Myeloma bone disease: Pathogenetic mechanisms and clinical assessment

Silvestris, Franco; Lombardi, Lucia; Matteo, Monica De; Bruno, Alfonso Sánchez; Dammacco, Franco

doi:10.1016/j.leukres.2006.04.014

Cited by 46 publications

(43 citation statements)

References 27 publications

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“…In our studies, BEZ235 overcomes the protection conferred to MM cells by IL-6 and IGF-1 cytokines, stromal cells, and osteoclasts. The activity of BEZ235 in MM cocultures with human stromal cells and osteoclasts suggests that the drug will be active in the bone where MM lesions interact with these cells, resulting in increased RANKL levels and the maturation of osteoclasts at these sites (29). We show that BEZ235 overcomes these factors in vitro and causes apoptotic MM cell death, shown by Annexin V/PI and immunoblotting analysis, in response to BEZ235 exposure.…”

Section: Discussionmentioning

confidence: 77%

Antimyeloma Activity of the Orally Bioavailable Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235

et al. 2009

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The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway mediates proliferation, survival, and drug resistance in multiple myeloma (MM) cells. Here, we tested the anti-MM activity of NVP-BEZ235 (BEZ235), which inhibits PI3K/Akt/mTOR signaling at the levels of PI3K and mTOR. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric survival assays showed that MM cell lines exhibited dose-and time-dependent decreased viability after exposure to BEZ235 (IC 50 , 25-800 nmol/L for 48 hours). MM cells highly sensitive (IC 50 , <25 nmol/L) to BEZ235 (e.g., MM.1S, MM.1R, Dox40, and KMS-12-PE) included both lines sensitive and resistant to conventional (dexamethasone, cytotoxic chemotherapeutics) agents. Pharmacologically relevant BEZ235 concentrations (25-400 nmol/L) induced rapid commitment to and induction of MM.1S and OPM-2 cell death. Furthermore, normal donor peripheral blood mononuclear cells were less sensitive (IC 50 , >800 nmol/L) than the majority of MM cell lines tested, suggesting a favorable therapeutic index. In addition, BEZ235 was able to target MM cells in the presence of exogenous interleukin-6, insulin-like growth factor-1, stromal cells, or osteoclasts, which are known to protect against various anti-MM agents. Molecular profiling revealed that BEZ235 treatment decreased the amplitude of transcriptional signatures previously associated with myc, ribosome, and proteasome function, as well as high-risk MM and undifferentiated human embryonic stem cells. In vivo xenograft studies revealed significant reduction in tumor burden (P = 0.011) and survival (P = 0.028) in BEZ235-treated human MM tumor-bearing mice. Combinations of BEZ235 with conventional (e.g., dexamethasone and doxorubicin) or novel (e.g., bortezomib) anti-MM agents showed lack of antagonism. These results indicate that BEZ235 merits clinical testing, alone and in combination with other agents, in

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Section: Discussionmentioning

confidence: 77%

Antimyeloma Activity of the Orally Bioavailable Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235

et al. 2009

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“…Conventional karyotyping to detect hypodiploidy and deletion 13 has value, but if FISH studies are done, additional value in initial risk-stratification is limited. Gene expression profiling (GEP) if available can provide additional prognostic value [22] Serum CrossLaps to measure carboxy-terminal collagen crosslinks (CTX) may be useful in assessing bone turnover and to determine adequacy of bisphosphonate therapy [23,24] Although plain radiographs of the skeleton are typically required to assess the extent of bone disease, PET/CT and MRI scans are more sensitive and are indicated when symptomatic areas show no abnormality on routine radiographs, when there is doubt about the true extent of bone disease on plain radiographs alone, and when solitary plasmacytoma or SMM are suspected [25]. The M protein is considered to be measurable if it is 1gm/dL in the serum and or 200 mg/day in the urine.…”

Section: Poems Syndromementioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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Disease overviewMultiple myeloma accounts for approximately 10% of hematologic malignancies.DiagnosisThe diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end‐organ damage.Risk stratificationIn the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk.Risk‐adapted initial therapyStandard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard‐risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months.Maintenance therapyAfter initial therapy, lenalidomide maintenance is considered for standard‐risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in pateints with intermediate or high‐risk myeloma.Management of refractory diseasePatients with indolent relapse can be treated first with two‐drug or three‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013. © 2013 Wiley Periodicals, Inc.

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“…1 Traditional treatments include autogenous bone graft, allograft bone transplantation, and artificial bone material transplantation. However, these three traditional treatments have some limitations.…”

Section: Introductionmentioning

confidence: 99%