The Lack of Clinical Efficacy of Flavopiridol in Patients with Relapsed Refractory Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3461-3461
Author(s):  
Angela Dispenzieri ◽  
Keith C. Bible ◽  
Martha Q. Lacy ◽  
Tom R. Fitch ◽  
Susan M. Geyer ◽  
...  

Abstract Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against multiple myeloma cells in vitro and ex vivo. It can induce apoptosis in non-cycling human cell lines, including RPMI-8226, a myeloma cell line. Suggested mechanisms of cytotoxicity include down regulation of anti-apoptotic regulators, direct binding to duplex DNA, disruption of transcription factor/DNA binding, upregulation of p53, inhibition of transcription, and inhibition of angiogenesis. A Phase II multicenter trial was conducted to determine the activity of flavopiridol in patients with relapsed or refractory multiple myeloma. Experimental Design: Eighteen patients were treated with 1 hour flavopiridol infusions (50 mg/m(2)/day) for 3 consecutive days every 21 days. Responses were assessed according to IBMTR criteria each cycle. Serial bone marrow aspirates were collected before and immediately after flavopiridol treatment to measure in vivo and ex vivo effects of flavopiridol on patient plasma cells. Immunoblotting for Mcl-1, Bcl-2, p53, cyclin D, phosphoRNA polymerase II and phosphoSTAT 3 was conducted on total cellular proteins isolated from sorted plasma/myeloma cells. Ex vivo assessment of flavopiridol sensitivity of freshly collected myeloma cells was performed for 5 patients pre-therapy. Results: Median age of patients ranged from 49 to 81 years, with a median of 65 years. Patients had received a median of 3 (range, 1–5) treatment regimens prior to enrollment. Sixty-one percent of patients were refractory to prior therapy and fifty-five percent had received prior high dose therapy with hematopoietic stem cell support. The immunoglobulin isotypes of the patients were as follows: IgG (10), IgA (4), light chain (3), and non-secretory (1). At enrollment, 13 patients had a beta-2 microglobulin greater than 3.5. Seven had a plasma cell labeling index greater than or equal to 1%. Four had an elevated LDH. The trial was stopped at time of interim analysis due to a lack of clinical efficacy. Of eighteen treated patients, 15 progressed (including 1 death on study) and 3 discontinued due to toxicity. All patients have ended the active treatment phase, and the mean number of cycles administered for all enrolled patients was 1.6 cycles (range 1–3). No objective responses were observed. The most frequent adverse events were leukopenia and diarrhea (83% each), followed by thrombocytopenia, nausea, and fatigue (61% each). Ex vivo flavopiridol treatment of pre-therapy patient plasma/myeloma cells led to cytotoxicity, but only after longer exposure times at higher flavopiridol concentrations than were anticipated to be achieved in vivo. Further, immunoblotting demonstrated no indication that known in vitro cellular effects of flavopiridol were recapitulated in vivo. Conclusions: Flavopiridol has little single-agent activity in relapsed or refractory multiple myeloma when administered at this dose and schedule, which is likely due to the inability to achieve biologically relevant concentrations in patients. .

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2974-2974
Author(s):  
David R Fooksman ◽  
Amitabha Mazumder ◽  
Mark McCarron

