Clinical Study of Fludarabine, Mitoxantrone, and Dexamethasone in the Treatment of Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5187-5187
Author(s):  
Shao-Kai Luo ◽  
Juan Li ◽  
Wen-De Hong ◽  
Ying Zhao ◽  
Xiu-Zhen Tong
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Study ◽  
Serum Calcium ◽  
Post Treatment ◽  
High Recurrence Rate ◽  
Treatment Level ◽  
Myeloma Cells ◽  
Number Of Patients ◽  
Pre Treatment

Abstract BACKGROUND & OBJECTIVE: Until today, multiple myeloma is still an incurable malignancy by conventional therapy; it has low complete remission rate and high recurrence rate. Recurrence or relapse of the disease is almost inevitable for most of the patients after several cycles of combined chemotherapy. A safe and effective therapy for the treatment of relapsed and refractory multiple myeloma is urgently needed in clinical practice. This clinical study was designed to compare the safety and efficacy of the fludarabine-based regimen (fludarabine, mitoxantrone and dexamethasone [FMD]) with that of pirarubicin, vincristine and dexamethasone (VAD) in refractory or relapsed multiple myeloma. METHODS: The clinical data were retrospectively analyzed. The following indices were assessed before, during, and after the treatment in FMD-arm and VAD-arm: the partial remission (PR) rate, overall response (OR) rate, time to achieve PR, the number of patients and time to achieve the following: a decline in the serum M-component of more than 50% of the pre-treatment value, the ratio of myeloma cells in bone marrow drop to less than 50% of the pre-treatment value, the ratio of myeloma cells in bone marrow drop to less than 5% or drop more than 80% than pre-treatment level, the hemoglobin level increased more than 20 g/L, the white blood cell and platelet count of the peripheral blood, serum calcium, creatinine, β2-microglobin and ALT level, adverse events. RESULTS: The PR rate and OR rate are significantly higher in the FMD-arm than in the VAD-arm (PR rates were 46.2% vs 22.7% and OR rates were 61.5% vs 31.8%, P <0.05, respectively). The median time to achieve PR was 88 days in the FMD-arm, compared to 68 days in the VAD-arm (P <0.05). Approximately 40.0% of patients in the FMD-arm had >50% decrease in M-component or >20 g/L elevation in hemoglobin, compared to 22.7% and 18.2% in the VAD-arm respectively (P <0.05). The median times to achieve >50% decrease in M-component, decline of >80% of myeloma cells in the bone marrow than the pre-treatment level or ratio drop to less than 5%, or >20g/L elevation in hemoglobin were 62 days, 57 days, and 70 days, respectively. There were no significant differences between groups in serum calcium, creatinine, and ALT level pre-and post-treatment. The level of serum β2-microglobin was (1042.8±72.3 mg/L) post-treatment in the FMD-arm, which was lower than that observed before treatment (2350.2±184.0 mg/L; P <0.05). Most patients (76.9%) in the FMD-arm occurred III/IV grade leukocytopenia while 81.8% patient were I/II grade in the VAD-arm. The incidences of fever and cough were higher in FMD-arm comparing to VAD-arm (P <0.05). The progression free survival (PFS) on 1st and 2nd year and overall survival (OS) on 2nd year were 46.2%, 30.8% and 53.8% in the FMD-arm, while they were 50%, 27.3% and 40.9% respectively in the VAD-arm, which had no significant statistic difference (P >0.05). CONCLUSION: The PR rate and OR rate of FMD-arm are significantly higher than in the VAD-arm in the treatment of refractory or relapsed multiple myeloma, but it took longer time to achieve PR. The regimen of FMD shows no significant renal or hepatic toxicity, it’s a safe and effective regimen in the treatment of refractory or relapsed multiple myeloma.

