Are Stromal Cells of Adipose Tissue From Multiple Myeloma Patients Are Normal ? A Comparison of Adipose Derived Stromals Cells From Healthy Donors and Multiple Myeloma Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3993-3993
Author(s):  
Benjamin Hebraud ◽  
Elodie Labat ◽  
Nicolas Espagnolle ◽  
Melanie Gadelorge ◽  
Louis Casteilla ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adipose Tissue ◽  
Board Of Directors ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Proliferation Rate ◽  
Population Doubling ◽  
Advisory Committees ◽  
Osteoblast Function ◽  
Significant Difference

Abstract Abstract 3993 Introduction: One of the main feature of MM is bone disease resulting from an increased osteoclastic activity and inhibition of osteoblast function; this imbalance also promotes MM growth leading to a vicious circle. Interestingly mature osteoblasts reduce osteoclastogenesis via high levels of OPG and reduced levels of RANKL and have anti-MM effect too, especially via decorin causing MM cells apoptosis. Hence, therapeutic approaches restoring osteoblast function could reduce osteoclastogenesis and MM growth. Mature osteoblasts originate from bone marrow mesenchymal stromal cells (MSC) that are key component of MM microenvironment. We and others showed that MSC from patients with MM are abnormal. In particular, they have an impaired capacity to diffentiate into osteoblasts. Hence we studied mesenchymal stromal cells from adipose tissue (AT) called the Adipose derived Stromal Cells (ASC). They have very similar properties than MSC, in particular osteoblastic differentiation capacity. The aim of our work is to demonstrate that ASC from patients with MM are normal, contrary to their MSC; we propose the first study comparing ASC from MM patients and ASC from Healthy Donor (HD) with functional and genomics tests. Patients and Methods: We studied ASC from 15 patients with newly diagnosed MM (MM ASC) and CRAB symptoms and from 15 HD (HD ASC) between 18 and 65 years. The stromal vascular fraction was isolated from subcutaneous AT by centrifugation and enzymatic digestion. The ASC were sorted by adhesion to the plastic flask and expanded for 3 passages of 21 days in culture medium MEMa containing 10% FBS and ciprofloxacine. We perform: Results: Our data confirm the stromal nature of MM and HD ASC. The cells were adherent and proliferate into plastic flasks; able to differentiate into osteogenic, chondrogenic and adipogenic lineage; positive for CD90, CD73, CD105 and negative for CD14, CD45. We next found that MM and HD ASC have the same expansion capacity (HD 470±45, MM 208±194, p=0.13), cell population doubling (HD 16.0±0.3, MM 15.0±1.3 p=0,17), and progenitor frequency (HD 3.4%±3, MM 3.7±5,5%, p=0.166). Phenotype didn't show any significant difference except for CD200. Osteogenic, chondrogenic and adipogenic differentiation assays didn't show any difference according to the origin of ASC; alizarin (mmol/l): HD 2.66±0.6, MM 2.15±2.1 p=0.15, chondroitin sulfate (ng/ml): HD 0.5±0.17, MM 0.58±0.58 p=0.2, glycerol (mg/well): HD 2.7±1.6, MM 3.28±1.2 p=0.26. Measurement of IL-6 (HD 7143±10029, MM 10192±6379 pg/ml p=0.15), DKK1 (HD 16698±2432, MM 15948±6558 pg/ml p=0.98), and GDF15 (HD 0.29±0.3, MM 0.43±0.37 ng/ml p=0.13) shows similar levels in both population. We then analysed proliferation rate of MOLP-6 in co-culture with ASC and observed no difference (proliferation rate HD 1.49±0.34, MM 1.66±0.80 p=0,33). MM ASC and HD ASC had the same capacity to support haematopoiesis. Finally, genomic analysis performed by GEP did not identify any difference between the two groups. miRNA analysis tested 1036 targets and found only one, HSA-MIR-196A, differentially expressed between HD and MM ASC(p=0,014). Conclusion: To our knowledge, this is the first exhaustive study that compare ASC from MM patients and HD. Our results strongly suggest that MM ASC are normal and could potentially be used in autologous stem cell transplantation in order to restore the patients' osteoblastic function. Disclosures: Roussel: celgene: Honoraria; janssen: Honoraria. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

Comparison of Stromal Cells of Adipose Tissue From Multiple Myeloma Patients and Healthy Donors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2979-2979
Author(s):  
Benjamin Hébraud ◽  
Elodie Labat ◽  
Nicolas Espagnolle ◽  
Jill Corre ◽  
Michel Attal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adipose Tissue ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Stromal Cells ◽  
Population Doubling ◽  
Healthy Donors ◽  
Significant Difference

