Clinical Profile of Multiple Myeloma in Asia - an Asian Myeloma Network (AMN) Study

Abstract Abstract 5035 Background: The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However the difference of clinical characteristics between ethnic groups is not well-defined. In Asian countries the incidence of MM has been lower compared with Western countries. However, there are growing evidences that MM is increasing very rapidly in this region. Until now, only few data of Asian patients has been reported. Asian myeloma network (AMN) decided to analyze the first multinational project to explore clinical characteristics of Asian MM patients and clinical practice performed in Asian countries. Methods: Data were collected from 22 centers from 7 countries and regions were collected retrospectively. Clinical characteristics of 3377 symptomatic MM patients at diagnosis were described. Overall survival (OS) and prognostic factors were analyzed for 3324 patients who have survival data. Results: Clinical and genetic characteristics were summarized at table 1. Median OS was 47 months (95% CI 48. 0–60. 0). Patients who were diagnosed before 2000 were shorter survival. Transplantation was performed to 607 patients with better survival (84 vs 40 months, p<0. 001). First line treatment of 2906 evaluable patients was analyzed. Overall response rate was 71% including VGPR or better 31%. Novel drug-based regimens including bortezomib, thalidomide or lenalidomide were used for 32. 5% of all 2906 patients without difference in response rate or OS. Conclusions: We successfully described clinical characteristics of Asian MM patients and this project will be the base for future studies or clinical trials for Asian MM patients. Updated analyses and comparison with Western data will be presented. AMN, supported by the International Myeloma Foundation (IMF) IMWG initiative. Disclosures: No relevant conflicts of interest to declare.

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Clinical profile of multiple myeloma in Asia: An Asian Myeloma Network (AMN) study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8097 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8097-8097 ◽

Cited By ~ 1

Author(s):

Jae Hoon Lee ◽

Kihyun Kim ◽

Jin Seok Kim ◽

Chang Ki Min ◽

Kazuyuki Shimizu ◽

...

Keyword(s):

Multiple Myeloma ◽

Survival Data ◽

Clinical Characteristics ◽

Overall Response Rate ◽

Response Rate ◽

New Drugs ◽

Asian Countries ◽

Asian Patients ◽

The Difference ◽

Few Data

8097 Background: The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However the difference of clinical characteristics between ethnic groups is not well-defined. In Asian countries the incidence of MM has been lower compared with Western countries. However, there are growing evidences that MM is increasing very rapidly in this region. Until now, only few data of Asian patients has been reported. Asian myeloma network (AMN) decided to analyze the first multinational project to explore clinical characteristics of Asian MM patients and clinical practice performed in Asian countries. Methods: Data were collected from 21 centers from 7 countries and regions were collected retrospectively. Clinical characteristics of 2969 symptomatic MM patients at diagnosis were described. Overall survival (OS) and prognostic factors were analyzed for 2273 patients who have survival data. Results: Median OS was 54 months (95% CI 48.0-60.0). Patients who were diagnosed before 2000 were shorter survival. Transplantation was performed to 513 patients with better survival (84 vs. 45 months, p<0.001). First line treatment of 2339 evaluable patients was analyzed. Overall response rate was 71% with 30%, VGPR or better. New drugs including bortezomib, thalidomide or lenalidomide were combined for 32.5% of all 2339 patients without difference in response rate or OS according to combination. Conclusions: We successfully described clinical characteristics of Asian MM patients and this project will be the base for future studies or clinical trials for Asian MM patients. Updated analyses and comparison with Western data will be presented. AMN, supported by the International Myeloma Foundation (IMF) IMWG initiative.

