scholarly journals P0291MYELOMA CAST NEPHROPATHY, LIGHT CHAIN DEPOSITION DISEASE, AND BOTH IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Zishan Lin ◽  
Xiaojuan Yu ◽  
Suxia Wang ◽  
Fude Zhou ◽  
Minghui Zhao
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Clinical Characteristics ◽  
Newly Diagnosed ◽  
Renal Survival ◽  
Light Chain Deposition Disease ◽  
Cast Nephropathy ◽  
Significant Difference ◽  
Peking University ◽  
Light Chain Deposition

Abstract Background and Aims The pathological patterns of myeloma-related kidney disease are various, in which myeloma cast nephropathy (MCN) and light chain deposition disease (LCDD) are two of the main patterns. Of note, in patients with multiple myeloma (MM), these two patterns of pathology can occur at the same time. However, there are limited data available showing the difference of clinical characteristics and outcomes among newly diagnosed MM patients with these three patterns of pathology. In this study, we retrospectively reviewed 42 newly diagnosed MM patients with renal biopsy-proven pure MCN, pure LCDD or MCN with coexistent LCDD in Peking University First Hospital, to describe the clinical characteristics, treatment, and outcomes, in order to help define the spectrum of prognostic profiles. Method All the native renal biopsies between September 1999 and October 2019 at Peking University First Hospital were retrospectively restudied. A total of 42 newly diagnosed MM patients with pure MCN (n=24), pure LCDD (n=8) and MCN with coexistent LCDD (n=10) were enrolled. The clinical features, as well as prognostic risk factors for renal survival and overall survival were retrospectively investigated. Results The 42 parents consisted of 26 men and 16 women with a mean age of 53.2±10.9 years. There was no significant difference in age and gender among the 3 groups. Patients with pure LCDD had significantly higher hemoglobin levels, a higher percentage of albumin in urine protein, a lower incidence of progressing to ESRD and more likely to present with AKD than patients with pure MCN or with MCN+LCDD. Patients with pure LCDD had significantly higher serum creatinine levels, a lower eGFR, a lower incidence of death and more likely to present with nephrotic syndrome than patients with pure MCN, but no different than patients with MCN+LCDD. No significant difference between pure MCN and MCN+LCDD. Median renal survival in LCDD group (not reached) was significantly higher compared to MCN (11 months, p = 0.002) group and MCN+LCDD group (1months, p = 0.012, Figure 1). Median overall survival in LCDD group (not reached) was significantly higher compared to MCN (39 months, p = 0.014) group, but had no difference with MCN+LCDD group (not reached, p = 0.199, Figure 2). According to the multivariate analysis, the independent predictors of renal survival were hemoglobin (HR: 0.957, 95% CI: 0.922-0.994; p = 0.022) and eGFR (HR: 0.940, 95% CI: 0.880-0.995; p = 0.034), the independent predictors of overall survival were hemoglobin (HR: 0.943, 95% CI: 0.895-0.993; p = 0.025) and pure MCN (HR: 7.597, 95% CI: 1.171-49.272; p = 0.034). Conclusion Patients with MCN+LCDD presented similar in clinical characteristics to patients with pure MCN and both suffer from more serious and more urgent renal damage than patients with pure LCDD. However, the overall survival in patients with MCN+LCDD was similar to patients with pure LCDD while the renal survival was worse. Hemoglobin and eGFR were independent predictors of renal survival and hemoglobin and pure MCN were independent predictors of overall survival.

Clinicopathological features and outcomes of coexistent light chain cast nephropathy and light chain deposition disease in patients with newly diagnosed multiple myeloma

2021 ◽  
pp. jclinpath-2021-207449
Author(s):  
Zi-Shan Lin ◽  
Xu Zhang ◽  
Dan-Yang Li ◽  
Xiao-Juan Yu ◽  
Ai-Bo Qin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Light Chain ◽  
Renal Outcome ◽  
Newly Diagnosed ◽  
Renal Survival ◽  
Light Chain Deposition Disease ◽  
Cast Nephropathy ◽  
Deposition Disease ◽  
Light Chain Deposition