Abstract Abstract 2979 Introduction: Multiple myeloma (MM) is a B-cell neoplasia characterized by the accumulation of malignant plasma cells in the bone marrow (BM) patients causing severe bone disease (with osteolytic lesions, pain, pathological fractures) and cytopenias. These lesions are irreversible, even for patients in complete response to treatment. We have proposed to treat those lesions with mesenchymal stem cells (MSC) of the BM using their ability to differentiate into osteoblasts and to support haematopoiesis. But our previous results demonstrated that MM MSC are abnormal. We thus studied cells from adipose tissue (AT) with similar properties than MSC; the Adipose derived Stromal Cells (ASC). The aim of this study is to demonstrate the normality of ASC in MM context for a potential use in autologous stem cell transplantation. Here we propose the first study comparing ASC issue from MM patients and healthy donors (HD). Patients and Methods: We studied ASC from 15 patients with newly diagnosed MM and 15 HD between 18 and 65 years. All gave their informed consent. The stromal vascular fraction was isolated from subcutaneous AT by and centrifugation. The ASC were sorted by adhesion to the plastic flask and expanded for 3 passages. We then performed the following assays to compare ASC from MM and HD: Results: The cell culture assay of ASC didn't show any difference between MM and HD for all the studied parameters: expansion capacity (HD 470± 45, MM 208±194; p=0.13), cell population doubling (HD 16.0±0.3, MM 15.0±1.3; p=0.17) and progenitor frequency (HD 3.4%±3, MM 3.7%±5.5; p=0.165). ASC phenotype didn't show any significant difference for all the checked markers and confirm their stromal feature: positive for CD90, CD73 and CD105, and negative for CD14 and CD45. The differentiation assay was evaluated for osteogenic, chondrogenic and adipogenic lineages. We did not underline any difference comparing ASC from MM or HD (Table 1). We previously showed that MM MSC secreted increased amount of IL-6, GDF15 and DKK-1 when compared with HD MSC. Interestingly, no difference was observed between MM ASC and HD ASC (Table 2). In the same way, contrary to MM MSC, MM ASC didn't promote the proliferation of MOLP-6 cell line better than HD ASC (proliferation rate: 1.49±0.34 for HD and 1.66±0.80 for MM; p=0.33). Conclusion: To our knowledge, this is the first study to compare ASC from MM patient and HD. These preliminary data suggest that ASC from MM patients are normal and could potentially be used in autologous stem cell transplantation for MM patients. We are currently completing this study by performing haematopoiesis support and microarrays assays. Disclosures: No relevant conflicts of interest to declare.

Comparative Analysis of Biological and Functional Properties of Bone Marrow Mesenchymal Stromal Cells Expanded in Media with Different Platelet Lysate Content

2018 ◽  
Vol 205 (4) ◽  
pp. 226-239 ◽  
Author(s):  
Marijana Skific ◽  
Mirna Golemovic ◽  
Kristina Crkvenac-Gornik ◽  
Radovan Vrhovac ◽  
Branka Golubic Cepulic
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Immunological Tolerance ◽  
Biological Properties ◽  
Platelet Lysate ◽  
Population Doubling ◽  
Population Doubling Time ◽  
Significant Difference

Due to their ability to induce immunological tolerance in the recipient, mesenchymal stromal cells (MSCs) have been utilized in the treatment of various hematological and immune- and inflammation-mediated diseases. The clinical application of MSCs implies prior in vitro expansion that usually includes the use of fetal bovine serum (FBS). The present study evaluated the effect of different platelet lysate (PL) media content on the biological properties of MSCs. MSCs were isolated from the bone marrow of 13 healthy individuals and subsequently expanded in three different culture conditions (10% PL, 5% PL, 10% FBS) during 4 passages. The cells cultured in different conditions had comparable immunophenotype, clonogenic potential, and differentiation capacity. However, MSC growth was significantly enhanced in the presence of PL. Cultures supplemented with 10% PL had a higher number of cumulative population doublings in all passages when compared to the 5% PL condition (p < 0.03). Such a difference was also observed when 10% PL and 10% FBS conditions were compared (p < 0.005). A statistically significant difference in population doubling time was determined only between the 10% PL and 10% FBS conditions (p < 0.005). Furthermore, MSCs cultured in 10% PL were able to cause a 66.9% reduction of mitogen-induced lymphocyte proliferation. Three chromosome aberrations were detected in PL conditions. Since two changes occurred in the same do nor, it is possible they were donor dependent rather than caused by the culture condition. These findings demonstrate that a 10% PL condition enables a higher yield of MSCs within a shorter time without altering MSC properties, and should be favored over the 5% PL condition.