Abstract Multiple myeloma is the 2nd most common blood cancer in adults with a median survival time of 5 years despite high-dose chemotherapy and bone marrow transplantation interventions. Syndecan-1 or CD138, is a heparan-sulfate coated glycoprotein, which is highly expressed on the surface of plasma cells and myeloma cells, important for adhesion and accumulating survival signals. Expression of CD138 is heterogeneous in myeloma tumors, in vivo and in vitro leading some to speculate it may distinguish stem-like subpopulations. While this role is highly disputed, we investigated the effect of CD138 expression on tumor pathology in vivo. To characterize CD138neg and CD138high subpopulations, we used GFP+ Vk*myc myeloma model from Leif Bergsagel, which develops myeloma tumors in BM and spleen of C57Bl/6 mice. We found CD138high populations were more proliferative in vivo based on EdU incorporation experiments. We transferred equal numbers of sorted subpopulations into hosts and found that CD138high cells generated larger tumors in the BM than CD138neg cells after 12 weeks. Analysis of these tumor-bearing mice revealed that all tumors contained both subpopulations, indicating that these two subsets are hierarchically equivalent. We find that in mice with small tumors, the majority of cells (80% or more) are CD138high cells, while in large tumors, the level drops (to 30-50% of tumor) with higher composition of CD138neg cells. We also find lower CD138 levels on myeloma cells found in the blood compared to BM. Using intravital two-photon time-lapse imaging in the tibial BM, we find that tumor cells from smaller, early stage tumors are physically arrested within the BM parenchyma, while in larger, more advanced tumors, myeloma cells are more motile and active. CD138neg cells were more apoptotic based on ex vivo Annexin V staining following serum starvation. Interestingly, serum starvation led to rapid reduction in CD138 surface expression. Taken together, we propose a model where CD138 expression regulates localization and survival in the BM niche, but is downregulated from the plasma membrane when tumor size outgrows the necessary resources, allowing myeloma cells to migrate and metastasize to distant new locations. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3301-3301
Author(s):  
Pritesh R. Patel ◽  
Annie L. Oh ◽  
Vitalyi Senyuk ◽  
Dolores Mahmud ◽  
Nadim Mahmud ◽  
...  

Abstract High dose melphalan is commonly used in patients with multiple myeloma (MM). Resistance to melphalan has been linked to the ability to repair DNA damage. To test whether DNA repair inhibitors overcome resistance to melphalan and and also have a direct anti-MM effect, we tested MM cell lines RPMI8226 and U266 in-vitro and in-vivo, using a NOD/SCID/ gamma null (NSG) xenograft model. RPMI8226 and U266 cells were initially treated in-vitro with the PARP inhibitor ABT-888. Using a proliferative assay, myeloma cells appeared sensitive to ABT-888 with low GI50 values (8.7μM for RPMI8226 cells, 49μM for U266 cells) and increased γH2AX foci, which persisted at 24 hours after treatment. This was confirmed in methycellulose colony assay where ABT-888 treatment reduced RPMI8226 colonies by 35% (p=0.002). Next we showed synergistic cytotoxicity between ABT-888 and melphalan. In both RPMI8226 and U266 cells strong synergy was displayed with a combination index (CI) less than 1 in proliferative assays (CI 0.5 and 0.3 at 50% proliferation respectively). Combination ABT-888 and melphalan treated cells underwent accelerated senescence compared to cells treated by melphalan alone (27% versus 51% βGal+ staining at 24 hours, p=0.02). This was confirmed by upregulation of senescence related genes p16 (1.6 fold increase) and p21 (1.5 fold increase). We did not find significant difference in apoptosis by Annexin V/ PI staining. Given that increased non-homologous end joining (NHEJ) activity has been shown to lead to resistance to melphalan, we tested whether an inhibitor of NHEJ could be synergistic with PARP inhibition and melphalan. Treatment with the DNA-PK inhibitor NU7026 at 10μM in addition to ABT-888 at 4μM resulted in 46% reduction in proliferation in RPMI8226 cells and 52% in U266 cells. When used in combination with melphalan chemotherapy, the dual DNA repair inhibitor therapy showed marked synergy in RPMI8226 cells with a combination index of 0.39. Finally we tested the ability of the combination of ABT-888 and melphalan to treat myeloma in-vivo. NSG mice were injected via tail vein with 5x106 RPMI8226 cells. Control (untreated) mice subsequently developed myeloma infiltrating the marrow, spleen and axial skeleton, with hind limb paralysis occurring at a median of 42 days. Treated mice received intraperitoneal injections of ABT-888 (3 times a week), or melphalan (weekly) or a combination of both agents starting on day 28 post-injection of MM cells for a total of 3 weeks. Using ABT-888, melphalan and a combination of both agents, median survival of mice was progressively prolonged (44 vs. 67 vs. 107 days, respectively) (p=0.02). Here we show that PARP and DNA-PK inhibition synergizes with melphalan in myeloma cells lines, providing a rationale for the addition of these agents to conditioning chemotherapy. In addition, we also show a direct anti-myeloma activity of these agents without the use of alkylator chemotherapy. Disclosures No relevant conflicts of interest to declare.


