scholarly journals Combination Treatment Approach Shows Promise for R/R Multiple Myeloma

2021 ◽  
Vol 43 (S4) ◽  
pp. 20-20
Author(s):  
Catlin Nalley
Keyword(s):  
Multiple Myeloma ◽  
Combination Treatment ◽  
Treatment Approach

Combination Treatment Approach to Melasma

2021 ◽  
Vol 4 (1) ◽  
pp. 97-107
Author(s):  
Emily L. Guo ◽  
Jordan V. Wang ◽  
Roy G. Geronemus ◽  
Paul M. Friedman
Keyword(s):  
Combination Treatment ◽  
Treatment Approach

scholarly journals Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 256
Author(s):  
Ichiro Hanamura
Keyword(s):  
Multiple Myeloma ◽  
Hematological Malignancy ◽  
Treatment Approach ◽  
Current Knowledge ◽  
Chromosome 1 ◽  
Plasma Cell Neoplasm ◽  
Chromosome Arm ◽  
Cell Neoplasm ◽  
Prognostic Implications ◽  
Tandem Duplications

Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+.

scholarly journals Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Jinsil Jang ◽  
Soo-Jin Jeong ◽  
Hee-Young Kwon ◽  
Ji Hoon Jung ◽  
Eun Jung Sohn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Treatment ◽  
Tyrosine Phosphatase ◽  
Combined Treatment ◽  
Parp Cleavage ◽  
Myeloma Cells ◽  
Stat3 Signaling Pathway ◽  
Human Multiple Myeloma ◽  
Induction Of Apoptosis ◽  
Apoptotic Activity

Background. Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin fromAngelica gigasand doxorubicin on the induction of apoptosis in three human multiple myeloma cells.Methodology/Principal Findings. Combined treatment of decursin and doxorubicin significantly exerted significant cytotoxicity compared to doxorubicin or decursin in U266, RPMI8226, and MM.1S cells. Furthermore, the combination treatment enhanced the activation of caspase-9 and -3, the cleavage of PARP, and the sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment downregulated the phosphorylation of mTOR and its downstream S6K1 and activated the phosphorylation of ERK in three multiple myeloma cells. Furthermore, the combined treatment reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells. Conversely, tyrosine phosphatase inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activation induced by combined treatment of doxorubicin and decursin in U266 cells.Conclusions/Significance. Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

scholarly journals Toxicities Associated With Metformin/Ritonavir Combination Treatment in Relapsed/Refractory Multiple Myeloma

2020 ◽  
Vol 20 (10) ◽  
pp. e667-e672
Author(s):  
Nitya Nathwani ◽  
Joycelynne Palmer ◽  
Timothy W. Synold ◽  
Behrouz Salehian ◽  
Michael Rosenzweig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Treatment ◽  
Refractory Multiple Myeloma

Delineation of Canonical and Non-Canonical NF-κB Pathways in Multiple Myeloma: Therapeutic Implications.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 670-670
Author(s):  
Teru Hideshima ◽  
Noopur Raje ◽  
Ruben Carrasco ◽  
Hiroshi Ikeda ◽  
Yutaka Okawa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Combination Treatment ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Canonical Pathway ◽  
Mobility Shift ◽  
Therapeutic Implications ◽  
Real Time Quantitative Pcr ◽  
Mobility Shift Assay