Bortezomib-Thalidomide-Dexamethasone Compared with Thalidomide-Dexamethasone as Induction and Consolidation Therapy Before and After Double Autologous Transplantation In Newly Diagnosed Multiple Myeloma: Results From a Randomized Phase 3 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 42-42 ◽  
Author(s):  
Michele Cavo ◽  
Giulia Perrone ◽  
Silvia Buttignol ◽  
Elisabetta Calabrese ◽  
Monica Galli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Autologous Transplantation ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Significant Difference

Abstract Abstract 42 We prospectively compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (MM). Three 21-d cycles of either VTD (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or TD were given as induction therapy. Consolidation therapy comprised two 35-d cycles of VTD (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle) or TD. 474 patients randomized to the VTD (n=236) or TD (n=238) arm were analyzed on an intention-to-treat basis for response rate, PFS and OS. Centrally reassessed CR/nCR rate was significantly higher in the VTD compared with the TD arm after all treatment phases, including induction therapy (30% vs 10%, p<0.0001), double autotransplantation (54% vs 42%, p=0.008) and consolidation therapy (60% vs 44%, p=0.001). Best confirmed overall CR/nCR rate was 71% in the VTD arm compared with 52% in the TD arm (p<0.0001); the corresponding values for VGPR or better were 89% vs 72%, respectively (p<0.0001). To evaluate the role of consolidation therapy we performed a per-protocol analysis of 323 patients, 161 treated with VTD and 162 with TD. Overall, upgraded responses with VTD and TD as consolidation therapy were observed in 55% vs 37% of patients, respectively (p=0.01; OR:1.15-3.77). Furthermore, the probability to improve responses from less than CR before consolidation to CR after consolidation was 28% with VTD vs 15% with TD (p=0.02; OR:1.07-4.57) (p=0.003 using the Mc Nemar's test). Post-consolidation molecular detection of minimal residual disease was the objective of a substudy; detailed results are reported in a separate abstract. Briefly, both qualitative and quantitative analyses confirmed the statistically significant superiority of VTD over TD in effecting higher rates of molecular remissions and reducing the burden of residual myeloma cells after ASCT. Any grade 3–4 non-hematologic adverse events were 10% with VTD (peripheral neuropathy: 1.3%, skin rash: 0.6%) vs 12% with TD. With a median follow-up of 31 months, median PFS was 42 months in the TD arm and was not yet reached in the VTD arm (44-month projected rate: 61%) (HR: 0.62 [CI: 0.45–0.87], p=0.006). Superior PFS in the VTD vs TD arm was retained across patient subgroups with poor prognosis, including those with t(4;14) and/or del(17p). Randomization to VTD overcome the adverse influence of t(4;14) on PFS (40-month projected rates: 69% vs 67% according to the presence or absence of this abnormality, respectively; p=0.6). By the opposite, in the TD arm corresponding median PFS values were 24.5 vs 41.5 months, respectively (p=0.01). The small numbers of patients with del(17p) in both arms of the study precluded a statistical comparison with del(17p)-negative group. In a multivariate analysis, variables favorably influencing PFS were beta2-m lower than 3.5 mg/L (HR:0.47; p=0.000), absence of t(4;14) and/or del(17p) (HR:0.52; p=0.000), randomization to VTD arm (HR:0.57; p=0.002), attainment of at least VGPR (HR:0.50; p=0.009) and CR (HR:0.8; p=0.01). No statistically significant difference between the overall treatment protocols was seen in terms of OS, although curves seemed to initially diverge after 40 months (44-month projected rates: 84% vs 74% for VTD and TD arms, respectively). A multivariate analysis showed the independent role of absence of t(4;14) and/or del(17p) (HR:0.42; p=0.003), ISS stage1-2 (HR:0.49; p=0.02) and randomization to VTD (HR:0.53; p=0.04) in prolonging OS. When time-dependent CR entered the model, absence of t(4;14) and/or del(17p) and less advanced ISS stage retained their positive prognostic value; attainment of CR (strictly related to VTD randomization) was an additional favorable variable. In conclusion, in comparison with the TD arm of the study, 1) VTD induction emerges as a new standard of care for maximizing the degree and speedy of tumor reduction in preparation for ASCT; 2) VTD consolidation effected significantly higher rates of upgraded responses, including CR, and of molecular remissions; 3) double ASCT incorporating VTD as induction and consolidation therapy resulted in significantly longer PFS, a benefit confirmed in a multivariate regression analysis and maintained in the subgroup of patients with adverse cytogenetic abnormalities. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib and thalidomide as induction therapy before, and consolidation after, autologous transplantation in newly diagnosed multiple myeloma. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