2020 ◽  
Author(s):  
Su-Lin Lim ◽  
Liang Xu ◽  
Bing-Chen Han ◽  
Pavithra Shyamsunder ◽  
Wee-Joo Chng ◽  
...  

AbstractCyclin Dependent Kinase 9 (CDK9) associates with Bromodomain and Extra-Terminal Domain (BET) proteins to promote transcriptional elongation by phosphorylation of serine 2 of RNAP II C-terminal domain. We examined the therapeutic potential of selective CDK9 inhibitors (AZD 4573 and MC180295) against human multiple myeloma cells in vitro. Short-hairpin RNA silencing of CDK9 in Multiple Myeloma (MM) cell lines reduced cell viability compared to control cells showing the dependency of MM cells on CDK9. In order to explore synergy with the CDK9 inhibitor, proteolysis targeting chimeric molecule (PROTAC) ARV 825 was added. This latter drug causes ubiquitination of BET proteins resulting in their rapid and efficient degradation. Combination treatment of MM cells with ARV 825 and AZD 4573 markedly reduced their protein expression of BRD 2, BRD 4, MYC and phosphorylated RNA pol II as compared to each single agent alone. Combination treatment synergistically inhibited multiple myeloma cells both in vitro and in vivo with insignificant weight loss. The combination also resulted in marked increase of apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) is effective against MM cells.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3987-3987
Author(s):  
Ines Tagoug ◽  
Lars Jordheim ◽  
Anne-Laure Huber ◽  
Stephanie Herveau ◽  
Eva Matera ◽  
...  

Abstract Abstract 3987 Multiple Myeloma (MM) is a clonal plasma cell disorder whose growth and proliferation are linked to a variety of growth factors, including insulin-like growth factor type 1 (IGF-1). Bortezomib, the first-in-class proteasome inhibitor, has displayed significant antitumor activity in multiple myeloma and has been suggested to induce apoptotsis by reducing NF-κB signalling. Other cytotoxic mechanisms have been suggested, including increased reticulum stress leading to an unfolded protein response. We analyzed the impact of recombinant IGF-1 combined with the proteasome inhibitor bortezomib on human plasma cell lines in vitro and in vivo and on fresh human myeloma cells ex vivo. Using an MTT assay, we found that IGF-1 enhanced the cytotoxic activity of bortezomib in vitro against the LP1, RPMI8226, U266 and MM1.S lines, at a concentration of IGF-1 of 100 ng/mL. This potentiating effect was confirmed on MM1.S cells using a flow cytometric analysis of annexin V staining, and showed that the enhanced toxicity could be inhibited by the presence of a monoclonal antibody directed against the IGF-1 receptor (IGF1-R). IGF-1 was also found to enhance the cytotoxic activity of other proteasome inhibitors against MM1.S cells, including MG115, MG132, PSI and epoximicin. In vivo studies were performed in SCID mice bearing MM1.S xenografts. Mice received weekly administrations of bortezomib (0.5 mg/kg, i.p.) with or without recombinant IGF-1 (0.03 mg/kg, i.p.). The co-administration of IGF-1 with bortezomib significantly delayed tumor growth in comparison to that observed in mice treated with bortezomib alone. Fresh human myeloma cells exposed to bortezomib ex vivo displayed a larger annexin V positive fraction when they were co-incubated with IGF-1 then when they were exposed to bortezomib alone. This effect, which could be observed in subpopulations of CD45 hi and CD45 lo cells, could be reversed by an antibody directed against IGF-1R. Thus in each of these situations, IGF-1 increased the sensitivity of multiple myeloma cells to the cytotoxic effect of bortezomib. Analysis of pro- and anti-apoptotic proteins in MM1.S cells by immunoblotting showed that the addition of IGF-1 to bortezomib significantly enhanced the content o Bax, Bad and Bak and significantly reduced the content of Bcl2, BclX-L and Bfl-1. Exploration the NFkB pathway showed that exposure to IGF-1 and bortezomib induced a reduction of IkBalpha, an increase in phosphor-IKBalpha as well as a decrease in NFkB p65. Other observations made with the IGF-1/bortezomib combination include an increase in the content of cleaved caspase 3 and in P21 protein. Cell cycle distributions of cells exposed to bortezomib alone or the IGF-1/bortezomib combination were similar. Preliminary data showed an increased content of CHOP protein, suggesting that the IGF-1/bortezomib combination might enhance reticulum stress in MM1.S cells, thus leading to an Unfolded Protein Response (UPR) and to cell death. These results suggest that IGF-1 sensitizes myeloma cells to proteasome inhibitors by contributing to the enhancement of the reticulum stress. Overall these results suggest that exposure of myeloma cells to one of their key growth factors, IGF-1, significantly enhanced their sensitivity to bortezomib as well as to other proteasome inhibitors. This phenomenon appears to involve several pathways and may be dependent on the high baseline level of reticulum stress present in myeloma cells. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3213-3213
Author(s):  
Leo Rasche ◽  
Stephanie Braendlein ◽  
Johannes Duell ◽  
Stefan Knop ◽  
Valentina Dubljevic ◽  
...  