AimsA varying proportion of patients with multiple myeloma suffer from more than one type of kidney disease simultaneously, of which the most common pattern is coexistent light chain cast nephropathy and light chain deposition disease (LCCN+LCDD). We investigated clinicopathological characteristics and outcomes of LCCN+LCDD in comparison with pure LCCN and pure LCDD.MethodsWe retrospectively analysed 45 newly diagnosed multiple myeloma patients with pure LCCN (n=26), LCCN +LCDD (n=9) and pure LCDD (n=10) between 2000 and 2019 at Peking University First Hospital.ResultsPathologically, patients with LCCN+LCDD were more likely to have λ light chain isotype and presented atypical features of LCDD including less nodular glomerulosclerosis and less deposit distribution than patients with pure LCDD. In clinical characteristics, patients with LCCN +LCDD and patients with pure LCCN shared similar features. The death-censored renal survival in patients with LCCN +LCDD was similar to patients with pure LCCN but worse than patients with pure LCDD, but the overall survival was much better than patients with LCCN alone and similar to patients with pure LCDD. For patients with pure LCCN, the independent predictor of death-censored renal survival was lactate dehydrogenase, and the independent predictors of overall survival were the mean number of casts and serum albumin.ConclusionsPatients with LCCN+LCDD had similar renal outcome compared with patients with pure LCCN but the overall survival is much better. Thus, for patients with LCCN, especially those with λ restriction, pathologists should carefully evaluate the kidney specimens to exclude the possibility of combined LCDD.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease

2017 ◽  
Vol 92 (8) ◽  
pp. 739-745 ◽  
Author(s):  
Meera Mohan ◽  
Amy Buros ◽  
Pankaj Mathur ◽  
Neriman Gokden ◽  
Manisha Singh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Light Chain ◽  
Clinical Characteristics ◽  
Light Chain Deposition Disease ◽  
Deposition Disease ◽  
Light Chain Deposition

scholarly journals P0259PARAPROTEIN-RELATED RENAL LESIONS IN NEWLY DIAGNOSED MULTIPLE MYELOMA: CLINICAL AND PATHOLOGICAL CHARACTERISTIC OF 51 PATIENTS WITH KIDNEY BIOPSIES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Zishan Lin ◽  
Xiaojuan Yu ◽  
Suxia Wang ◽  
Xinan Cen ◽  
Fude Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Renal Involvement ◽  
Laboratory Data ◽  
Lower Percentage ◽  
Newly Diagnosed ◽  
Light Chain Deposition Disease ◽  
Renal Lesions ◽  
Common Diagnosis ◽  
Male Sex

Abstract Background and Aims Renal involvement is common in multiple myeloma (MM). In this study, we examined kidney biopsy findings in patients with newly diagnosed MM (NDMM) and correlated them with clinical characteristics and survival. Method Renal pathological findings were retrospectively studied in 56 patients with NDMM. Clinical and laboratory data as well as outcomes were collected from 51 patients with paraprotein-related renal lesions in NDMM. Patients were categorized according to the with or without myeloma cast nephropathy (MCN). Results Among 56 patients with NDMM, 51 had paraprotein-related renal lesions, of which MCN was the most common lesion in 31 patients (60.8%), followed by amyloidosis in 12 patients (23.5%) and light chain deposition disease (LCDD) in 8 patients (15.7%). Five patients had nonparaprotein-associated lesions, of which minimal change disease was the most common diagnosis, seen in 3 patients (60%). Patients with MCN had significantly higher serum creatinine levels, a lower eGFR, a higher percentage of requiring dialysis at diagnosis, a higher incidence of progressing to end-stage renal disease (ESRD), lower hemoglobin levels, a lower percentage of albumin in urine protein, a higher level of serum albumin and were more likely to have a detectable M-spike but less likely to have a detectable monoclonal whole immunoglobulin than patients without MCN. Compared with patients with MCN, the median overall survival time of patients without MCN was significantly longer (not reached vs 39 months (95% CI: 9–69 months); P=0.047; Fig.1). According to the multivariate analysis, the independent predictors of overall survival were the number of myeloma casts (HR: 1.12, 95% CI: 1.07-1.25; P=0.014) and male sex (HR: 4.99, 95% CI: 1.36-18.38; P=0.016). Conclusion Patients with MCN suffer from more serious and more urgent renal damage and can also present with high-grade albuminuria but without hypoalbuminemia. The number of myeloma casts and male sex are independent predictors of overall survival.