Ornithine Decarboxylase: Novel Prognostic Marker and Target for Multiple Myeloma Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1824-1824
Author(s):  
Sonali Panchabhai ◽  
Ilana Miriam Schlam ◽  
Sinto Sebastian Chirackal ◽  
Rafael Fonseca
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Prognostic Marker ◽  
Ornithine Decarboxylase ◽  
Therapeutic Target ◽  
Research Funding ◽  
Preclinical Model ◽  
Advisory Committees ◽  
Survival Difference ◽  
Significant Difference

Abstract Multiple myeloma (MM) is an age dependent second most common hematopoietic malignancy which remains incurable despite recent advances in therapies. Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant condition that precedes MM. Dysregulation and mutations of myriad of molecules is implicated in pathogenesis of MM. Cyclins (CCND) are almost universally dysregulated in MGUS and MM, while c-MYC overexpression and sometimes RAS mutations are associated with MGUS to MM progression. c-MYC, because of its strong association in this malignant transformation and it being a master regulatory factor is a logical therapeutic target. But, a therapeutic approach to target c-MYC has not been successful. So a strategy to target either upstream or downstream molecules in c-MYC pathway is worth considering. Ornithine decarboxylase (ODC) is one such downstream effector of c-MYC which regulates polyamine synthesis and thus regulates cell proliferation. ODC is also downstream of RAS which makes it common to two of the important oncogenes involved in MM. To know whether ODC plays a role in MM pathogenesis, we looked into its gene expression profile in the MM patients. In the Mayo cohort of 100 patients we found significant difference in ODC expression as disease progresses from MGUS to MM. We found significant survival difference in MM patients from this cohort which were divided by ODC expression and this survival difference was more pronounced in non-hyperdiploid group (median survival were for ODC < 1 - 66 mo vs for ODC > 1 - 29.5 mo, Figure 1A) which is a known poor prognostic group. When looked at ODC expression among different TC classes in MMRC dataset, we find ODC expression significantly higher in known high risk and poor prognostic groups 4p16 and MAF than other groups. These findings suggest higher ODC expression associated with poor survival. To further strengthen our observation, we analyzed TT3 group of Arkansas cohort and we observe prolonged event free survival (Figure 1B) and overall survival in patients with low ODC expression as compared to patients with high ODC expression (Figure 1C). After establishing poor prognostic role of ODC, we wanted to test it as a potential therapeutic target. For this purpose, we employed DFMO (Difluromethylornithine) which is the enzymatic irreversible inhibitor of ODC. We tested 15 different MM cell lines for proliferation with DFMO, majority of them respond to DFMO and IC 50 ranged from 28uM to 70 uM. DFMO generally halted cell cylce in G1S and had a cytostatic effect. We further tested efficacy of DFMO in combination with standard anti-myeloma agents lenalidomide, bortezomib, Vorinostat, melphalan and dexamethasone. We found these combinations to be synergistic except with melphalan where the combination was antagonistic. We therefore suggest that DFMO, which has a good toxicity profile can be advantageous in MM patients who are relatively old and many times cannot tolerate extensive chemotherapy for its toxicity. Moreover since it is synergistic in preclinical model with two main anti-myeloma agents lenalidomide and bortezomib, it may well be combined with both to decrease the amount of drug needed and hence toxicity. We think it will be especially beneficial to those patients who have high ODC levels. So we propose ODC to be a prognostic marker and therapeutic target in MM. Disclosures Chirackal: Mayo Clinic: Patents & Royalties: Filed a professional US patent for quantifying cellular anti-oxidative capacity. Fonseca:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees.

scholarly journals High Levels of APOBEC3B Gene Expression Contribute to Poor Prognosis in Multiple Myeloma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3897-3897
Author(s):  
Valeriy V Lyzogubov ◽  
Pingping Qu ◽  
Cody Ashby ◽  
Adam Rosenthal ◽  
Antje Hoering ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
Target Genes ◽  
Plasma Cells ◽  
Nuclear Fraction ◽  
Advisory Committees ◽  
Significant Difference

