The Current Situation of Multiple Myeloma Treatment in Japan: A Cross-Sectional Analysis Based on Health Insurance Claims Data

Abstract Introduction: Multiple myeloma (MM) is a rare disease with an estimated annual prevalence of 5.3 per 100,000 persons in Japan (Center for Cancer Control and Information Services, 2017). The median age of Japanese patients at the time of diagnosis is 66 years (Japanese Society of Myeloma, 2016). Bortezomib, thalidomide, lenalidomide, pomalidomide, panobinostat, carfilzomib, elotuzumab, ixazomib, and daratumumab have been approved for MM treatment in Japan. Despite a systematic review on treatment costs for relapsed/refractory MM patients in Japan (Yamabe et al. 2015) and a study identifying factors influencing drug choice for first-line treatment of MM (Bolt et al., 2018), comprehensive data on the current situation with MM treatment costs in Japan are lacking. We analyzed health insurance claims data to demonstrate the current status of MM treatment patterns and associated costs in Japan. Methods: We used a health insurance claims database containing records of 19.8 million individuals from 314 acute care hospitals. Diagnostic information was based on the 10th revision of the International Classification of Diseases (ICD10). Drugs were coded based on the Anatomical Therapeutic Chemical Classification System. The monthly medical cost per patient (MMCP) was analyzed from April 2008 to December 2016 as follows: total MMCP, MMCP for MM drugs, and MMCP for other costs (hospitalization, surgery and tests, etc.). The share of each agent in the medical cost of MM drugs was also analyzed throughout the same period. We selected patients with ≥ 1 diagnosis of MM (ICD10 code C90.0). The observation period for each patient started at the latter date of first medical care day for any disease or the first MM diagnosis and ended at the last medical care day for any disease. Results: We identified 19,137 MM patients. Total MMCP showed an increasing trend until lenalidomide was launched in Japan in 2010, at which point MMCP began to stabilize (Figure 1). MMCP per MM drug showed an increasing trend during the entire study period, but other medical costs showed a decreasing trend after the launch of lenalidomide (Figure 2). Detailed analysis of other costs showed that oral medication cost ratio increased just after the launch of lenalidomide and further increased gradually from 2015, while the basic hospitalization cost ratio gradually decreased after the launch of lenalidomide (Figure 3). Analysis of the contribution of each drug to the medical cost of MM drugs showed that the lenalidomide cost reached almost 40% of the share immediately after its launch and remained stable thereafter (Figure 4). Lenalidomide maintained its stable share even after the launch of newer drugs (eg, pomalidomide and carfilzomib) (Figure 4). Discussion: Although a significantly better prognosis has been reported in MM patients treated after 2010 (Shibayama et al. 2013), our data show that lenalidomide addition to MM treatment in Japan did not increase total MMCP for approximately 5 years following lenalidomide launch. This may be due to the prescription of lenalidomide leading to improved MM management in clinical practice, as indicated by changes in the medical cost share of each drug. Such interpretation is also corroborated by a decrease in injection cost and an increase in oral medication cost. It can be argued that as lenalidomide is orally administered, hospitalization and the use of other materials are reduced, resulting in treatment cost reduction. The hospitalization costs for patients receiving lenalidomide maintenance therapy were lower than those for patients not receiving any maintenance therapy (Ashcroft et al. 2018). The Guidelines for the Treatment of Multiple Myeloma (Japanese Society of Myeloma, 2016) present the regimen lenalidomide + low-dose dexamethasone (Rd) for newly diagnosed MM patients and the induction regimen Rd + bortezomib (RVd) for transplant-eligible MM patients as a grade A treatment recommendation and specify a lenalidomide-based triplet regimen as a salvage treatment option for relapsed and/or refractory MM patients. Such a recommendation may explain the relatively stable share of lenalidomide medical care costs despite the launch of new drugs (pomalidomide and carfilzomib) in Japan. Disclosures Uno: Celgene K.K.: Employment. Saito:Celgene K.K.: Employment. Janune:Milliman: Employment. Iwasaki:Milliman: Employment. Ohtsu:Celgene K.K.: Employment. </jats:sec

CCN3-mediated promotion of sulfated proteoglycan synthesis in rat chondrocytes from developing joint heads

Chondrocytes forming articular cartilage are embedded in a vast amount of extracellular matrix having physical stiffness and elasticity, properties that support the mechanical load from bones and enable the flexible movement of synovial joints. Unlike chondrocytes that conduct the growth of long bones by forming the growth plate, articular chondrocytes show suppressed cell proliferation, unless these cells are exposed to pathological conditions such as mechanical overload. In the present study, we found that one of the members of the CCN family, CCN3, was significantly expressed in chondrocytes isolated from the epiphyseal head in developing rat synovial joints. Evaluation of the effect of recombinant CCN3 on those chondrocytes revealed that CCN3 promoted proteoglycan synthesis, whereas this factor repressed the proliferation of the same cells. These results suggest a critical role for CCN3 in the regulation of the biological properties of articular chondrocytes

CCN family protein 2 (CCN2) promotes the early differentiation, but inhibits the terminal differentiation of skeletal myoblasts.