A Novel Small Molecule with Epigenetic Activity Prolongs Survival in a Mouse Model of Multiple Myeloma Refractory to Standard Drugs

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5121-5121
Author(s):  
Sergei Vatolin ◽  
Khan Nazeer Shahper ◽  
Yvonne Parker ◽  
Daniel Lindner ◽  
Frederic J. Reu
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Chromatin Condensation ◽  
Xenograft Model ◽  
Myeloma Cells ◽  
Tail Vein ◽  
Tail Vein Injection ◽  
Mouse Xenograft Model ◽  
Number Of Patients

Abstract Abstract 5121 Multiple myeloma refractory to bortezomib, IMiDs™, and conventional therapies represents an unmet medical need. An increasing number of patients progress to this stage since treatment related mortality has decreased. To test promising compounds for activity in this setting we established an NSG mouse xenograft model with serial transplantation by tail vein injection of myeloma cells from a patient with IgG kappa myeloma relapsed and refractory to all standard drugs. Eight days after tail vein injection monoclonal human IgG can be detected in serum. Bone marrow engraftment in young (6–12 weeks) NSG mice after sublethal radiation (275cGy) is close to 100% (n=32). Untreated mice die within less than 2 months, usually with liver and spleen metastasis (anti-human CD138 flow cytometry). In a drug screen that used a novel method developed in our lab, chromatin condensation PCR, we identified a non nucleoside compound (4I3) that potently (1mM) reactivated expression of epigenetically silenced genes and displayed cancer-specific growth and survival inhibition in myeloma cell lines but not normal cells. Normal bone marrow cells continued to divide at doses 10x higher than required to kill 80% of myeloma cells. 4I3 suppressed DNMT1 protein but rapid cell kill (within 1–2 days) suggested additional mechanisms which we currently investigate. Given IV to mice after documentation of engraftment by IgG serum immunoblots, it prolonged survival in an ongoing experiment. Updated results will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Whole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eva Kriegova ◽  
Regina Fillerova ◽  
Jiri Minarik ◽  
Jakub Savara ◽  
Jirina Manakova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Copy Number ◽  
Optical Mapping ◽  
Chromosome 1 ◽  
Gene Copy ◽  
Whole Genome ◽  
Myeloma Cells ◽  
Genomic Architecture

AbstractExtramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM). EMM is frequently associated with high-risk cytogenetics, but their complex genomic architecture is largely unexplored. We used whole-genome optical mapping (Saphyr, Bionano Genomics) to analyse the genomic architecture of CD138+ cells isolated from bone-marrow aspirates from an unselected cohort of newly diagnosed patients with EMM (n = 4) and intramedullary MM (n = 7). Large intrachromosomal rearrangements (> 5 Mbp) within chromosome 1 were detected in all EMM samples. These rearrangements, predominantly deletions with/without inversions, encompassed hundreds of genes and led to changes in the gene copy number on large regions of chromosome 1. Compared with intramedullary MM, EMM was characterised by more deletions (size range of 500 bp–50 kbp) and fewer interchromosomal translocations, and two EMM samples had copy number loss in the 17p13 region. Widespread genomic heterogeneity and novel aberrations in the high-risk IGH/IGK/IGL, 8q24 and 13q14 regions were detected in individual patients but were not specific to EMM/MM. Our pilot study revealed an association of chromosome 1 abnormalities in bone marrow myeloma cells with extramedullary progression. Optical mapping showed the potential for refining the complex genomic architecture in MM and its phenotypes.

scholarly journals Multiple Myeloma Cells Induce Lipolysis in Adipocytes and Uptake Fatty Acids through Fatty Acid Transporter Proteins

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Cristina Panaroni ◽  
Keertik Fulzele ◽  
Tomoaki Mori ◽  
Chukwuamaka Onyewadume ◽  
Noopur S. Raje
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Fatty Acid ◽  
Board Of Directors ◽  
Metabolic Reprogramming ◽  
Glycerol Production ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
Long Chain