Abstract Introduction: Poor prognosis and drug resistance in multiple myeloma (MM) is associated with increased mutational load. APOBEC3B is a major contributor to mutagenesis, especially in myeloma patients with t(14;16) MAF subgroup. It was shown recently that presence of the APOBEC signature at diagnosis is an independent prognostic factor for progression free survival (PFS) and overall survival (OS). We hypothesized that high levels of APOBEC3B gene expression at diagnosis may also have a prognostic impact in myeloma. To consider APOBEC3B as a potential target for therapy more studies are necessary to understand how APOBEC3B expression is regulated and how APOBEC3B generates mutations. Methods: Gene expression profiling (GEP, U133 Plus 2.0) of MM patients was performed. APOBEC3B gene expression levels were investigated in plasma cells of healthy donors (HD; n=34), MGUS (n=154), smoldering myeloma (SMM; n=219), MM low risk (LR; n=739), MM high risk (HR; n=129), relapsed MM (RMM; n=74), and primary plasma cell leukemia (pPCL; n=19) samples. The samples from relapse were taken on or after the progression/relapse date but within 30 days after progression/relapse from Total Therapy trials 3, 4, 5 & 6. GEP70 score was used to separate samples into LR and HR groups. We also investigated APOBEC3B expression in different MM molecular subgroups and used logrank statistics with covariate frequency distribution to determine an optimal cut off APOBEC3B expression value. Gene expression was compared in cases with low expression of APOBEC3B (log2<7.5) and high expression of APOBEC3B (log2>10), and an optimal cut-point in APOBEC3B expression was identified with respect to PFS. To explore the role of MAF and the non-canonical NF-ĸB pathway we performed functional studies using a cellular model of MAF downregulation. TRIPZ lentiviral shRNA MAF knockdown in the RPMI8226 cell lines was used to explore MAF-dependent genes. NF-ĸB proteins, p52 and RelB, were investigated in the nuclear fraction by immunoblot analysis. Results: Expression of APOBEC3B in HD control samples (log2=10.9) was surprisingly higher than in MGUS (log2=9.51), SMM (log2=9.09), and LR (log2=9.40) and was comparable to HR (log2=10.4) and RMM (log2=10.6) groups. Expression levels of APOBEC3B were gradually increased as disease progressed from SMM to pPCL. The high expression of APOBEC3B in HD places plasma cells at risk of APOBEC induced mutagenesis where the regulation of APOBEC3B function is compromised. The correlation between APOBEC3B expression and GEP70 score in MM was 0.37, and there was a significant difference in APOBEC3B expression between GEP70 high and low risk groups (p=0.0003). An optimal cut-point in APOBEC3B expression of log2=10.2 resulted in a significant difference in PFS (median 5.7 yr vs.7.4 yr; p=0.0086) and OS (median 9.1 yr vs. not reached; p<0.0001), between high and low expression. The highest APOBEC3B expression was detected in cases with a t(14;16). We analyzed t(14;16) cases with the APOBEC mutational signature and compared them to t(14;16) cases without the APOBEC signature and found elevated MAF (2-fold) and APOBEC3B (2.7-fold) gene expression in samples with the APOBEC signature. No APOBEC signature was detected in SMM cases, including those with a t(14;16). High APOBEC3B levels in myeloma patients was associated with overexpression of genes related to response to DNA damage and cell cycle control. Significant (p<0.05) increases of NF-κB target genes was seen in high APOBEC3B cases: TNFAIP3 (4.4-fold), NFKB2 (1.7-fold), NFKBIE (1.9-fold), RELB (1.4-fold), NFKBIA (2.0-fold), PLEK (2.5-fold), MALT1 (2.5-fold), WNT10A (2.4-fold). However, in t(14;16) cases there was no significant increase of NF-κB target genes except BIRC3 (2.5-fold) and MALT1 (2.0-fold). MAF downregulation in RPMI8226 cells did not lead to changes in NF-κB target gene expression but MAF-dependent genes were identified, including ETS1, SPP1, RUNX2, HGF, IGFBP2 and IGFBP3. Analysis of nuclear fraction of NF-ĸB proteins did not show significant changes in expression of p52 and RelB in RPMI8226 cells after MAF downregulation. Conclusions: Increased expression of APOBEC3B is a negative prognostic factor in multiple myeloma. MAF is a major factor regulating expression of APOBEC3B in the t(14;16) subgroup. NF-ĸB pathway activation is most likely involved in upregulation of APOBEC3B in non-t(14;16) subgroups. Disclosures Davies: TRM Oncology: Honoraria; MMRF: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria.