Combination therapy based on bortezomib for 102 patients with newly-diagnosed multiple myeloma: a Chinese experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5116-5116
Author(s):  
Jingsong He ◽  
Li Yang ◽  
Xiaoyan Han ◽  
Gaofeng Zheng ◽  
Xiaojian Meng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Peripheral Neuropathy ◽  
Combination Therapy ◽  
Adverse Events ◽  
Chinese Population ◽  
Median Overall Survival ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Significant Difference

Abstract Abstract 5116 Multiple myeloma (MM) is a malignant neoplasm of plasma. The rates of complete remission (CR) or very good partial remission (VGPR) for patients received conventional chemotherapy are still low with median overall survival about 3 years. Here we report our results with combination therapy based on bortezomib in the Chinese population and investigat the efficacy and safety of Bortezomib-based therapies in previously untreated MM patients. Metohds: Between 1st Feb. 2006 and 31st Dec. 2010, 102 consecutive newly-diagnosed patients with symptomatic MM were treated with combination therapies based on bortezomib. Sixty-four patients were male and 38 were female. Median age was 59 years (range 31–86 years). Forty-two patients were stage 3 according to the International Staging System, 36 patients were stage 2 and 24 patients were stage 1. The combinations included dexamethasone (BD group ), dexamethasone plus subsequent thalidomide (BDT group ) and dexamethasone plus cyclophosphamide (BDC group ) or epirubicin (BDA group ) based on bortezomib. Thirty-five patients were in BDT group, 19 in BD group, 32 in BDC group and 16 in BDA. All patients received a median of three cycles of therapy (range 1–5 ). The IMWG criteria was used for response evaluation and toxicities were evluated according to the NCI Common Toxicity Criteria version 3. Results: The efficacy of the triplet combination therapy based on bortezomib including BDT, BCD and BAD were better than BD group, with response rate greater than or equal to partial remission(≥PR) 85.7%, 90.6%, 93.7% and 68.4%, respectively. The efficacy of BDA and BDC group were significantly superior to BD group (P=0.048,0.050). Bortezomib in combination with chemotherapy was highly effective as treatment for symptomatic multiple myeloma, even only after one cycle. The efficacy for patients received one cycle of BDT, BD, BCD and BAD was 65.7%, 42.1%, 65.6% and 62.5%, respectively. Patients treated with BD had suboptimal responses to those received BDT, BCD and BAD treatment and one cycle of BCD was superior to one cycle of BD (P=0.019).The median follow-up time was 17m (1–60m), including 31m (1–60m) for 35 patients in BDT group and 16m (2–29m) for the remaining 67 patients. The median progression-free survival (PFS ) of BDT group was 15m (9.8–20.2m ) while BD group was 12m (8.1–15.8m), BCD group was 13m (5.9–20.1m ), and BAD group was 12m (7.8–16.2m ), without significant difference. The median overall survival (OS ) of BDT group was 35m (13.2–56.8m ) while BD, BCD and BAD groups was not reached yet. There was no significant difference in OS among groups, but BCD and BAD were superior to BD group (P=0.104, 0.142 ). The frequent treatment-emergent adverse events includes hematologic adverse events such as neutropenia, anemia, thrombocytopenia and the non-hematologic adverse events like fatigue, infection, constipation, diarrhea, pleural effusion and ascites, herpes zoster and peripheral neuropathy. Patients treated with BDT were more likely to show peripheral neuropathy than those treated with BD, BCD and BAD (91.4% vs 73.6%, 68.7%, 74.9% ), but there is no statistical significant difference (P = 0.131), Grade 2 or 3 peripheral neuropathy was occurred in 45.7% of BDT group significantly higher than BD, BCD and BAD groups. (21.0%, 15.7% and 18.7%, P = 0.028 ). Other related adverse events in all the groups had no significant difference. Routine anticoagulation or anti-thrombsis were not used. Only 1 patient suffered from DVT/PE but did well with treatment. Conclusions: Our preliminary experience in Chinese patients indicated that combination chemotherapy based on bortezomib is highly effective in newly-diagnosed multiple myeloma and BDC, BDA or BDT regimens may be more superior to BD in Chinese population. There were relative lower rates of DVT/PE in the Chinese patients with MM received combination chemotherapy based on bortezomib. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparison of bortezomib-cyclophosphamide-dexamethasone versus bortezomib-dexamethasone based regimens in newly diagnosed multiple myeloma patients

