The impact of response on bone-directed therapy in patients with multiple myeloma

Larocca, Alessandra; Child, J. A.; Cook, Gordon; Jackson, Graham; Russell, Nigel H.; Szubert, Alexander J.; Gregory, Walter M.; Brioli, Annamaria; Owen, Roger G.; Drayson, Mark T.; Wu, Ping; Palumbo, Antônio; Boccadoro, Mario; Davies, Faith E.; Morgan, Gareth J.

doi:10.1182/blood-2013-04-498139

Cited by 19 publications

(13 citation statements)

References 19 publications

(18 reference statements)

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“…Dysregulation of the mevalonate pathway activates Vg9Vd2 T cells. For example, N-BPs, such as zoledronate, which represents the standard of care in the treatment of bone disease in patients with multiple myeloma (76), inhibit FPP synthase (Fig. 2) (12).…”

Section: Multiple Mevalonate Metabolites Are Potent Agonists Of Gd T mentioning

confidence: 99%

T lymphocyte regulation by mevalonate metabolism

Thurnher

Gruenbacher

2015

Sci. Signal.

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Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to tumor cells, shift metabolic activity to aerobic glycolysis, which also fuels mevalonate metabolism. Both sterol and nonsterol derivatives of mevalonate affect T cell function. The intracellular availability of sterols, which is dynamically regulated by different classes of transcription factors, represents a metabolic checkpoint that modulates T cell responses. The electron carrier ubiquinone, which is modified with an isoprenoid membrane anchor, plays a pivotal role in OXPHOS, which supports the proliferation of T cells. Isoprenylation also mediates the plasma membrane attachment of the Ras, Rho, and Rab guanosine triphosphatases, which are involved in T cell immunological synapse formation, migration, proliferation, and cytotoxic effector responses. Finally, multiple phosphorylated mevalonate derivatives can act as danger signals for innate-like γδ T cells, thus contributing to the immune surveillance of stress, pathogens, and tumors. We highlight the importance of the mevalonate pathway in the metabolic reprogramming of effector and regulatory T cells.

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Section: Multiple Mevalonate Metabolites Are Potent Agonists Of Gd T mentioning

confidence: 99%

T lymphocyte regulation by mevalonate metabolism

Thurnher

Gruenbacher

2015

Sci. Signal.

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“…Drug combinations targeting both myeloma cells and bone marrow microenvironment could be potentially useful in inducing disease response and halting bone resorption [52]. In this setting, thalidomide and lenalidomide represent a new treatment paradigm because of their alternative mechanism of action that includes disruption of the interaction between plasma cells and bone marrow stromal cells, inhibition of cytokine secretion, antiangiogenic activity, and immunomodulatory effects [53].…”

Section: Treatmentmentioning

confidence: 99%

“…In this setting, thalidomide and lenalidomide represent a new treatment paradigm because of their alternative mechanism of action that includes disruption of the interaction between plasma cells and bone marrow stromal cells, inhibition of cytokine secretion, antiangiogenic activity, and immunomodulatory effects [53]. These drugs interact with bone marrow stromal cells and inhibit the production of cytokines that are known to be directly involved in osteoclastogenesis, including IL-6, IL-12, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF)-alpha [52], so that an important role in inhibiting osteoclast recruitment, maturation, and activity can be postulated. Upon treatment with a combination of thalidomide and dexamethasone, a reduction of serum and urine markers of bone resorption has been demonstrated in newly diagnosed patients [54], especially in cases showing a greater tumor response; in relapsed and refractory patients a progressive decrease of the sRANKL/OPG ratio was also observed during the course of the treatment with thalidomide plus dexamethasone [55].…”

Section: Treatmentmentioning

confidence: 99%

Diagnosis and Treatment of Bone Disease in Multiple Myeloma: Spotlight on Spinal Involvement