scholarly journals Maintenance and Consolidation Regimens after a Second Autologous Transplant for Multiple Myeloma: A Decade of Experiences

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5700-5700
Author(s):  
Ghulam Rehman Mohyuddin ◽  
Maire Okoniewski ◽  
Osama Diab ◽  
Siddhartha Ganguly ◽  
Al-Ola Abdallah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Standard Of Care ◽  
Advisory Board ◽  
Advisory Committees ◽  
Fda Approval ◽  
Novel Drugs ◽  
Significant Difference

Introduction: Autologous stem cell transplant (ASCT) followed by maintenance is the standard of care for eligible patients with multiple myeloma (MM). For patients that relapse, a second ASCT remains a viable option. However, the maintenance regimen to use for such patients remains an unanswered question, particularly in those with prior lenalidomide exposure. We retrospectively analyzed patients receiving two autologous transplants for a diagnosis of MM at our institution from 2008 to 2018 to determine maintenance strategies and outcomes upon completion of a second transplant. Methods: A total of 189 patients received two or more autologous transplants for MM at our institution from 2008 to 2018. Patients with planned tandem transplants, or those that proceeded directly to another transplant without interval progression were excluded. The remaining 135 patients were analyzed. Results: Patient characteristics are shown in Table 1. After first ASCT, 94 out of 135 patients (69.6 %) started maintenance therapy. The most commonly used maintenance regimen was lenalidomide in 63 patients, followed by bortezomib in 12 patients and thalidomide in 10 patients. Median time to initiation of maintenance from the date of transplant was 3.9 months. Overall median progression free survival (PFS) from transplant was 24.7 months with no significant difference between groups that received lenalidomide (median PFS: 21.2 months) or bortezomib (median PFS: 19.2 months, p:0.12). 10 (15.8%) patients discontinued lenalidomide due to toxicity, and 1 patient (8.3%) discontinued bortezomib due to toxicity. The median time from the onset of disease progression post first ASCT to time of second ASCT was 5.8 months. Strategies used post second ASCT includedconsolidation with triplet regimens followed by de-escalation (n=11) versus monotherapy (n=100). Table 2 highlights differing maintenance regimens used after the second ASCT. Median time from second ASCT to initiation of maintenance was 4.0 months. Median PFS post ASCT was 20.7 months. There was no statistically significant difference in PFS between the different regimens used (p=0.26), although there was a numerically higher discontinuation rate due to toxicity with older agents such as lenalidomide and bortezomib compared with newer agents such as daratumumab and pomalidomide. There was no statistically significant difference in the cytogenetic risk profile (p=0.21) or stage at diagnosis (p=0.36) between the groups that received different types of maintenance agents. However, patients receiving daratumumab as maintenance were more likely to have received more lines of therapy (median 5 for Daratumumab vs 3 for Lenalidomide, p=0.0001), and more likely to have previous exposure to daratumumab prior to second ASCT (92% vs 0% for other agents p=0.0001). Patients receiving daratumumab, carfilzomib or triple therapy were more likely to have been refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (p=0.0001). Despite stratifying for use of newer novel drugs (FDA approval after 2010- pomalidomide, daratumumab, carfilzomib) vs older novel drugs (FDA approval before 2010- lenalidomide, bortezomib, thalidomide), there was no difference in PFS ( 21.2 months vs 20.4 months, p= 0.92), between these groups when used as part of a maintenance strategy. Conclusions: Our data show a variety of maintenance and consolidation regimens are used for patients with MM after their second ASCT. In this single-center, retrospective analysis, there was no clear superiority of a consolidative strategy using triplet over monotherapy, and no superiority of newer agents compared to older agents. This suggests that toxicity, prior therapies and their tolerance may be the more important patient-related factors for consideration when selecting an agent/agents. Randomized, prospective data will be important to ascertain the standard of care in this situation. Disclosures Ganguly: Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. McGuirk:Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 536-536 ◽  
Author(s):  
Antonio Palumbo ◽  
Valeria Magarotto ◽  
Sara Bringhen ◽  
Massimo Offidani ◽  
Giuseppe Pietrantuono ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Alkylating Agents ◽  
Second Primary ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Significant Difference ◽  
Grade 3 ◽  
To Receive

Abstract Background Rd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. Methods Patients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). Results Between October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71) At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). Conclusion In a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