Abstract NF-κB pathway plays a crucial role in the pathogenesis in cancer cells including multiple myeloma (MM). The NF-κB complex is dimer in different combinations of Rel family proteins, including p65 (RelA), RelB, c-Rel, p50 (NF-κB1), and p52 (NF-κB2). Recent studies have revealed that NF-κB activity is mediated via two distinct pathways. In the canonical pathway, NF-kB is typically a heterodimer composed of p50 and p65 subunits. In the non-canonical pathway, NF-kB is typically a heterodimer composed of RelB and p100 subunits. We have shown anti-MM activities of IKKβ inhibitors (PS-1145, MLN120B); however, effects of these agents were modest. Our studies therefore suggest that baseline NF-kB activity in MM cells is not totally dependent on the canonical pathway, and that inhibition of only canonical NF-κB pathway may not be sufficient to block total NF-kB activity. In this study, we therefore hypothesized whether non-canonical inhibitors significantly enhanced NF-κB inhibition induced by canonical inhibitors in MM cells. We first examined baseline NF-κB activity using electrophoretic mobility shift assay (EMSA). NF-κB activity varied between cell lines; for example MM.1S, MM.1R and H929 cells have higher level of NF-κB activity than in RPMI8226, INA6 and OPM2 cells. To define the role of canonical and non-canonical pathway, we next examined protein expression of p50, p65 and p52 NF-κB in these cell lines: p65 was highly expressed in all MM cell lines; however, expression of p50 and 52 is variable. Surprisingly, no detectable or weak expression of p50 was observed in U266, RPMI8226, LR5, H929 and OPM2 cell lines, suggesting that baseline NF-kB activity in these cell lines is not maintained only by the canonical pathway. We then attempted to block non-canonical NF-κB pathway in MM cell lines. Specifically since IKKα and IKKβ are client proteins of heat shock protein (Hsp) 90, we examined whether 17AAG could inhibit expression and/or function of IKKα and IKKβ in MM cells. Importantly, both IKKα and IKKβ were significantly downregulated by 17AAG in MM cell lines. To determine whether downregulation of these IKK proteins by 17AAG was due to inhibition of transcription, we next performed real-time quantitative PCR and no significant inhibition of relative expression of IKKβ was observed by 17AAG treatment, suggesting that downregulation of these proteins was a post transcription event. We further examined whether 17AAG enhanced the effect of IKKβ inhibitor MLN120B on NF-κB activity. Although the inhibitory effect by either MLN120B or 17AAG alone on phosphorylation (p) of IκBα triggered by TNFα was marginal, combination treatment of MLN120B with 17AAG almost completely blocked IκBα, suggesting that this combination synergistically inhibit canonical NF-κB activity in MM cells. Importantly, the combination of MLN120B with 17AAG also significantly blocked baseline and TNFα-triggered NF-κB activity, assessed by EMSA, in MM cells. Finally, 17AAG augmented the growth inhibitory effect of MLN120B in the context of bone marrow stromal cells. Taken together, these results showed that baseline and TNFα-triggered NF-κB activities were completely blocked by this combination treatment, and provide the rationale for its clinical evaluation to induce maximum inhibition of NF-κB activity and improve patient outcome in MM.

