclear Cells ◽  
Heparin Binding ◽  
Gene Encoding ◽  
Affymetrix Microarrays

Abstract The heparan sulfate (HS) proteoglycan, syndecan-1, plays a major role in multiple myeloma (MM) by concentrating heparin-binding growth factors on the surface of MM cells (MMCs). Using Affymetrix microarrays and real-time reverse transcriptase–polymerase chain reaction (RT-PCR), we show that the gene encoding heparanase (HPSE), an enzyme that cleaves HS chains, is expressed by 11 of 19 myeloma cell lines (HMCLs). In HSPEpos HMCLs, syndecan-1 gene expression and production of soluble syndecan-1, unlike expression of membrane syndecan-1, were significantly increased. Knockdown of HPSE by siRNA resulted in a decrease of syndecan-1 gene expression and soluble syndecan-1 production without affecting membrane syndecan-1 expression. Thus, HPSE influences expression and shedding of syndecan-1. Contrary to HMCLs, HPSE is expressed in only 4 of 39 primary MMC samples, whereas it is expressed in 36 of 39 bone marrow (BM) microenvironment samples. In the latter, HPSE is expressed at a median level in polymorphonuclear cells and T cells; it is highly expressed in monocytes and osteoclasts. Affymetrix data were validated at the protein level, both on HMCLs and patient samples. We report for the first time that a gene's expression mainly in the BM environment (ie, HSPE) is associated with a shorter event-free survival of patients with newly diagnosed myeloma treated with high-dose chemotherapy and stem cell transplantation. Our study suggests that clinical inhibitors of HPSE could be beneficial for patients with MM.

scholarly journals Multiple Myeloma Cell Defects Erythropoiesis and Results Anemia Via High Level of CCL3 in Bone Marrow Microenvironment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 55-55
Author(s):  
Lanting Liu ◽  
Zhen Yu ◽  
Hui Cheng ◽  
Weiwei Sui ◽  
Shuhui Deng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Mouse Model ◽  
Conflicts Of Interest ◽  
Erythroid Differentiation ◽  
Myeloma Cell ◽  
Cell Infiltration ◽  
Prognostic Impact ◽  
Multiple Myeloma Cell ◽  
Increased Risk

Background: Anemia is the most common complication of myeloma, and is associated with worse clinical outcomes including diminished quality of life, and increased risk of morbidity and mortality. Bone marrow (BM) is the main location of the growth and differentiation of HSPCs. Although marrow replacement by myeloma cell is widely considered a mechanistic rationale for myeloma-related anemia, however the molecular mechanism has not been fully understood. Methods: The clinical characteristics and the prognostic impact of myeloma-related anemia were investigated in patients with multiple myeloma. The erythroid differentiation defects of HSPCs were examined by flow cytometry and colony-formation assay. RNA-seq were conducted to clarify the different gene expression and the signaling pathway in HSPCs. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. 5TGM1 murine myeloma mouse model was utilized. Results: The data of our large cohort of 1,363 myeloma patients demonstrated that 84.4% of patients had anemia (Hgb<120 g/L), more than 50% of patients had moderate (Hgb=90-120 g/L) or severe anemia (Hgb=60-90 g/L) at the time of diagnosis. Anemia positively correlated with myeloma cell infiltration in the BM and worse outcome of patient. Patient sample and mouse model indicated that the quantity and the erythroid differentiation of HSPCs were affected by myeloma cell infiltration. The number of HPCs was significantly declined in the BM of myeloma, and negatively correlated with the quantity of tumor cells. The master regulator of erythropoiesis GATA1 and KLF1, was obviously down-regulated in myeloma HSPCs cells. However, the gene of chemokine CCL3 was significantly upregulated. Elevated CCL3 in the BM plasma of myeloma further inhibited erythropoiesis of HSPCs through activation of CCL3/CCR1/p38 signaling, and suppressed the expression of GATA1. CCR1 antagonist treatment effectively inhibits CCL3 activity and recovered the expression of GATA1 and rescued the erythropoiesis of HSPCs. Conclusions: myeloma cell infiltration causes the elevation of CCL3 in microenvironment that suppresses the erythropoiesis of HSPCs and results in anemia by downregulating the level of GATA1 of HSPCs. Thus, our study indicates targeting CCL3 would be a potential strategy against anemia and improvement the survival of myeloma patient. Disclosures No relevant conflicts of interest to declare.