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Retrospective Study Of Incidence Of Thromboses In Chinese Versus African Americans With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1121.1121 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1121-1121

Author(s):

Radha Raghupathy ◽

Sabarish Ayyappan ◽

Dhivya Prabhakar ◽

Frankie KF Mo ◽

Erica L. Campagnaro ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Retrospective Study ◽

Lower Risk ◽

Conflicts Of Interest ◽

Significant Risk ◽

Chinese Patients ◽

Asian Patients ◽

Venous Thromboembolic Events ◽

The Difference

Abstract Background Risk of arterial (ATE) and venous thromboembolic events (VTE) is increased in multiple myeloma (MM). Immunomodulator therapy (Imid) concurrent with steroids further increases this risk. Retrospective single arm studies suggest that Asian patients with MM may have a lower risk of TE than in other ethnicities. We performed a retrospective study comparing Chinese (C) and African American (AA) patients in two centers, the Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong (PWH) and the University hospitals, Case Medical Center, Cleveland, Ohio (CMC), for ethnic differences in incidence of TE in MM. Methods 120 Chinese patients from PWH and 100 AA patients from CMC fulfilling IMWG consensus criteria for MM diagnosis between Jan 1st 2000 and Dec 31st 2011 were identified and selected for analysis. Data regarding demographics, comorbidities, myeloma characteristics, therapy and thrombotic complications were collected by electronic and paper chart review. Data collection was censored as of Dec 31st 2012. Results The Chinese cohort comprised more men, lower baseline incidence of diabetes (DM), hypertension (HTN) and non-myeloma related renal failure (CRF), advanced myeloma at diagnosis and more IgA subtype than AA. Over 90% of patients of both groups received chemotherapy. 72% of Chinese and 80% of AA received Imid based treatment. Lenalidomide with steroids was used more often in AA (36.8% AA vs 3.6%C, p<0.0001), Chinese received more thalidomide with steroids. (62.2% C vs 42.1%, p:0.004) Use of thromboprophylaxis (TP) is not routine in PWH, less Chinese were on TP during the disease course (11.7% vs 68%, p<0.0001) or during Imid based treatment. (16% vs 85%, p: 0.0001) Relative rates of aspirin, low molecular weight heparin and warfarin usage for TP were similar across both groups. Despite lower TP rates, a significantly lower rate of symptomatic VTE was observed in the Chinese. (3.3% vs 22%, p:0.001) The difference in VTE detection persisted on correction for number of imaging studies performed, 24 imaging tests in Chinese and 145 in AA. (16.7% vs 48.3%, p:0.004). Amongst the Chinese, all 4 events (100%) occurred on thalidomide dexamethasone (TD), 3 events (75%) in the absence of TP. In the AA, 21 of 26 events (81%) occurred on Imid based treatment. 12 events (46%) occurred in the absence of TP. On binary logistic regression using race, gender, prior venous thrombosis, any TP, TD and lenalidomide dexamethasone therapy as covariates, AA race (OR: 5.022, 95% CI:1.3- 19.4) and TD therapy (OR: 4.07, 1.26- 3.13) emerged as significant risk factors for VTE. Overall incidence of VTE on TD treatment was 4.5% in Chinese versus 22% in AA. (p:0.002) An increased number of arterial events were seen in the Chinese (9.2% vs 3% in AA) but the difference did not reach statistical significance. Of the 11 arterial events in Chinese, 5 (46%) occurred on Imid based therapy, 9 events (82%) were in the absence of TP. 7 were cardiac and 4 cerebrovascular. Of the 3 arterial events in AA, 1 (33.3%) occurred on Imids and all patients were receiving TP. 1 was cardiac, 1 abdominal and 1 upper limb. Conclusion Our study suggests that the Chinese have a lower risk of VTE than AA in the setting of MM. However , despite lower prevalence of most vascular risk factors in Chinese, ATE rates in Chinese were higher than AA, while not statistically significant. Larger studies are necessary to further elucidate these differences in thrombosis risk and to develop specific guidelines for TP in Asian patients with MM Disclosures: No relevant conflicts of interest to declare.

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Thalidomide-Dexamethasone Versus Melphalan-Prednisolone as First Line Treatment in Elderly Patients with Multiple Myeloma: An Interim Analysis.