A Lower Dose Of Melphalan (140 mg/m2) As Preparative Regimen For Multiple Myeloma In Patients >65 Or With Renal Dysfunction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5536-5536 ◽  
Author(s):  
Ila Maewal Saunders ◽  
Alison M Gulbis ◽  
Richard E Champlin ◽  
Muzaffar H. Qazilbash
Keyword(s):  
Multiple Myeloma ◽  
Renal Dysfunction ◽  
Board Of Directors ◽  
Response Rate ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Overall Response ◽  
Significant Difference ◽  
Preparative Regimen ◽  
Related Mortality

Abstract Background Melphalan at a dose of 200 mg/m2 IV (MEL 200) is considered the standard preparative regimen for autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma. However, reduced doses of melphalan such as140 mg/m2 (MEL 140) are often used in older patients or patients with renal dysfunction. Methods The purpose of this retrospective analysis was to determine if there was a difference in toxicity, treatment-related mortality (TRM), response rate, progression- free survival (PFS) or overall survival (OS) in patients that received 140 mg/m2 of melphalan (MEL 140) compared to those receiving MEL 200 for auto-HCT. From June 1, 1996 through December 31, 2012, 63 patients received MEL 140. We compared their outcomes with 252 patients that received MEL 200. Results Patient characteristics and outcomes are shown in the attached Table. Patients in the MEL 140 group were older, had a higher β2 microglobulin (β2M) level both at diagnosis and auto-HCT, and had a higher serum creatinine (Cr) at auto-HCT (Table). A higher proportion of patients in MEL 140 were older than 65 with serum Cr > 2 mg/dL. There was no significant difference in disease status or high-risk cytogenetics between the 2 groups (Table). NCI CTCv3 > III non-hematologic toxicity was not significantly different between MEL 140 and MEL 200. Transplant-related mortality (TRM) at 100 days and at 1 year was 0% and 0.4% in MEL 140 and 200 (p=1.0), respectively. Complete remission (CR) rates in MEL 140 and MEL 200 were 16% and 29%, respectively (p=0.03). There was no significant difference in (CR) + very good partial remission (VGPR), or overall response (CR + VGPR + PR) between MEL 140 and MEL 200. Median follow up in surviving patients in MEL 140 and 200 was 7.6 and 25 months, respectively. Fifteen (24%) and 64 (25%) patients died in MEL 140 and MEL 200 groups, respectively, with >90% of deaths due to recurrent disease. Median PFS was 26.4 and 30.6 months in MEL 140 and MEL 200 groups, respectively (p=0.46). Median OS was 38.4 and 93.0 months in MEL 140 and MEL 200 groups, respectively (p=0.02). However, there was no significant difference in PFS or OS in patients older than 65 or with serum Cr > 2 mg/d between MEL 140 and MEL 200. Conclusion The dose of melphalan can be safely reduced to 140 mg/m2 in patients >65 or with renal insufficiency without adversely impacting the overall response rate or PFS. Disclosures: Qazilbash: Otsuka Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Fluorescence in Situ Hybridization (FISH) abnormalities and Baseline Clinical Features at Diagnosis in African American Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2351-2351
Author(s):  
Megan H Jagosky ◽  
Kyle L Madden ◽  
Blake B Goodbar ◽  
Virginia Thurston ◽  
Manisha Bhutani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
African American ◽  
Board Of Directors ◽  
Clinical Features ◽  
Research Funding ◽  
Advisory Committees ◽  
Significant Difference ◽  
Caucasian Patients ◽  
Caucasian Cohort