scholarly journals Heparanase Influences Expression and Shedding of Syndecan-1, and Its Expression by the Bone Marrow Environment Is a Bad Prognostic Factor in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3502-3502 ◽  
Author(s):  
Karene Mahtouk ◽  
Dirk Hose ◽  
Thierry Reme ◽  
Michael Hundemer ◽  
Michel Jourdan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Mrna Expression ◽  
Extracellular Enzymes ◽  
Staging System ◽  
Myeloma Cell ◽  
High Dose Chemotherapy ◽  
Biologically Active ◽  
High Dose ◽  
High Level

Abstract The heparan sulfate (HS) proteoglycan (PG) syndecan-1 plays a major role in multiple myeloma (MM), in part by concentrating HS-binding growth factors on the surface of MM cells (MMC). The function of HSPG is regulated by extracellular enzymes that modulate the structure of HS-chains. One such enzyme is heparanase (HPSE), an endo-glucuronidase that cleaves HS chains at only a few sites, resulting in fragments of 10–20 sugar units long that are biologically active. Using Affymetrix microarrays and real-time RT-PCR, we showed that the gene encoding HPSE was expressed by 11/19 myeloma cell lines (HMCLs). In HSPE-positive HMCLs, syndecan-1 mRNA expression and production of soluble syndecan-1, unlike expression of membrane syndecan-1, were significantly increased. Downregulation of HPSE by HPSE-siRNA resulted in a decrease of syndecan-1 mRNA expression and soluble syndecan-1 production, without affecting membrane syndecan-1. Contrary to HMCLs, HPSE was expressed in only 4/39 primary MMC samples at a low level, whereas it was highly expressed in 36/39 whole bone marrow (WBM) microenvironment samples. In the latter, HPSE was expressed at a median level in polynuclear cells and T cells, at high level in monocytes and osteoclasts, and it was not expressed in BM stromal cells. In order to investigate the connection of clinical parameters with HPSE gene expression, 30/39 myeloma patients treated with high dose chemotherapy and autologous stem cell transplantation where classified into two groups: 15 patients with the lowest or the highest HPSE expression in the WBM. The HPSEhigh group had an increased percentage of patients with elevated C-reactive protein and β2-microglobulin. According to the international staging system (ISS), the HPSEhigh group included a significant higher frequency of patients with stage III MM and a lower frequency of patients with stage I MM. HPSEhigh patients had a shorter event free survival (EFS) (p=.017) and overall survival (OAS) (p=.023) than HPSElow patients. Classifying these 30 patients into two groups according to HPSE expression in MMC did not yield to any EFS or OAS significant differences between the two groups. Altogether, those data provide evidence that HPSE not only modulate syndecan-1 activity through the cleavage of HS chains but also regulates syndecan-1 mRNA expression and shedding. We report for the first time that the expression of a gene in the BM, i.e. HSPE, is an indicator of poor prognostic for MM patients. Therefore, HPSE inhibitors like PI-88, which is currently in clinical trial, will be of interest for the treatment of patients with MM.

Bone Morphogenic Protein 6: A Prognostic Factor Expressed by Normal Plasma Cells and Multiple Myeloma Cells Inhibiting Their Proliferation and Angiogenesis Induction

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2701-2701
Author(s):  
Anja Seckinger ◽  
Tobias Meißner ◽  
Jérôme Moreaux ◽  
Hartmut Goldschmidt ◽  
Axel Benner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Cell Lines ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Myeloma Cells