Blood ◽

10.1182/blood.v106.11.782.782 ◽

2005 ◽

Vol 106 (11) ◽

pp. 782-782 ◽

Cited By ~ 11

Author(s):

Heinz Ludwig ◽

Johannes Drach ◽

Elena Tóthová ◽

Heinz Gisslinger ◽

Werner Linkesch ◽

...

Keyword(s):

Multiple Myeloma ◽

Elderly Patients ◽

Interferon Alpha ◽

Survival Data ◽

Response Rate ◽

Skin Toxicity ◽

Thromboembolic Complications ◽

Interferon Alpha 2B ◽

Best Response ◽

Present Trial

Abstract Thalidomide-Dexamethasone (TD) is an active regimen in patients with relapsing/refractory multiple myeloma (MM). Recent phase II and III studies revealed an even higher response rate in previously untreated patients. In the present trial we compare TD with standard Melphalan-Prednisone (MP) in previously untreated elderly patients with multiple myeloma. The trial is designed to include 350 pts with MM, 190 patients have been enrolled so far (median age: 72 years, stage I: 9 (5%), stage II: 61 (32%), stage III: 120 (63%). Patients are randomized to Thalidomide 200mg/day and Dexamethasone 40mg, days 1–4 and 15–18 (on odd cycles) and days 1–4 (on even cycles) or Melphalan 2.5mg/kg day 1–4 and Prednisone 2mg/kg days 1–4, q 4–6 weeks. Thalidomide should be dosed up to 400mg/day, if feasible. Patients achieving response or stabilization are randomized to maintenance treatment either with Thalidomide (maximal dose 200mg/day)-Interferon alpha-2b (3Mega U, TIW) or Interferon alpha-2b (3Mega U/TIW). All patients are scheduled for monthly Zometa (4mg) during the entire period. Response is defined according Blade’s criteria, statistical results are given by intend to treat analysis. 125 patients are evaluable for response as yet. Best response to TD was: CR 6 (10%), NCR 7 (12%), and VGPR 9 (15%) PR 9 (15%), MR 10 (16%) yielding an ORR of 67%. Four pts had SD (7%) and 16 PD or failure (26%). The respective results in pts on MP were: CR 2 (3%), NCR 4 (6%), VGPR 5 (8%), PR 13 (20%), MR 7 (11%), ORR 48% (p<0.05). Analysis per protocol revealed an ORR of 89% in the TD and 66% in the MP group (p<0.02). Time to response and time to best response was significantly shorter in the TD (8, 11 weeks, respectively) compared to the MP group (10, 39 weeks, respectively; p<0.01, p<0.0047, respectively). Due to the interim nature of the analysis, survival data will be presented only for both groups combined at the meeting. Grade III-IV thrombocytopenia was more frequent and leucopoenia was statistically significant more common in pts on MP (4 (7%) vs. 1 (2%); ns. and (8 (13%) vs. 1 (2%); p< 0.05, respectively). Patients on TD had more grade II-III neuropathy 15 (25%), psychological toxicity 12 (20%) and, skin toxicity 7 (12%) compared to those on MP (5 (8%), 5 (8%), 3 (3%), respectively). Thromboembolic complications were seen in 5 (8%) pts on TD and in 2 (3%) on MP. In conclusion, time to response and time to best response was significantly shorter in pts on TD. Both, the intend to treat and per protocol analysis showed a higher response rate in TD treated pts (67% vs. 48%, p<0.05 and 89% vs. 66%, p<0.02, respectively). Leucopoenia was more frequent in pts on MP and neuropathy more common in TD treated pts. There was a tendency for increased incidence of thromboembolic complications, psychological disturbances and skin toxicity in pts on TD. In relation to the high median age (72 years) of pts studied, TD was well tolerated.

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First Asia-Pacific Co-Operative Multicenter Multiple Myeloma Clinical Trial: Preliminary Results of the “dtZ”/“DAZZLE” Study.