Multiple myeloma (MM) originates in the bone marrow where adipocytes occupy 65% of the cellular volume in a typical myeloma patient. Cancer associated adipocytes support the initiation, progression, and survival of solid tumors via mechanisms including adipokine secretion, modulation of the tumor microenvironment, and metabolic reprogramming of cancer cells. Although MM cells are surrounded by abundant bone marrow adipocytes (BMAd), the nature of their interaction remains unclear. Recent studies have elucidated the role of BMAds in supporting the survival of MM cells, in part, through secreted adiponectin. Increased fatty acid (FA) metabolism may result in metabolic reprogramming of cancer cells impacting their growth and survival. Here, we hypothesize that MM cells extract FA from adipocytes for their growth. We first characterized mesenchymal stem cells (MSCs) from MGUS, smoldering MM (SMM), and newly diagnosed MM (NDMM) patients by flow cytometry analysis. MSCs showed significant increase in Pref1, leptin receptor and perilipin A, suggesting increased adipogenic commitment. MSCs from healthy donors (HD), MGUS, SMM, and NDMM patients were induced to differentiate into adipocytes and then co-cultured with human MM MM.1S cells. After 72 hr of co-culture, CyQUANT assay demonstrated significant increase in proliferation of MM.1S cells in the presence of BMAd from HD; this was further increased in the presence of BMAd from MGUS/SMM and NDMM. These data suggest that the BMAd support the growth of MM cells and this effect is more pronounced in patient derived BMAd. A PCR-array targeting lipid metabolism on BM fat aspirates showed significant deregulation of genes involved in FA synthesis and lipolysis. Taken together, our data suggest that BMAd in MM patients are altered to further support the aggressive expansion of MM cells. The proliferative-supportive role of adipocytes was further validated in co-culture of OP9 murine BM stromal preadipocytes with 5TGM1 murine MM cells. To study the bidirectional interaction of MM/ BMAd, mature OP9 adipocytes were co-cultured with 5TGM1 or human OPM2 MM cells for 24 hr. Intracellular lipid droplets were labelled with Deep Red LipidTox stain. The lipid droplet sizes were significantly decreased in the presence of both 5TGM1 and OPM2 cells compared to OP9 alone. The decrease in lipid size suggested that MM cells may induce lipolysis in adipocytes. Indeed, 24hr co-culture of 5TGM1 cells with OP9 mature adipocytes significantly increased lipolysis 3-fold as measured by glycerol secretion in conditioned media. Co-culture of OP9 adipocytes with other MM cell lines of human origin, MM.1S, INA6, KMS-12 PE, and OPM2 also significantly increased the glycerol production as much as 4-fold. Taken together these data indicate that MM cells induce lipolysis in adipocytes. In contrast, treatment of 5TGM1 cells with synthetic catecholamine isoproterenol did not induce lipolysis, or glycerol production, indicating lack of triglyceride storage. Next, we hypothesized that the free FAs released from adipocytes are taken up by MM cells for various biological processes. To test this, 5TGM1, MM.1S and OPM2 cells were incubated with BODIPY-C12 and BODIPY-C16, the BODIPY-fluorophore labelled 12-carbon and 16-carbon long chain FA. All MM cells showed saturated uptake of the FA within 10 minutes suggesting that MM cells have efficient FA transporters. To confirm this uptake, unstained 5TGM1, OPM2 and KMS12 PE cells were co-cultured with the LipidTox-labelled OP9 mature adipocytes. After 24 hours, flow cytometric analysis showed LipidTox signal in MM cells. These data demonstrate that FAs released by MM induced adipocyte lipolysis are taken up by MM cells. Long-chain FAs such as BODIPY-C12 and BODIPY-C16 are transported into cells through FA transporter protein (FATP) family of lipid transporters. We therefore analyzed patient samples which showed that CD138+ plasmacells and myeloma cells expressed high levels of FATP1 and FATP4 whereas, their expression was absent in lineage-sibling T-cells. Moreover, pretreatment with Lipofermata, a FATP inhibitor, was able to decrease the uptake of BODIPY-C12 and -C16 in 5TGM1 cells. Taken together, our data show that myeloma cells induce lipolysis in adipocytes and the released free FAs are then uptaken by myeloma cells through FATPs. Inhibiting myeloma cell induced lipolysis or uptake of FA through FATPs may be a potential anti-tumor strategy. Disclosures Fulzele: FORMA Therapeutics, Inc: Current Employment, Other: Shareholder of Forma Therapeutics. Raje:Amgen: Consultancy; bluebird bio: Consultancy, Research Funding; Caribou: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immuneel: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Immuneel: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy.

scholarly journals Modulating the Haematological and Cytogenetic Effects of Mitomycin C by Aqueous Extract of Nut Grass (Cyperus rotundus L.)