Tosi

2013

Scientifica

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Bone disease is observed in almost 80% of newly diagnosed symptomatic multiple myeloma patients, and spine is the bone site that is more frequently affected by myeloma-induced osteoporosis, osteolyses, or compression fractures. In almost 20% of the cases, spinal cord compression may occur; diagnosis and treatment must be carried out rapidly in order to avoid a permanent sensitive or motor defect. Although whole body skeletal X-ray is considered mandatory for multiple myeloma staging, magnetic resonance imaging is presently considered the most appropriate diagnostic technique for the evaluation of vertebral alterations, as it allows to detect not only the exact morphology of the lesions, but also the pattern of bone marrow infiltration by the disease. Multiple treatment modalities can be used to manage multiple myeloma-related vertebral lesions. Surgery or radiotherapy is mainly employed in case of spinal cord compression, impending fractures, or intractable pain. Percutaneous vertebroplasty or balloon kyphoplasty can reduce local pain in a significant fraction of treated patients, without interfering with subsequent therapeutic programs. Systemic antimyeloma therapy with conventional chemotherapy or, more appropriately, with combinations of conventional chemotherapy and compounds acting on both neoplastic plasma cells and bone marrow microenvironment must be soon initiated in order to reduce bone resorption and, possibly, promote bone formation. Bisphosphonates should also be used in combination with antimyeloma therapy as they reduce bone resorption and prolong patients survival. A multidisciplinary approach is thus needed in order to properly manage spinal involvement in multiple myeloma.

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“…A standard therapeutic approach in the management of bone disease occurring in multiple myeloma involves nitrogen-containing bisphosphonates (N-BPs), such as zoledronate that, 11 inhibit farnesyl pyrophosphate (FPP) synthase, a key enzyme at an important branching point of the mevalonate pathway. 12 N-BP-induced depletion of FPP and downstream geranylgeranyl pyrophosphate (GGPP) prevents protein farnesylation and geranylgeranylation, respectively, including multiple members of the Ras superfamily 13 Thus, mevalonate pathway inhibitor therapy has strong anti-bone resorptive activities, as well as direct and indirect antitumor effects.…”

Section: Introductionmentioning

confidence: 99%

Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism

et al. 2014

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The potentially oncogenic mevalonate pathway provides building blocks for protein prenylation and induces cell proliferation and as such is an important therapeutic target. Among mevalonate metabolites, only isopentenyl pyrophosphate (IPP) has been considered to be an immunologically relevant antigen for primate-specific, innate-like Vg9Vd2 T cells with antitumor potential. We show here that Vg9Vd2 T cells pretreated with the stress-related, inflammasome-dependent cytokine interleukin 18 (IL-18) were potently activated not only by IPP but also by all downstream isoprenoid pyrophosphates that exhibit combined features of antigens and cell-extrinsic metabolic cues. Vg9Vd2 T cells induced this way effectively proliferated even under severe lymphopenic conditions and the antioxidant N-acetylcysteine significantly improved reconstitution of gd T cells predominantly with a central memory phenotype. The homeostatic cytokine IL-15 induced the differentiation of effector cells in an antigen-independent fashion, which rapidly produced abundant interferon g (IFNg) upon antigen re-encounter. IL-15 induced effector gd T cells displayed increased levels of the cytotoxic lymphocyte-associated proteins CD56, CD96, CD161 and perforin. In response to stimulation with isoprenoid pyrophosphates, these effector cells upregulated surface expression of CD107a and exhibited strong cytotoxicity against tumor cells in vitro. Our data clarify understanding of innate immunosurveillance mechanisms and will facilitate the controlled generation of robust Vg9Vd2 T cell subsets for effective cancer immunotherapy.

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The impact of response on bone-directed therapy in patients with multiple myeloma

Abstract: Key Points The use of ZOL is better than CLO in the improvement of SREs and survival in symptomatic myeloma patients at diagnosis. Response category posttransplant may influence the impact of bisphosphonate therapy.

Cited by 19 publications

References 19 publications

T lymphocyte regulation by mevalonate metabolism

T lymphocyte regulation by mevalonate metabolism

Diagnosis and Treatment of Bone Disease in Multiple Myeloma: Spotlight on Spinal Involvement

Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism

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