Blood ◽

10.1182/blood.v114.22.4940.4940 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4940-4940

Author(s):

Gerrard Teoh ◽

Kihyun Kim ◽

Alok Srivastava ◽

Vasant Pai ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Conflicts Of Interest ◽

Complete Response ◽

Osteonecrosis Of The Jaw ◽

High Rate ◽

Asia Pacific ◽

Hematopoietic Stem ◽

Asian Patients ◽

Tract Infections

Abstract Abstract 4940 Introduction Many physicians have anecdotally reported that Asian patients with multiple myeloma (MM) are frequently unable to tolerate full doses of dexamethasone (Dex) and/or thalidomide (Thal). Unfortunately, co-operative clinical studies from the Asia-Pacific countries are presently lacking and the effective dose of the Dex/Thal combination in Asians is unknown. Since higher doses of zoledronic acid (Zol) have been shown to exert an anti-MM effect in pre-clinical models of MM, we investigated whether higher frequency dosing of Zol combined with lower doses of Dex/Thal could be an effective and better tolerated regimen in Asian patients. Moreover, since attainment of very good partial response (VGPR), near complete response (nCR) or complete response (CR) prior to autologous hematopoietic stem cell transplantation (AHSCT) correlates with good outcome in MM, we wanted to determine if this lower-dose Dex/Thal with higher-frequency dosing Zol regimen could be a good preparative regimen in transplant-eligible patients. Patients and Methods In this international co-operative multicenter phase II non-randomized single arm study in previously untreated patients with MM (n=44), all patients received up to 6 cycles of three-weekly Dex/Thal/Zol (or “dtZ”). Doses of Dex ranged from 20 mg weekly to 20 mg four times a week; and doses of Thal ranged from 50 mg weekly to 100 mg every night. Zol 4 mg was given three-weekly. Response was graded using Blade's criteria. Results The study population included 67.3% Oriental (Korean and Chinese), 30.8% Indian and 1.9% Malay patients. 15.4% of patients were ISS stage I, 61.5% stage II and 23.1% stage III prior to treatment. 39 (88.6%) patients demonstrated at least a partial response (PR); and 23 (52.3%) of patients achieved VGPR (18.2%), near nCR (15.9%) or CR (18.2%). The fastest time to VGPR/nCR/CR was 1 cycle. Most patients tolerated treatment very well and were managed in the outpatient clinic. Sepsis was the most frequently reported grade 3 or 4 toxicity – 8 (18.2%) patients developed bronchopneumonia, and 3 (6.8%) gastrointestinal or urinary tract infections. 1 (2.3%) patient was suspected of having pulmonary embolism. There were 4 (9.1%) deaths – 3 from severe sepsis and 1 from an unknown cause. Importantly, there were no reports of peripheral neuropathy, osteonecrosis of the jaw (ONJ) or end stage renal failure. In fact, there was an overall 2.4% improvement in the median creatinine clearance time (CCT). Finally, the percentage of CD34 stem cells was not adversely affected by treatment with dtZ. Conclusions The dtZ regimen appears to be an effective and well-tolerated treatment regimen for Asian patients with newly-diagnosed MM. The high rate of VGPR/nCR/CR will greatly facilitate AHSCT in transplant-eligible patients. Judicious use of low-dose Thal has abrogated the numerous side-effects associated with Thal and greatly improved patient tolerance. Even though Zol is administered at a higher frequency, it is not associated with worsening of renal function or ONJ. Infections are the most frequent and worrisome complications of treatment. These are likely to be related to the dose of Dex. Accordingly, it is probably wise to further lower the dose of Dex in future studies. (This study is registered with NIH PRS # 00263484.) Disclosures No relevant conflicts of interest to declare.

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Real World Outcomes with VTD and Cybord Induction Treatment for Transplant Eligible Multiple Myeloma Patients in a Latin American Country. Retrospective Cohort Study from Gamm (Grupo Argentino de Mieloma Multiple)

Blood ◽

10.1182/blood-2018-99-116243 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3301-3301

Author(s):

Natalia Paola Schutz ◽

Paola Ochoa ◽

Patricio Duarte ◽

Guillermina Remaggi ◽

Sebastian Yantorno ◽

...