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Rafiye Ciftciler ◽  
Hakan Goker ◽  
Yahya Buyukasik ◽  
Nilgun Sayınalp ◽  
Ibrahim C. Haznedaroglu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Mortality Rate ◽  
Care Center ◽  
Tertiary Care ◽  
Progression Free Survival ◽  
Tertiary Care Center ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Significant Difference

The treatment landscape and clinical outcome of multiple myeloma (MM) patients have changed in the last decades, with an improved median survival of 8-10 years. This study aimed to evaluate the bortezomib, cyclophosphamide and dexamethasone (VCD) regimen versus bortezomib and dexamethasone (VD) regimen in patients with newly diagnosed MM. This study has been performed in a retrospective manner. One hundred and three patients with newly diagnosed MM who received chemotherapy at our tertiary care center between the years of 2009 and 2018 were evaluated. A total of 103 patients were included. The 5-year overall survival (OS) for patients who received VD regimen and patients who received VCD regimen were 75% and 83%, respectively. The OS for VD patients was 113.1±12.5 versus 122.2±9.5 months for VCD patients with no statistically significant difference (P=0.47). The 5- year PFS (progression free survival) for patients who received VD regimen and patients who received VCD regimen were 66% and 75%, respectively. The PFS for VCD patients was higher than the PFS for VD patients (67.1±7.4 versus 97.7±13.4 months), but no statistically significant difference was observed (P=0.59). Relapse rate (P=0.002) and mortality rate (P=0.01) were higher in VD group than VCD group and they were statistically significant. The OS and PFS were clinically longer in patients receiving VCD regimen than in patients receiving VD regimen, although not statistically significant. Cyclophosphamide should be given to patients at physician discretion and depending on patient’s frailty function.

scholarly journals Elevated Serum Soluble Interleukin-2 Receptor Level Is a Useful Prognostic Factor for Disease-Specific Overall Survival in Patients with Newly Diagnosed Follicular Lymphoma before Initiation of Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3985-3985
Author(s):  
Kenji Nozaki ◽  
Hiroyuki Sugahara ◽  
Shuji Ueda ◽  
Jun Ishikawa ◽  
Shigeo Fuji ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factor ◽  
Clinical Characteristics ◽  
Interleukin 2 ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Soluble Interleukin 2 Receptor ◽  
Pretreatment Serum ◽  
Disease Specific