Abstract BACKGROUND: Pathogenesis of multiple myeloma is partly attributed to an aberrant expression of proliferation-, pro-angiogenic and bone-metabolism modifying factors by malignant plasma-cells. AIM. Given the long and variable time-span from first diagnosis of early-stage plasma-cell dyscrasias to overt myeloma and the low proliferation rate of malignant plasma-cells, we hypothesize these to concomitantly express a novel class of anti-proliferative factors of potential prognostic relevance. Here, bone morphogenic proteins (BMPs) represent possible candidates, as they inhibit proliferation, stimulate bone formation, and have an impact on the survival of cancer patients. PATIENTS AND METHODS. We assessed expression of BMPs and its receptors by Affymetrix DNA-microarrays (n=434) including CD138-purified primary myeloma-cell-samples, normal bone-marrow plasma-cell-samples, polyclonal plasmoblasts-samples, human myeloma-cell-lines (HMCL), and whole bone-marrow. Presence and differential gene expression was determined by PANP-algorithm and empirical Bayes statistics. Event-free (EFS) and overall survival (OAS) were investigated for the 168 patients undergoing high-dose chemotherapy (HM-group) using Cox’s proportional hazard model. Findings were validated using the same strategy on an independent group of 345 patients from the Arkansas-group. For validation, quantitative real-time PCR and flow cytometry were performed. In vitro induction of angiogenesis was assessed using the AngioKit-assay. Effect of BMP6 on proliferation of HMCL was assessed by 3H-thymidine uptake. RESULTS. BMP6 is the only BMP expressed by normal- (13/14 samples) and malignant plasma-cells (228/233 samples). It is significantly lower expressed in proliferating non-malignant plasmablastic cells and human myeloma cell-lines. In vitro, BMP6 significantly inhibits proliferation of myeloma-cell-lines with an IC50 ranged from 0.08–2.15μg/ml, survival of primary myeloma-cells, and in vitro tubule formation down to the level of the negative control. High BMP6-expression in malignant plasma cells delineates significantly superior overall-survival for patients undergoing high-dose chemotherapy in both independent series of patients (n=168, P=.02 and n=345, P=.03, respectively, see below). CONCLUSION. With BMP6 we report for the first time the autocrine expression of a prognostically relevant anti-angiogenic and anti-proliferative factor and its receptors by normal and malignant plasma-cells. Figure Figure

scholarly journals Long-Lasting Remissions for Myeloma Patients on Daratumumab Therapy from the GEN501 and GEN503 Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3308-3308
Author(s):  
Agoston Gyula Szabo ◽  
Monique C Minnema ◽  
Hareth Nahi ◽  
Torben Plesner
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Response To Therapy ◽  
Whole Body ◽  
Trial Participation ◽  
High Dose ◽  
Refractory Multiple Myeloma ◽  
Best Response ◽  
Line Of Therapy

Abstract Introduction The first two trials to test the activity of daratumumab (DARA) in relapsed/refractory multiple myeloma (MM) were GEN501 (DARA monotherapy) and GEN503 (DARA in combination with lenalidomide [LEN] and dexamethasone [DEX]). GEN501 enrolled 104 participants from 2008 and GEN503 enrolled 45 participants from 2012. GEN501 has been completed; GEN503 is active but has finished accrual. We are reporting on ten patients that are still responding to DARA therapy, several years after their inclusion in the GEN501 and GEN503 trials. Methods Ten patients were included from three participating centers in Denmark, The Netherlands and Sweden. DARA therapy had to be continuous from the initiation of trial participation with no evidence of progressive disease. Data were collected retrospectively from patient charts. Clinical characteristics, ISS and FISH results were assessed at the time of diagnosis. Lines of myeloma therapy prior to inclusion in GEN501 or GEN503 were reviewed; duration of therapy, time to next therapy (TNT) and response to each of the prior lines of therapy were determined. Results of minimal residual disease (MRD) assessments were reviewed. Results Ten patients (six men, four women) were identified, three from GEN501 and seven from the GEN503. Four out of seven patients in GEN503 stopped LEN and DEX treatment due to side effects, but all ten patients are still treated with DARA intravenously every four weeks. Patients were diagnosed with MM between 2005 and 2012. The median age at diagnosis was 59 years (range 49-62). Seven patients had IgG-kappa, two had kappa light-chain only and one patient had IgG-lambda M-protein. Nine patients had anemia, eight had bone disease, three had renal insufficiency and one had hypercalcemia at diagnosis. ISS was available in nine patients. Three patients had ISS I, five had ISS II and one had ISS III. FISH at diagnosis was available in eight patients; none of which had high-risk cytogenetics, defined as the presence of either del 17p, t(4;14) or t(14;16). The prior lines of therapy are summarized in Table 1. The median number of prior lines of therapy was 3 (range 1-5). Nine patients had received high-dose melphalan with autologous stem cell transplantation; one of these was a tandem autologous transplantation. All patients had been treated with bortezomib; seven patients had been treated with LEN. Three patients were refractory to bortezomib; two were refractory to LEN. The best response to any prior line of therapy was CR in three, VGPR in two, PR in four patients and PD in one patient. The median TNT was 37 months (range 2-68) for the first (n=10), 11 months (range 1-63) for the second (n=7) and 29 months (range 1-55) for the third (n=5) prior line of therapy. One patient had been treated with five prior lines of therapy; the TNT for the fourth and fifth lines were 22 months each. DARA therapy and MRD results are summarized in Table 2. Patients were enrolled in GEN501 or GEN503 between 2013 and 2015. The median time from diagnosis to the start of DARA therapy was 57 months (range 12-168). The best response to therapy was sCR in eight patients, CR in one patient and VGPR in one patient. The median duration of DARA therapy was 49 months (range 39-62). Eight of ten patients achieved a longer response to DARA therapy with or without LEN and DEX than to any previous regimen. Bone marrow MRD assessments were carried out by flow-cytometry between 2014 and 2018 in all patients. The sensitivity of the used assay was 10-6 in two, 10-5 in three and 10-4 in five patients. Eight subjects were bone marrow MRD-negative and two subjects were MRD-positive at a sensitivity of 10-4 and 10-5, respectively. Imaging MRD assessments were carried out in eight patients between 2017 and 2018. PET-CT was carried out in all eight patients; diffusion-weighted whole-body MRI was carried out in five patients. All patients were imaging MRD-negative. Conclusions Continuous DARA treatment, either as monotherapy or combined with LEN and DEX can achieve MRD-negative disease and unprecedented long-lasting remissions in select patients with relapsed or refractory multiple myeloma in the absence of high-risk cytogenetics. Disclosures Minnema: Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Servier: Consultancy. Plesner:Celgene: Other: Independent Response Assessment Comittee; Janssen: Consultancy.