Many studies have reported that CCN family protein 2 (also known as connective tissue growth factor) induces fibrotic response in skeletal muscle, thus emphasizing the pathological role of CCN2 in muscle tissues. However, the physiological role of CCN2 in myogenesis is still unknown. This study clarified the CCN2 functions during myogenesis. Recombinant CCN2 (rCCN2) promoted proliferation and MyoD production in C2C12 cells and primary myoblasts, but inhibited myogenin production. In accordance with these findings, the gene expression levels of myosin heavy chain, which is a marker of terminally differentiated myoblasts and desmin, which is the main intermediate filament protein of muscle cells, were decreased by rCCN2 treatment. In vivo analyses with Ccn2-deficient skeletal muscle revealed decreased proliferating cell nuclear antigen (PCNA)/MyoD double positive cells and muscle hypoplasia. Consistent with this finding, myogenic marker genes and myotube formation were repressed in Ccn2-deficient myoblasts. The protein production of CCN2 was increased in C2C12 myoblasts treated with tumor necrosis factor-α, which is a pro-inflammatory cytokine, suggesting its role in muscle regeneration after inflammation. These findings indicate that CCN2 promotes proliferation and early differentiation but inhibits the terminal differentiation of myoblasts, thus suggesting that CCN2 plays a physiological role in myogenesis

Effect of CCN2 on FGF2-Induced Proliferation and MMP9 and MMP13 Productions by Chondrocytes

CCN2 (also known as connective tissue growth factor) interacts with several growth factors involved in endochondral ossification via its characteristic four modules and modifies the effect of such growth factors. Presently we investigated whether CCN2 interacts with fibroblast growth factor 2 (FGF2). Solid-phase binding assay, immunoprecipitation-Western blot analysis, and surface plasmon resonance (SPR) spectroscopy revealed that the C-terminal module of CCN2 (CT) directly bound to FGF2 with a dissociation constant of 5.5 nm. Next, we examined the combinational effects of CCN2 and FGF2 on the proliferation of and matrix metalloproteinase (MMP)-9 and -13 productions by cultured chondrocytes. FGF2 promoted not only the proliferation but also the production of MMP9 and -13, however, combined of FGF2 with CT module nullified the enhancement of both MMP productions and proliferation. To clarify the mechanism, we investigated the binding of CCN2 or its CT module to FGF receptor 1. As a result, we found that CCN2 bound to FGF receptor 1 with a dissociation constant of 362 nm, whereas the CT module did not. In addition, when we tested FGF signaling in chondrocytic HCS-2/8 cells stimulated by the combination of FGF2 with CT module, the level of ERK1/2, p38 MAPK, and c-Jun N-terminal kinase phosphorylation was decreased compared with that found with FGF2 alone. These findings suggest that CCN2 may regulate the proliferation and matrix degradation of chondrocytes by forming a complex with FGF2 as a novel modulator of FGF2 functions.</jats:p

CCN family protein 2 (CCN2) promotes the early differentiation, but inhibits the terminal differentiation of skeletal myoblasts.

Many studies have reported that CCN family protein 2 (also known as connective tissue growth factor) induces fibrotic response in skeletal muscle, thus emphasizing the pathological role of CCN2 in muscle tissues. However, the physiological role of CCN2 in myogenesis is still unknown. This study clarified the CCN2 functions during myogenesis. Recombinant CCN2 (rCCN2) promoted proliferation and MyoD production in C2C12 cells and primary myoblasts, but inhibited myogenin production. In accordance with these findings, the gene expression levels of myosin heavy chain, which is a marker of terminally differentiated myoblasts and desmin, which is the main intermediate filament protein of muscle cells, were decreased by rCCN2 treatment. In vivo analyses with Ccn2-deficient skeletal muscle revealed decreased proliferating cell nuclear antigen (PCNA)/MyoD double positive cells and muscle hypoplasia. Consistent with this finding, myogenic marker genes and myotube formation were repressed in Ccn2-deficient myoblasts. The protein production of CCN2 was increased in C2C12 myoblasts treated with tumor necrosis factor-α, which is a pro-inflammatory cytokine, suggesting its role in muscle regeneration after inflammation. These findings indicate that CCN2 promotes proliferation and early differentiation but inhibits the terminal differentiation of myoblasts, thus suggesting that CCN2 plays a physiological role in myogenesis

Novel effects of CCN3 that may direct the differentiation of chondrocytes

AbstractIdentification and characterization of local molecules directing the differentiation of chondrocytes to either transient or permanent cartilage are major issues in cartilage biology. Here, we found CCN family protein 3 (CCN3) was abundantly produced in rat developing epiphyseal cartilage. Evaluations in vitro showed that CCN3 repressed epiphyseal chondrocyte proliferation, while promoting matrix production in multiple assays performed. Furthermore, CCN3 enhanced the articular chondrocytic phenotype; whereas it repressed the one representing endochondral ossification. Additionally, the phenotype of growth plate chondrocytes and chondrogenic progenitors also appeared to be affected by CCN3 in a similar manner. These findings suggest a significant role of CCN3 in inducing chondrocytes to articular ones during joint formation