Denosumab for bone lesions in multiple myeloma - what is its value?
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ABSTRACT:
SUBMITTER: Goldstein DA
PROVIDER: S-EPMC5927995 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:It is unclear whether the new anti-catabolic agent denosumab represents a viable alternative to the widely used anti-catabolic agent pamidronate in the treatment of Multiple Myeloma (MM)-induced bone disease. This lack of clarity primarily stems from the lack of sufficient clinical investigations, which are costly and time consuming. However, in silico investigations require less time and expense, suggesting that they may be a useful complement to traditional clinical investigations. In this paper, we aim to (i) develop integrated computational models that are suitable for investigating the effects of pamidronate and denosumab on MM-induced bone disease and (ii) evaluate the responses to pamidronate and denosumab treatments using these integrated models. To achieve these goals, pharmacokinetic models of pamidronate and denosumab are first developed and then calibrated and validated using different clinical datasets. Next, the integrated computational models are developed by incorporating the simulated transient concentrations of pamidronate and denosumab and simulations of their actions on the MM-bone compartment into the previously proposed MM-bone model. These integrated models are further calibrated and validated by different clinical datasets so that they are suitable to be applied to investigate the responses to the pamidronate and denosumab treatments. Finally, these responses are evaluated by quantifying the bone volume, bone turnover, and MM-cell density. This evaluation identifies four denosumab regimes that potentially produce an overall improved bone-related response compared with the recommended pamidronate regime. This in silico investigation supports the idea that denosumab represents an appropriate alternative to pamidronate in the treatment of MM-induced bone disease.
| S-EPMC3448612 | biostudies-literature
Project description:Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast-mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanisms underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remain unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell-secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent or treat patients with myeloma bone disease.
| S-EPMC9237076 | biostudies-literature
Project description:Bone destruction is a hallmark of multiple myeloma and affects more than 80% of patients. However, current therapy is unable to completely cure and/or prevent bone lesions. Although it is accepted that myeloma cells mediate bone destruction by inhibition of osteoblasts and activation of osteoclasts, the underlying mechanism is still poorly understood. This study demonstrates that constitutive activation of p38 mitogen-activated protein kinase in myeloma cells is responsible for myeloma-induced osteolysis. Our results show that p38 is constitutively activated in most myeloma cell lines and primary myeloma cells from patients. Myeloma cells with high/detectable p38 activity, but not those with low/undetectable p38 activity, injected into severe combined immunodeficient (SCID) or SCID-hu mice caused bone destruction. Inhibition or knockdown of p38 in human myeloma reduced or prevented myeloma-induced osteolytic bone lesions without affecting tumor growth, survival, or homing to bone. Mechanistic studies showed that myeloma cell p38 activity inhibited osteoblastogenesis and bone formation and activated osteoclastogenesis and bone resorption in myeloma-bearing SCID mice. This study elucidates a novel molecular mechanism-activation of p38 signaling in myeloma cells-by which myeloma cells induce osteolytic bone lesions, and indicates that targeting myeloma cell p38 may be a viable approach to treating or preventing myeloma bone disease.
| S-EPMC3381862 | biostudies-other
Project description:Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies.
| S-EPMC3727863 | biostudies-other
Project description:The incidence and importance of bone marrow involvement and/or early bone lesions in multiple myeloma (MM) precursor diseases is largely unknown. This study prospectively compared the sensitivity of several imaging modalities in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM. Thirty patients (10 each with MGUS, SMM and MM) were evaluated with skeletal survey, [18F]FDG-PET/CT, [18F]NaF-PET/CT and morphologic dynamic contrast enhanced (DCE)-MRI. An additional 16 SMM patients had skeletal surveys and FDG-PET/CT. Among MGUS patients, DCE-MRI found only one focal marrow abnormality; other evaluations were negative. Among 26 SMM patients, five (19%) were re-classified as MM based on lytic bone lesions on CT and six had unifocal or diffuse marrow abnormality. Among MM, marrow abnormalities were observed on FDG-PET/CT in 8/10 patients and on DCE-MRI in nine evaluable patients. Abnormal NaF uptake was observed only in MM patients with lytic lesions on CT, providing no additional clinical information.
