Year: 2019
Type: article
Abstract: Multiple myeloma remains an incurable malignancy with devastating impact on the skeleton.1-3 The mechanisms governing the increased osteoclastic action and the decreased osteoblastic maturation that underlie myeloma bone disease are at least partially understood.4, 5 However, the skeletal manifestations of multiple myeloma continue to represent significant morbidity that is often intractable.3, 6 Strategies to inhibit bone resorption are routinely used, with significant benefits in halting disease.6 Even though multiple myeloma therapy has been shown, at least in pelvic lesions, to lead to some remineralization,7 multiple myeloma treatment does not commonly lead to repair of skeletal lesions. Therefore, novel approaches are needed. Recently, a number of studies, including the one presented in this issue of JBMR,8 have proposed combination of inhibition of bone resorption with the use of agents stimulating bone formation, a strategy that has also been explored in bone metastases in solid tumors and in osteoporosis. The current article by Paton-Hough and colleagues focuses on transforming growth factor β (TGFβ), previously reported to be produced not only by bone marrow stromal cells but also by multiple myeloma cells9-11 and known to inhibit osteoblastic differentiation.12 TGFβ is also present in the bone matrix, from which it is released and activated by resorptive activity.13 The authors first convincingly show that 1D11 reverses TGFβ-induced inhibition of osteoblastic differentiation in vitro. Based on the recently reported beneficial effect of TGFβ inhibition in multiple myeloma treatment,14 in this article, the authors use the well-accepted JJN3 multiple myeloma murine model to demonstrate that the anti-TGFβ antibody 1D11, in combination therapy with zoledronic acid, improves trabecular bone microarchitecture. Extending these findings, the authors also show significant repair of bone lesions with combination therapy in another model of multiple myeloma (U266-bearing mice), suggesting that this combination of therapies not only could arrest skeletal disease but also could lead to improvement, if not resolution, of myeloma bone lesions. The latter, of course, could have important clinical implications. Surprisingly, 1D11 did not result in improved osteoblastic numbers, but rather it was associated with lower osteoclast numbers, both in vitro and in vivo, even without the addition of zoledronic acid. Interleukin 6 (IL6) is known to be produced by multiple myeloma cells as well as by bone marrow stromal cells, to be a key supportive microenvironmental signal for multiple myeloma,15 and to impact osteoclastogenesis.16 Therefore, IL6 was quantified in the sera of mice with multiple myeloma and found to be decreased with 1D11 treatment. These data suggest that IL6 may be modulated by TGFβ in multiple myeloma and that this mechanism may also be responsible for the beneficial effect of 1D11. The efficacy of 1D11 has been previously shown in multiple myeloma,17 where it increased trabecular bone volume and was associated with significantly greater spinal strength, although it did not inhibit tumor burden unless 1D11 was associated with bortezomib. However, in the current article, the authors uniquely combine this successful strategy with zoledronic acid. Based on these data, combination of bortezomib with 1D11 and zoledronic acid may therefore represent an approach with mutual benefits to reduce tumor burden and improve skeletal healing. The authors present compelling data in vivo and in vitro to show that the effect of 1D11 on the skeletal lesions in these models of multiple myeloma are not due to direct effects on tumor burden. This is an important point because inhibition of TGFβ with 1D11 was previously shown to decrease tumor growth in a murine model of breast cancer in combination with cyclophosphamide treatment18 and in murine models of glioma.19 Notably, data in both works suggested a role of 1D11 in modulation of cancer immunity. Neither models evaluated the impact of 1D11 on bone disease. In acute myeloid leukemia (AML) in vitro, 1D11 inhibited accumulation of quiescent cells, a well-established mechanism of resistance to therapy. Moreover, in a murine model of AML, in combination with chemotherapy and with the inhibition of microenvironmental support, 1D11 decreased leukemic burden and prolonged survival,20 although, again, impact on bone was not evaluated. In a murine model of establishment of breast cancer in vivo, treatment with 1D11 before and after inoculation with breast cancer cells decreased the incidence of osteolytic bone lesions.21 This effect was dependent on myeloid cell populations, consistent with the well-established role of TGFβ in metastatic bone disease in solid tumors.22 A limitation of this study is that it employs solely well-established immunodeficient murine models of multiple myeloma.23 However, this choice was justified by the need to use models with a rate of disease progression sufficiently slow to allow the evaluation of a therapeutic intervention aimed at osteolytic bone lesions. In fact, when 1D11 was tested in immunocompetent solid tumor models, TGFβ inhibition was found to be beneficial in enhancing tumor immunity.18 Therefore, it is possible that there may be additional benefit of this combination therapy when examined in an immunocompetent multiple myeloma model. As a caveat, currently approved osteo-anabolic drugs, teriparatide and abaloparatide, are contraindicated in malignancies out of concern that their stimulation of the mesenchymal stem cell niche may translate into more pronounced tumor homing into the bone and/or progress of bone metastases. In light of the unmet medical need in advanced myeloma bone disease, it will be important to define whether novel anabolic strategies such as sclerostin or TGFβ inhibitors may enhance bone formation and strength but lack tumor-promoting effects. In summary, the work by Paton-Hough and colleagues suggests a novel therapeutic approach to myeloma bone disease that could provide benefits not only by arresting skeletal lesions but also by facilitating their repair. Further studies are now needed to test whether combination of this strategy with bortezomib or other chemotherapeutic agents would provide further benefits and to test in patients the promising approach studied by Paton-Hough and colleagues in preclinical models. The authors state that they have no conflicts of interest. This study was supported in part by the Department of Defense, award W81XWH-18-1-0485, and by the Harry T. Mangurian, Jr. Foundation (to LMC) and the Schwerpunktprogramm µBONE (SPP-2084) from Deutsche Forschungsgemeinschaft (to LCH).
DOI: 10.1002/jbmr.3723
Authors: Laura M Calvi, Lorenz C Hofbauer
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2944516044