Abstract Monoclonal antibodies have entered the therapy of multiple myeloma (MM) and are currently being evaluated in phase I-III trials. PAT-SM6 is a fully human IgM antibody that specifically binds to a cancer-specific cell surface variant of the chaperone molecule glucose regulated protein 78 (GRP78). Finding a GRP78 cancer-specific form on the surface of cancer cells, but not normal cells in vivo, presents an opportunity for cancer-specific targeting. This antibody is able to specifically target primary myeloma cells without showing cross-reactivity to healthy tissues (including plasma cells from healthy donors). Moreover, antibody treatment in vitro led to apoptosis in primary myeloma cells (Rasche L; PLOS One 2013). In vitro,PAT-SM6 was combined with Lenalidomide and/or Bortezomib and Dexamethasone in double and triple combinations on myeloma cell lines. Synergistic and additive cytotoxic effects were analyzed using the Chou-Talalay method. All double and triple combinations showed synergistic effect with a combination index (CI) <1. In all double combinations, low doses of agents appear more effective than high doses. In triple, PAT-SM6 + Dexamethasone + Lenalidomide seem to be the most efficient combination (CI from 0.005 to 0.011). In vitro data is further supported by positive in vivodata using PAT-SM6 in a 5T33 multiple myeloma mouse model. Upon injection of 5T33 cells mice developed multiple myeloma disease with clinical, biological and genetic characteristics similar to those of the human disease. A total of 6 doses PAT-SM6 were given i.p. followed by the collection of serum and bone marrow samples. Doses >10mg/kg resulted in a significant reduction of plasma cells in the bone marrow (up to 54%) and a reduction of blood levels (up to 48%) of M protein. No cytotoxicity was observed. Based on these results we performed a Phase I clinical trial to examine the tolerability and safety of the PAT-SM6 antibody in patients with relapsed / refractory multiple myeloma. A pilot Phase I dose-escalating study was initiated (NCT01727778). Relapsed myeloma patients according to IMWG criteria were treated in different dose cohorts (0.3, 1,3 and 6mg/kg/dose) with at least four doses of PAT-SM6 as single agent in a two week cycle. A serological staging was performed on day 36. At the date of the abstract submission 9/12 subjects were treated. PAT-SM6 therapy was very well tolerated. No dose limiting toxicity (DLT), no related SAE and no related adverse events greater than grade 3 were observed. Mild leucopenia seemed to be a specific side effect. At date of submission 8 patients are evaluable for response. Two out of 8 patients showed stable disease according to IMWG criteria. In summary, PAT-SM6 provides a very promising approach for the immune therapy of patients with relapsed and refractory multiple myeloma. Disclosures: Braendlein: Patrys Ltd: Consultancy. Dubljevic:Patrys Ltd: Employment. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Topp:Patrys Ltd: Honoraria.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3478-3478
Author(s):  
Dale Wright ◽  
Shannon L. Winski ◽  
Deborah Anderson ◽  
Patrice Lee ◽  
Mark Munson ◽  
...  