A Selective PIM Kinase Inhibitor Is Highly Active In Multiple Myeloma: Mechanism of Action and Signal Transduction Studies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4084-4084 ◽  
Author(s):  
Veerendra Munugalavadla ◽  
Leanne Berry ◽  
Yung-Hsiang Chen ◽  
Gauri Deshmukh ◽  
Jake Drummond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Combination Treatment ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Myeloma Cell ◽  
Negative Regulator ◽  
Combination Drug ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 4084 Related work from our group has shown the therapeutic utility of PIM inhibition in multiple myeloma cell lines, xenografts, and primary patient samples (Ebens A. et al., ASH 2010 submitted abstr.). In this study we provide detailed mechanistic findings to show that PIM kinase inhibition co-regulates several important elements of the PI3K/AKT/mTOR pathway, resulting in significant synergy for combination drug treatments. The PIM kinases are a family of 3 ser/thr growth factor- & cytokine-induced proteins hypothesized to have redundant survival and growth functions. GNE-652 is a pan-PIM kinase inhibitor with picomolar biochemical potencies and an excellent kinase selectivity profile. Myeloma cell lines exhibit sensitivity to single agent PIM inhibition and a striking synergy in combination with the PI3K inhibitor GDC-0941. Cells respond to this combination with cell cycle arrest and marked apoptosis in vitro. We tested a panel of selective PI3K/AKT/mTOR inhibitors and found PI3K and AKT inhibitors showed the greatest extent of synergy with GNE-652, whereas mTOR inhibitors were synergistic to a lesser extent. These results suggest that PIM signaling converges on both TORC1 and AKT to generate these differential synergies. BAD is a negative regulator of both Bcl-2 and Bcl-XL, and we were able to confirm previous reports that AKT and PIM cooperate to inactivate BAD (Datt et al., 1997; Yan et al., 2003). Pim has been shown to potentially inactivate PRAS40, a negative regulator of TORC1 (Zhang et al., 2009). We demonstrate that PIM or PI3K inhibition caused a loss of phosphorylation on PRAS40 and results in a physical association of PRAS40 and TORC1 and a decrease in phosphorylated p70S6K and S6RP. These reductions were apparent in 7 of 7 cell lines assayed and enhanced by the combination of PI3K and PIM inhibition in these cell lines. Consistent with prior reports (Hammerman et al., 2005), we show that a second node of convergence between PIM and TORC1 is 4E-BP1. Both GDC-0941 and GNE-652 treatments reduced phosphorylation of 4E-BP1 in 7 of 7 myeloma cell lines. Since dephosphorylated 4E-BP1 competes with eIF4G for the mRNA cap binding factor eIF4E, we assayed immunoprecipitates of eIF4E for the presence of eIF4G and 4E-BP1 and observed increased BP1 and decreased 4G. The combination treatment significantly enhanced the loss of 4G relative to either single agent, and importantly, even at 5× the IC50 concentrations for single agents, combination drug treatment achieved greater extent of effect than single agent treatment. Thus PI3K and PIM pathways are redundant at the level of cap-dependent translational initiation mediated by eIF4E. It has been hypothesized a subset of mRNAs are particularly sensitive to inhibition of cap-dependent translation, and that this includes a number of oncogenes such as cyclin D1. We assayed global protein synthesis in MM1.s cells using 35S-methionine and as expected we observed only a modest ≂∼f20% decrease caused by either GNE-652 or GDC-0941 and this decrease was not enhanced by combination treatment. However, we noted across 7 different myeloma cell lines, strong decreases in levels of cyclin D1 that were enhanced by combination treatment. In summary, we have identified several points at which PIM and PI3K/AKT/mTOR converge to provide synergistic apoptosis in multiple myeloma cell lines. These results provide the rationale for further preclinical development of PIM inhibitors and provide the basis for a possible clinical development plan in multiple myeloma. Disclosures: Munugalavadla: Genentech: Employment, Equity Ownership. Berry:Genentech: Employment, Equity Ownership. Chen:Genentech: Employment, Equity Ownership. Deshmukh:Genentech: Employment, Equity Ownership. Drummond:Genentech: Employment, Equity Ownership. Du:Genentech: Employment, Equity Ownership. Eby:Genentech: Employment, Equity Ownership. Fitzgerald:Genentech: Employment, Equity Ownership. S.Friedman:Genentech: Employment, Equity Ownership. E.Gould:Genentech: Employment, Equity Ownership. Kenny:Genentech: Employment, Equity Ownership. Maecker:Genentech: Employment, Equity Ownership. Moffat:Genentech: Employment, Equity Ownership. Moskalenko:Genentech: Employment, Equity Ownership. Pacheco:Genentech: Employment, Equity Ownership. Saadat:Genentech: Employment, Equity Ownership. Slaga:Genentech: Employment, Equity Ownership. Sun:Genentech: Employment, Equity Ownership. Wang:Genentech: Employment, Equity Ownership. Yang:Genentech: Employment, Equity Ownership. Ebens:Genentech Inc: Employment, Equity Ownership.

HDAC3 Maintains DNMT1 through Dual Mechanisms in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4472-4472 ◽  
Author(s):  
Takeshi Harada ◽  
Hiroto Ohguchi ◽  
Yohann Grondin ◽  
Shohei Kikuchi ◽  
Morihiko Sagawa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Board Of Directors ◽  
Combination Treatment ◽  
Hdac Inhibitors ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Rpmi 8226 ◽  
Dnmt1 Expression

