Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study

Ghobrial, Irène M.; Weller, Edie; Vij, Ravi; Munshi, Nikhil C.; Banwait, Ranjit; Bagshaw, Meghan; Schlossman, Robert; Leduc, Renee; Chuma, Stacey; Kunsman, Janet; Laubach, Jacob P.; Jakubowiak, Andrzej; Maiso, Patricia; Roccaro, Aldo M.; Armand, Philippe; Dollard, Akari M.; Warren, Diane; Harris, Brianna; Poon, Tiffany; Sam, Amy; Rodig, Scott J.; Anderson, Kenneth C.; Richardson, Paul G.

doi:10.1016/s1470-2045(11)70028-6

Cited by 86 publications

(45 citation statements)

References 32 publications

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“…Moreover, the abnormal activation of these two pathways is associated with drug resistance and a poor prognosis of multiple myeloma (15)(16)(17). Nevertheless, previous studies have demonstrated that a sole inhibition of either the RAS/MAPK/ERK or PI3K/AKT pathways was not sufficiently efficacious to eradicate myeloma cells (10,16,(18)(19)(20)(21). The inhibition of RAS is only effective against myeloma cells with mutated RAS, whereas the inhibition of AKT results in compensative activation of the RAS/RAF/ERK pathway in myeloma cells (16,(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

et al. 2014

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Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. Cancer Res; 74(24); 7418-29. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

et al. 2014

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“…49 Interestingly, weekly bortezomib combined with temsirolimus showed promising activity in relapsed MM, with responses in patients who had been refractory to prior bortezomib-containing regimens. 50 Since everolimus as a single agent showed promising activity, with a limited rate of side effects, in relapsed and/or refractory MM patients, efforts should be made to evaluate optimal combination partners to enhance the anti-myeloma activity and to target the PI3K-AKT-mToR signaling network at multiple sites. …”

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confidence: 99%

Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study

Günther¹,

Baumann²,

Burger³

et al. 2015

Haematologica

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“…A newer exciting approach is immunotherapy with modified virus use, 74 natural killer cell therapy, 75,76 or chimeric antigen receptor strategies, 77 combining activity against malignant plasma cells and T-cell receptors. The above and other potential effective drugs in MM [78][79][80][81][82][83][84][85][86] are listed in Table 3. However, all of these newer agents are only used in clinical trials and are not yet available for most practitioners.…”

Section: Future Directionsmentioning

confidence: 99%

How I treat relapsed myeloma

Bladé

Rosiñol

Larrea

2015

Blood

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Multiple myeloma (MM) is a plasma cell malignancy leading to significant life-expectancy shortening. Although the incorporation of the novel agents thalidomide, bortezomib, and lenalidomide in the front-line therapy has resulted in significant improvement, almost all patients relapse, making the treatment of relapse a real challenge. In the present article, when and how to treat relapsed MM is discussed. Treatment can be safely delayed in a subset of patients with asymptomatic relapse, whereas those with symptomatic relapse, advanced disease at diagnosis, or significant paraproteinemic increase require prompt rescue therapy. The benefit of retreatment and the use of a sequential approach for successive relapses considering drug synergism are highlighted. For patients with aggressive relapses and for those who have exhausted all available options, continued therapy until disease progression is recommended, particularly when using regimens with a long-term safety profile. Patients with a duration response to a first autologous stem cell transplantation (ASCT) longer than 2 years may benefit from a second ASCT. Patients with aggressive disease and/or poor cytogenetics at diagnosis relapsing within the first 2 years from ASCT should be considered for an allogeneic transplantation. Finally, a number of newer promising drugs are being actively investigated and the enrolment of patients in clinical trials is encouraged.

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Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study

Cited by 86 publications

References 32 publications

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study

How I treat relapsed myeloma

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