2007 ◽  
Vol 1 (1) ◽  
pp. 52-54
Author(s):  
Ali H. Ad'hiah ◽  
Mohammed M. F. Al-Halbosiy ◽  
Rakad M. Al-Jumaily
Keyword(s):  
Bone Marrow ◽  
Mitotic Index ◽  
Mitomycin C ◽  
Aqueous Extract ◽  
Leucocyte Count ◽  
Bone Marrow Cells ◽  
Post Treatment ◽  
Cyperus Rotundus ◽  
Micronucleus Formation ◽  
Pre Treatment

The aqueous extract (5, 10 and 15 mg/kg) of nut grass (Cyperus rotundus L.) rhizomes was evaluated orally in albino male mice using some haematological (total leucocyte count) and cytogenetic (mitotic index, micronucleus formation and chromosomal aberrations of bone marrow cells) parameters. The extract interaction with the mutagen mitomycin C (MMC) was also evaluated through two types of treatments (pre- and post-treatments). The results revealed that the dose 15 mg/kg of the extract significantly increased the total count of leucocytes (7634.4 vs. 6783.3 cells/cu.mm. blood), while the mitotic index showed no significant differences, as compared to negative controls. However, the spontaneous formation of micronuclei in the bone marrow cells was significantly decreased in the three investigated doses of the extract (0.30, 0.32 and 0.29, respectively vs. 0.62%), while the chromosomal assay showed similar frequencies in the negative control and nut grass-treated animals. With respect to the interaction with MMC, the pre-treatment (15 mg/kg) enhanced the leucocyte count (10358.6 vs. 3800.2 cells/cu.mm.blood) and mitotic index (11.9 vs. 6.5%), and a similar picture was drawn when the pos-treatment was considered (8884.2 vs. 4292.7 cells/cu.mm.blood; 14.6 vs. 7.6%). However, the doses 5 and 10 mg/kg of the plant extract were much more effective in reducing the MMC-induced micronucleus formation in both types of treatments especially the dose 5 mg/kg (pre-treatment: 4.24 vs. 16.29%; post-treatment: 3.79 vs. 14.34%). With respect to chromosomal aberration assay, the dose 15 mg/kg of the extract was the most effective dose in reducing the MMC-induced aberrations, but the post-treatment was better than pre-treatment in this respect (0.29 vs. 0.79 aberration/cell).

scholarly journals B cells suppress medullary granulopoiesis by an extracellular glycosylation-dependent mechanism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Eric E Irons ◽  
Melissa M Lee-Sundlov ◽  
Yuqi Zhu ◽  
Sriram Neelamegham ◽  
Karin M Hoffmeister ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitors ◽  
Myeloma Cells ◽  
Human B Cells ◽  
Extrinsic Cues ◽  
Bone Marrow Niches ◽  
Dependent Mechanism

The immune response relies on the integration of cell-intrinsic processes with cell-extrinsic cues. During infection, B cells vacate the marrow during emergency granulopoiesis but return upon restoration of homeostasis. Here we report a novel glycosylation-mediated crosstalk between marrow B cells and hematopoietic progenitors. Human B cells secrete active ST6GAL1 sialyltransferase that remodels progenitor cell surface glycans to suppress granulopoiesis. In mouse models, ST6GAL1 from B cells alters the sialylation profile of bone marrow populations, and mature IgD+ B cells were enriched in sialylated bone marrow niches. In clinical multiple myeloma, ST6GAL1 abundance in the multiple myeloma cells negatively correlated with neutrophil abundance. These observations highlight not only the ability of medullary B cells to influence blood cell production, but also the disruption to normal granulopoiesis by excessive ST6GAL1 in malignancy.

scholarly journals CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

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