scholarly journals PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 164
Author(s):  
Federica Costa ◽  
Valentina Marchica ◽  
Paola Storti ◽  
Fabio Malavasi ◽  
Nicola Giuliani
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Survival ◽  
Immune Suppression ◽  
Metabolic Pathways ◽  
Therapeutic Strategy ◽  
Myeloma Cell ◽  
Immune Microenvironment ◽  
Potential Use

The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.

scholarly journals Establishment of Cell Lines from Both Myeloma Bone Marrow and Plasmacytoma: SNU_MM1393_BM and SNU_MM1393_SC from a Single Patient

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Youngil Koh ◽  
Woo-June Jung ◽  
Kwang-Sung Ahn ◽  
Sung-Soo Yoon
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Cultured Cells ◽  
Clonal Evolution ◽  
Myeloma Cell ◽  
Mouse Bone Marrow ◽  
Single Patient ◽  
U266 Cell

Purpose.We tried to establish clinically relevant human myeloma cell lines that can contribute to the understanding of multiple myeloma (MM).Materials and Methods.Mononuclear cells obtained from MM patient’s bone marrow were injected via tail vein in an NRG/SCID mouse. Fourteen weeks after the injection, tumor developed at subcutis of the mouse. The engraftment of MM cells into mouse bone marrow (BM) was also observed. We separated and cultured cells from subcutis and BM.Results.After the separation and culture of cells from subcutis and BM, we established two cell lines originating from a single patient (SNU_MM1393_BM and SNU_MM1393_SC). Karyotype of the two newly established MM cell lines showed tetraploidy which is different from the karyotype of the patient (diploidy) indicating clonal evolution. In contrast to SNU_MM1393_BM, cell proliferation of SNU_MM1393_SC was IL-6 independent. SNU_MM1393_BM and SNU_MM1393_SC showed high degree of resistance against bortezomib compared to U266 cell line. SNU_MM1393_BM had the greater lethality compared to SNU_MM1393_SC.Conclusion.Two cell lines harboring different site tropisms established from a single patient showed differences in cytokine response and lethality. Our newly established cell lines could be used as a tool to understand the biology of multiple myeloma.

166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2684-2691 ◽  
Author(s):  
Sergio Giralt ◽  
William Bensinger ◽  
Mark Goodman ◽  
Donald Podoloff ◽  
Janet Eary ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
High Dose ◽  
Two Phase ◽  
Hematopoietic Stem

Abstract Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation. (Blood. 2003;102:2684-2691)

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

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

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

scholarly journals Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4331-4340 ◽  
Author(s):  
Dirk Hose ◽  
Thierry Rème ◽  
Tobias Meissner ◽  
Jérôme Moreaux ◽  
Anja Seckinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Aberrations ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Aurora Kinase ◽  
Myeloma Cell ◽  
High Dose ◽  
Aurora A ◽  
Myeloma Cells

Abstract Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.

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