| S-EPMC5576169 | biostudies-literature
Project description:BackgroundMost patients with destructive bone lesions undergo a comprehensive diagnostic procedure to ensure that proper treatment decisions are pursued. For patients with multiple myeloma, this can lead to delays in diagnosis and treatment initiation. This study was conducted to develop a diagnostic rule that could serve as a tool for early identification of multiple myeloma and promote timely referral of patients to haematologists.MethodsThe clinical prediction rule was developed using a retrospective case-series of patients with multiple myeloma (MM) and those with bone metastasis (BM) at Chiang Mai University Hospital from 2012 to 2015. Multivariable fractional polynomial logistic regression was used to derive a diagnostic model to differentiate between MM and BM patients (MM-BM DDx).ResultsA total of 586 patients (136 MM patients and 450 BM patients) were included. Serum creatinine, serum globulin, and serum alkaline phosphatase were identified as significant indicators for the differentiation of MM and BM patients. The MM-BM DDx model showed excellent discriminative ability [AuROC of 0.90 (95%CI 0.86 to 0.93)] and good calibration.ConclusionsThis MM-BM DDx model could potentially allow for early myeloma diagnosis and improvement of overall prognosis. A prospective validation study is needed to confirm the accuracy of the MM-BM DDx model prior to its application in clinical practice.
| S-EPMC7579980 | biostudies-literature
Project description:Multiple myeloma (MM) is the most frequent cancer to involve the skeleton with patients developing osteolytic bone lesions due to hyperactivation of osteoclasts and suppression of BMSCs differentiation into functional osteoblasts. Although new therapies for MM have greatly improved survival, MM remains incurable for most patients. Despite the major advances in current anti-MM and anti-resorptive treatments that can significantly improve osteolytic bone lysis, many bone lesions can persist even after therapeutic remission of active disease. Bone marrow mesenchymal stem cells (BMSCs) from MM patients are phenotypically distinct from their healthy counterparts and the mechanisms associated with the long-term osteogenic suppression are largely unknown. In this review we will highlight recent results of transcriptomic profiling studies that provide new insights into the establishment and maintenance of the persistent pathological alterations in MM-BMSCs that occur in MM. We will we discuss the role of genomic instabilities and senescence in propagating the chronically suppressed state and pro-inflammatory phenotype associated with MM-BMSCs. Lastly we describe the role of epigenetic-based mechanisms in regulating osteogenic gene expression to establish and maintain the pro-longed suppression of MM-BMSC differentiation into functional OBs.
| S-EPMC6303385 | biostudies-other
Project description:This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28-d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept-treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept-treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept-treated patients, with a trend suggesting a dose-related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well-tolerated in MM patients.
| S-EPMC4312883 | biostudies-literature
Project description:Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanism underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remains unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent, or treat patients with, myeloma bone disease.
2022-04-23 | GSE200987 | GEO
Project description:IntroductionThe primary analysis of a global phase 3 study that evaluated the efficacy and safety of denosumab versus zoledronic acid for preventing skeletal-related events (SREs) in adults with newly diagnosed multiple myeloma (MM) indicated that denosumab was noninferior to zoledronic acid for time to first on-study SREs. Here we present a subgroup analysis to evaluate efficacy and safety in Asian patients.MethodsPatients were randomized 1:1 to receive denosumab 120 mg subcutaneously or zoledronic acid intravenously 4 mg every 4 weeks in a double-blind, double-dummy fashion. All patients received standard-of-care first-line antimyeloma treatment. Each patient received either study drug until an estimated 676 patients experienced at least one on-study SRE and the primary efficacy and safety analyses were completed.ResultsOf 1718 total enrolled patients, 196 Asian patients (denosumab, n = 103; zoledronic acid, n = 93) were included in this subgroup analysis. Fewer patients in the denosumab group developed first on-study SRE compared with the zoledronic acid group; the crude incidence of SREs at the primary analysis cutoff was 38.8% and 50.5%, respectively (HR [95% CI], 0.77 [0.48-1.26]). All 194 patients receiving at least one dose of study drug experienced at least one treatment-emergent AE. The most common AEs reported in either group (denosumab, zoledronic acid) were diarrhea (51.0%, 51.1%), nausea (42.2%, 46.7%), and pyrexia (38.2%, 41.3%). Treatment-emergent renal toxicity occurred in 9/102 (8.8%) and 20/92 (21.7%) patients, respectively. Similar rates of positively adjudicated osteonecrosis of the jaw (7 [6.9%] vs 5 [5.4%]) and treatment-emergent hypocalcemia (19 [18.6%] vs 17 [18.5%]) were reported in the denosumab and zoledronic acid groups, respectively.ConclusionEfficacy and safety outcomes from this Asian subgroup were comparable to those of the full study population. Overall, this analysis supports denosumab as an additional treatment option for standard of care for Asian patients with newly diagnosed MM with lytic bone lesions.Clinical trial registrationClinicalTrials.gov NCT01345019.
| S-EPMC7467415 | biostudies-literature