Abstract Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells within the bone marrow. Their growth, survival, and migration are mediated in part via cytokines. Interleukin 6 (IL-6) is necessary for sustaining the in vitro growth of many MM cell lines and enhancing the proliferation of explanted human myeloma cells. The mitogen-activated protein kinase family member, p38, is activated by cytokines and growth factors and plays a significant role in inflammatory diseases. However, its role in the pathogenesis of multiple myeloma is poorly understood. Specific p38 inhibitors inhibit paracrine MM cell growth which is associated with IL-6 and VEGF secretion from bone marrow stromal cells (BMSCs). Furthermore, p38 inhibition blocks TNF-alpha-induced IL-6 secretion in BMSCs, thereby further inhibiting MM cell growth and survival. Although these data suggest an important role for p38 in MM, the direct effects of p38 inhibiton on MM has not been extensively explored. Therefore, we investigated the effects of p38 inhibition on in vitro and in vivo IL-6 production and MM cell growth in vivo after lipopolysaccaride (LPS) stimulation. LPS has been shown to induce various cytokines, including TNF-alpha and IL-6, via the p38 pathway. ARRY-797, an orally bioavailable, small molecule inhibitor of p38 directly inhibited LPS-induced IL-6 production from RPMI-8226 (IC50 = 100 pM) in vitro. In SCID-beige mice, LPS (3 μg/kg) induced IL-6 (7897 ± 827 pg/mL) and TNF-alpha (1922 ± 282 pg/mL) after 2 hours and these cytokines were inhibited by oral administration of ARRY-797 (30 mg/kg) by 91% and 95%, respectively. In MM xenograft models, ARRY-797 (30 mg/kg, BID, PO) inhibited RPMI 8226 tumor growth by 72% as a single agent and by 56% when LPS was administered to stimulate growth in vivo. In addition, ARRY-797 inhibited LPS-induced phosphorylation of p38 in RPMI-8226 xenografts. Together, these data support a role for p38 in IL-6-mediated growth of multiple myelomas. To our knowledge, ARRY-797 is the first small molecule p38 inhibitor to demonstrate single agent activity in a MM xenograft model and it has been advanced into preclinical development.


1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.


Author(s):  
Fatima Aerts-Kaya

: In contrast to their almost unlimited potential for expansion in vivo and despite years of dedicated research and optimization of expansion protocols, the expansion of Hematopoietic Stem Cells (HSCs) in vitro remains remarkably limited. Increased understanding of the mechanisms that are involved in maintenance, expansion and differentiation of HSCs will enable the development of better protocols for expansion of HSCs. This will allow procurement of HSCs with long-term engraftment potential and a better understanding of the effects of the external influences in and on the hematopoietic niche that may affect HSC function. During collection and culture of HSCs, the cells are exposed to suboptimal conditions that may induce different levels of stress and ultimately affect their self-renewal, differentiation and long-term engraftment potential. Some of these stress factors include normoxia, oxidative stress, extra-physiologic oxygen shock/stress (EPHOSS), endoplasmic reticulum (ER) stress, replicative stress, and stress related to DNA damage. Coping with these stress factors may help reduce the negative effects of cell culture on HSC potential, provide a better understanding of the true impact of certain treatments in the absence of confounding stress factors. This may facilitate the development of better ex vivo expansion protocols of HSCs with long-term engraftment potential without induction of stem cell exhaustion by cellular senescence or loss of cell viability. This review summarizes some of available strategies that may be used to protect HSCs from culture-induced stress conditions.


Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.


Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.


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