Introduction: Serum soluble interleukin-2 receptor (sIL-2R) is recognized as a tumor-related biomarker of malignant lymphomas, including follicular lymphoma (FL). The objective of this study is to assess the prognostic significance of pretreatment serum sIL-2R level for disease-specific overall survival (DSS) in patients with FL. Methods: We retrospectively analyzed medical records of our 10 individual institutions to identify all patients (pts) ≥ 18 years old with newly diagnosed FL between 01/01/2008 and 12/31/2018. Only pts with FL grade 1-3b, confirmed at pathological review, were included. Pts with histological transformation at diagnosis were excluded. Serum sIL-2R was determined by sandwich enzyme-linked immunosorbent assay. Clinical characteristics, therapies, response, relapse patterns and follow up status were collected and analyzed in the cohort. DSS was defined from the time of initial diagnosis to death due to lymphoma or last follow up. DSS was analyzed according to Kaplan Meier method and differences between subgroups were compared with log-rank test. Multivariate cox regression analysis was used to investigate associations of sIL-2R, FL International Prognostic Index (FLIPI) and progression or relapse within 24 months after diagnosis (POD24) with DSS. Serum levels of sIL-2R was measured before initiation of treatment and the data on the nearest date of the diagnostic biopsy within six months was adopted. Results: We recorded 565 pts and 535 pts of them with pretreatment serum sIL-2R levels available were included in the analysis with median age 64 years (range: 30-90) and 305 females (57%). Clinical characteristics are summarized in Table 1. The median of the serum sIL-2R level was 896 IU/mL (range: 145 - 23800). We decided an optimal cutoff value of 1800 IU/mL by using receiver operating characteristic (ROC) analysis, which showed it was 1830 IU/mL (AUC : 0.76, 95%CI : 0.67 - 0.84). Various poor prognostic indicators, such as bulky mass, increased LDH, ≥5 nodal lesions, poor performance status (PS), bone marrow invasion, FLIPI and FLIPI-2 high-risk, decreased Hb, advanced disease, high tumor burden, increased β2MG and existence of B symptoms, were strongly associated with high serum sIL-2R level (≥1800 IU/mL), and high sIL-2R level correlated with POD24 (P<0.001, Chi-squared test). The estimated 10-year DSS rate was 87.2% with a median follow up duration of 4.4 years. In pts with POD24 (96 pts, 18%), DSS was significantly worse than those with non-POD24; 64.3% vs 93.0% (P<0.001) and rituximab maintenance did not improve DSS in both groups (P=0.85 and 0.98, respectively). In patients with sIL-2R level of ≥1800 (high sIL-2R, 378 pts, 71%), DSS was significantly worse than those with sIL-2R level of <1800 IU/mL (low sIL-2R, 157 pts, 29%); 68.2% vs 96.0% (P<0.001), respectively (Figure 1). Multivariate analyses employing sex, PS, sIL-2R, FLIPI and POD24 demonstrated that high sIL-2R was an independent prognostic factor for DSS (HR : 2.88, 95% CI : 1.15-7.21, P<0.05). Regardless of POD24 status, pts with high sIL-2R had significantly worse DSS than those with low sIL-2R; 44.6% vs 91.5% in pts with POD24 (P<0.05) and 82.6% vs 96.8% in pts without POD24 (P<0.001), respectively. Among pts treated with rituximab plus anthracycline-containing chemotherapy as the 1st line regimen (222 pts, 41%), pts with high sIL-2R had significantly worse DSS than those with low sIL-2R; 68.1% vs 97.2% (P<0.001). Among pts treated with rituximab-bendamustine as the 1st line regimen (48 pts, 9%), there was no significant difference between high and low sIL-2R populations (P=0.2), however, among pts treated with bendamustine-containing regimen at least once in their life time (180 pts, 34%), there was significant difference between them; 63.1% vs 87.8% (P<0.05). Even in pts achieving complete metabolic response after 1st line treatment (178 pts, 33%), high pretreatment sIL-2R level was a significant factor affecting poor DSS; 75.9% vs 94.3% (P<0.05). Conclusions: High sIL-2R level ( ≥1800 IU/mL) is a significant and independent adverse prognostic factor for DSS in pts with newly diagnosed FL. This study provides us useful information to predict population with worse DSS before initiation of treatment. Disclosures Nozaki: Chugai: Honoraria; Celgene: Honoraria. Kida:Eisai Co., Ltd: Honoraria. Kosugi:Novartis Pharma Co.: Honoraria; Bristol-Myers Squibb Co.: Honoraria; Eisai Co., Ltd: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene K.K.: Honoraria; Pfizer Inc.: Honoraria. Shibayama:Astellas, Teijin, MSD, Shionogi, Eisai, Sumitomo Dainippon, Taiho, Nippon Shinyaku: Research Funding; Celgene, Chugai, Eisai, AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda, Novartis, Janssen, Chugai, Eisai, Mundi Pharma, Ono, Otsuka, Kyowa Kirin, Sumitomo Dainippon, AstraZeneca, Avvie, DaiichiSankyo, Fujimoto, Nippon Shinyaku, Sanofi, Bristol-Myers Squibb, Pfizer: Honoraria.

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