Abstract Histone deacetylases (HDACs) represent novel therapeutic targets for the treatment of multiple myeloma (MM). Although non-selective HDAC inhibitors demonstrate remarkable anti-MM activity, they also are associated with side effects. To avoid these adverse events without reducing anti-MM efficacy, we have been developing isoform- or class-selective HDAC inhibitors. Specifically, we showed that HDAC3 plays an important role in MM cell proliferation (Minami J, et al, Leukemia. 2014), and here delineate the mechanism whereby HDAC3 inhibition abrogates MM cell growth. We first carried out gene expression profiling before and after knocking down of HDAC3 in MM.1S cells. Among significantly downregulated genes (adjusted P values < 0.001, log fold change > 1.0), we selected DNA methyltranseferase 1 (DNMT1) for further studies. Downregulation of DNMT1 by HDAC3 knockdown was first confirmed by quantitative real time PCR (Q-PCR) and immunoblotting in both MM.1S and RPMI 8226 cells. HDAC3 selective inhibitor BG45 also downregulated DNMT1 expression. Importantly, knockdown of DNMT1triggers apoptosis in MM cells, suggesting that DNMT1 downregulation plays, at least in part, a role in HDAC3 inhibitor-induced MM cell growth inhibition. Previous studies show that HDAC inhibitors downregulate c-Myc expression (Hideshima T, et al. Blood Cancer J. 2015), and we confirmed that c-Myc was downregulated by genetic downregulation and pharmacological inhibition of HDAC3 by HDAC3 shRNA and BG45, respectively. Moreover, treatment of MM.1S cells with BG45 markedly increased c-Myc acetylation. Importantly, c-Myc was significantly degraded after treatment of MM.1S with HDAC3 inhibitor BG45 in the presence of cycloheximide (CHX), indicating that downregulation of c-Myc by HDAC3 inhibition is due to loss of protein stability. To determine whether DNMT1 expression is regulated by c-Myc, we next analyzed ChIP-Seq data in MM.1S cells (GSE36354) and found that c-Myc binds to DNMT1 promoter region. We confirmed downregulation of DNMT1 after knockdown of MYC in MM.1S and RPMI 8226 cells by Q-PCR and immunoblotting. These results suggest that HDAC3 inhibition downregulates DNMT1 through downregulation of c-Myc. A recent study reported that acetylation of DNMT1 leads to its ubiquitination, resulting in degradation of DNMT1 (Cheng J, et al. Nat Commun. 2015). We showed that treatment of MM.1S cells with BG45 in the presence of CHX triggered hyperacetylation of DNMT1, followed by its degradation. We further confirmed this association of acetylation and ubiquitination of DNMT1 protein using a dequbiquitination assay in 293T cells. As expected, HDAC3 blocked DNMT1 ubiquitination. Taken together, these results suggest that HDAC3 inhibition modulates DNMT1 via both c-Myc and by acetylation and thereby altering protein stability. Finally, Azacytidine (AZA) is used as a DNMT1 inhibitor in the treatment of acute myeloid leukemia and myelodysplastic syndrome. We therefore examined combination treatment of MM cells with BG45 combined with AZA. Importantly, this combination triggered synergistic downregulation of DNMT1 and growth inhibition through apoptosis in both MM cell lines and patient MM cells. Efficacy of combination treatment was confirmed in a murine xenograft MM model, evidenced by both tumor growth inhibition and prolonged overall host survival. Our results therefore provide the rationale for combination treatment with HDAC3 inhibitor and DNMT1 inhibitor to improve patient outcome in MM. Disclosures Mazitschek: Acetylon: Equity Ownership. Hideshima:Acetylon: Consultancy; C4 Therapeutics: Equity Ownership. Anderson:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study

2011 ◽  
Vol 153 (6) ◽  
pp. 729-740 ◽  
Author(s):  
Paul G. Richardson ◽  
Asher A. Chanan-Khan ◽  
Sagar Lonial ◽  
Amrita Y. Krishnan ◽  
Michael P. Carroll ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Treatment ◽  
Phase 1 ◽  
Refractory Multiple Myeloma

scholarly journals Extramedullary disease in multiple myeloma

2021 ◽  
Vol 11 (9) ◽  
Author(s):  
Radhika Bansal ◽  
Sagar Rakshit ◽  
Shaji Kumar
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Palliative Care ◽  
Standard Treatment ◽  
Plasma Cells ◽  
Treatment Approach ◽  
Biological Perspective ◽  
Rising Incidence ◽  
Prospective Trials ◽  
Poor Outcomes

AbstractWhen clonal plasma cells grow at anatomic sites distant from the bone marrow or grows contiguous from osseous lesions that break through the cortical bone, it is referred to as extramedullary multiple myeloma (EMD). EMD remains challenging from a therapeutic and biological perspective. The pathogenetic mechanisms are not completely understood and it is generally associated with high-risk cytogenetics which portends poor outcomes. There is a rising incidence of EMD in the era of novel agents, likely a reflection of longer OS, with no standard treatment approach. Patients benefit from aggressive chemotherapy-based approaches, but the OS and prognosis remains poor. RT has been used for palliative care. There is a need for large prospective trials for development of treatment approaches for treatment of EMD.

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