Abstract BACKGROUND: Multiple myeloma (MM) is the most common hematologic malignancy in the African American (AA) population with an incidence more than 2-3 times higher than Caucasians [Landgren O et al Blood 2006]. In the pre-novel therapy era, SEER data [1975-2008] indicated better survival outcomes for AA patients with MM. However, with the recent advent of novel drugs for treatment of MM, the survival gap for Caucasian patients with MM has closed [Ailawadhi S et al Br J Haematol 2012]. A recent pooled analysis of diagnostic cytogenetics in 292 AA MM patients [Greenberg et al Blood Cancer J 2015] reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between AA and Caucasian MM patients. The large and diverse population of patients with MM at our institution prompted us to examine diagnostic cytogenetics in our MM patients along with other clinical features. PATIENTS & METHODS: The MM database was interrogated for all patients presenting with MM between January 2012 and February 2016. Baseline clinical and pathology variables were compared between the AA and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), t(14;16), t(14:20), amplification 1q21, monosomy13/del13q and del17p) were compared using Fisher's exact tests. RESULTS: A total of 398 patients were identified for the analysis (African Americans n = 168, Caucasian n = 230). The median age of AA MM patients was significantly younger than Caucasian MM patients (median age 63 years vs. 68 years, p<0.0001), with a similar sex distribution. There was no significant difference in the degree of anemia, renal insufficiency, serum LDH levels, bone marrow flow cytometry, bone marrow cellularity or plasmacytosis in the two cohorts. Although there was a trend toward more ISS I amongst Caucasian MM patients, there was no statistical difference in ISS stages (p = 0.126) and no significant difference in R-ISS stage between the cohorts (p = 0.361). There was 72.7% agreement between the ISS and R-ISS staging (88 of 121 evaluable subjects had the same stage by ISS and R-ISS staging criteria), while 27.3% of the patients were upstaged from Stage I or II by ISS criteria to Stage III by R-ISS criteria. Of those upstaged, 19 patients were in the Caucasian cohort and 14 were in the AA cohort. The magnitude of this upstaging was significant when evaluated with a Generalized McNemar's test (p < 0.001). Additionally, there was a similar incidence of common FISH abnormalities in the AA cohort compared to the Caucasian cohort [Table 1]. CONCLUSIONS: This is the largest single institution report of FISH data in AA MM patients. Unlike previous reports, we show similar clinical, pathological, and cytogenetic features between AA and Caucasian patients with MM at presentation. It is possible that molecular abnormalities not detectable by FISH in our patient cohort could account for differences in our data and the published literature. Table 1 FISH Abnormalities Table 1. FISH Abnormalities Disclosures Bhutani: Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy; Endocyte: Consultancy. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Usmani:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

scholarly journals Outcomes of Myeloma Patients with Deletion 1p Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1884-1884 ◽  
Author(s):  
Levani Odikadze ◽  
Nisha Joseph ◽  
Timothy M. Schmidt ◽  
Leonard Heffner ◽  
Craig C Hofmeister ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Progression Free Survival ◽  
Control Group ◽  
Advisory Committees ◽  
Best Response ◽  
Significant Difference ◽  
1P Deletion

Abstract Introduction: Previous studies indicated that 1p deletion (del 1p) in multiple myeloma patients has a negative effect on overall survival (OS) and progression free survival (PFS). However, majority of studies were conducted before the introduction of current first line therapy of Lenalidomide, Bortezomib and Dexamethasone (RVD). Our study investigated the association between del 1p and clinical outcomes in patients with MM treated with RVD. Methods: Single-center, retrospective analysis of an IRB approved myeloma database of 1000 newly diagnosed multiple myeloma patients treated with RVD induction therapy per Richardson et al (Blood 2010), planned stem cell transplant and risk adapted maintenance (Nooka et al, Leukemia, 2014). 1p deletion status was determined by FISH. The primary outcomes were response to RVD, response to ASCT, progression free survival (PFS), and overall survival (OS). Treatment responses were evaluated as per IMWG Uniform Response Criteria. Results: We identified 1000 multiple myeloma patients who started RVD treatment from July 2005 to August 2016. Among these, 83 patients (8.3 %) were found to have 1p deletion on FISH. The remaining 917 patients formed the control group. Median age at diagnosis, sex and race were similar between groups. Patients with del 1p were more likely to have IgA isotype compared to controls (28.1% vs 19.7%, P=0.054). There was no significant difference between groups in baseline hemoglobin, calcium, platelet count, creatinine and albumin levels. Baseline LDH levels were more likely to be high in the del 1p group (P=0.009). 49.6% of del 1p patients had high risk status (t(4:14), t(14:16), 17p deletion) vs 26.6% in the control group (p<0.0001). There was no significant difference in the best response to induction therapy between groups, with an achievement of a VGPR or better in 62.8% vs 69.3% in the del 1p and control groups respectively (p=0.148). However, the del 1p group had lower best response after transplant, with a VGPR or better in 67.1% vs 89.2% respectively (P<0.001). Univariate regression analysis also showed a significant association of del 1p with decreased PFS (HR 1.782, P=0.002), which stayed significant after adjusting for disease stage, high risk FISH and maintenance (HR 2.265, p<0.001). There was no statistical decrease in OS in the del 1p population. Conclusion: This analysis demonstrated that the del 1p continues to be associated with adverse outcomes in the era of uniform induction therapy with RVD, transplant and risk-adapted maintenance. There was no significant difference in response to induction treatment, however, del 1p was a significant independent adverse prognostic factor for best response and PFS after ASCT. The lack of decrease in OS may be due to the routine use of risk adapted maintenance. Disclosures Heffner: Genentech: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; ADC Therapeutics: Research Funding. Hofmeister:Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy.

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