Keyword(s):

Multiple Myeloma ◽

Cohort Study ◽

Adverse Events ◽

Latin American ◽

Research Funding ◽

Response Rate ◽

Response Rates ◽

Induction Treatment ◽

The Difference

Abstract Introduction: There are scarce data regarding treatment outcomes and toxicity in Latin American countries. Argentina is the second largest country in the region and the fourth most populated one. National Guidelines from the Argentinean Society of Hematology (SAH) recommends the use of bortezomib based triplets for induction treatment in transplant eligible newly diagnosed Multiple Myeloma patients. Objective: To compare response rates and adverse events after induction treatment with Cyclophosphamide Bortezomib and Dexamethasone (CyBorD) or Bortezomib Thalidomide and Dexamethasone (VTD) outside of clinical trials in a Latin American country. Methods: Retrospective multicentric cohort study. All centers participating in the Argentinean Multiple Myeloma Study Group (GAMM) were invited to participate in the study. Eligible patients were 75 years of age or younger, with a diagnosis of Multiple Myeloma according to the IMWG 2014 criteria, transplant eligible, treated with at least one cycle of CyBorD or VTD as induction therapy in the time period from December 2012 until December 2017. Main exclusion criteria were amyloidosis, plasma cell leukemia and previous neuropathy. Patients were identified from local registries at each center and included consecutively in the study database. Epidemiological and clinical data were obtained from medical records and collected in a standardized clinical report form. Patients were followed from diagnosis until death or lost to follow up. Response was evaluated according to IMWG Response Criteria 2016. Adverse events were graded by CTCAE 4.3. Comparisons of response rates were performed using a Chi2 test and differences in rates were expressed as proportions with 95% confidence intervals (CI). Crude odds ratios (OR) and OR adjusted by potential confounders were calculated using a logistic regression model. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS). Stata 13 software was used. Results: A total of 322 patients from 15 centers in Argentina were included in the study. The median age at diagnosis was 57 years (range 26-74), 52% (167) of the patients were male, 18% (58) had renal failure, 28% (85) ISS 3 , 7% (22) extramedullary disease, and 14% (46) high risk cytogenetics. Median time of follow up was 34 months (IQR 21-58). CyBorD was the most common treatment, indicated as induction therapy in 74% (238) of the cases. The characteristics of the patients were similar in both groups except age and LDH levels. The median number of cycles was 5 (range 1-12). Bortezomib was administered once per week in 85% (272) of the patients and subcutaneously in 86% (276) with no differences between both treatment arms. The median cumulative cyclophosphamide dose per month was 1.5 g (IQR 1.5-2.4) and thalidomide dose per day was 100 mg. In the VTD arm, 72,62% (61) of the patients achieved at least very good partial response (VGPR) vs 53.36% (127) with CyBorD [OR of 2.31 (CI 1.35 - 3.99) p=0.002]. The difference in VGPR was 19.26% (CI 15 - 24). Complete response rate (CR) was 35.92% in patients treated with VTD vs 22.55% with CyBorD [OR of 1.87 (CI 1.04 - 3.35) p=0.03). The difference in CR was 13,37% (CI 9.6 -17.53). There was no difference in overall response rate (ORR) with 94.05% vs 91.18% (p=0.406). Adverse events were more common with VTD (69.05% vs 55.46% p=0.030), especially neuropathy grade 3 - 4 (7.14% vs 1.26% p=0.005) and thrombosis (13.10 % vs 3.36 % p=0.001). Deep venous thrombosis prophylaxis was inadequate in 20.24% of the patients. Hematologic adverse events were more common with CyBorD, especially thrombocytopenia (5.95% vs 16.39% p=0.017). Autologous stem cell transplantation (ASCT) was performed in 78% (249) of patients. There was 5% (17) stem cell mobilization failure, all in the CyBorD arm. Response rates after ASCT with VTD and CyBorD induction treatment were: 76.19 vs 73.11% VGPR (p=0.580) and 48.53% vs 40% CR (p=0.20). Maintenance treatment was indicated in 67.86% (57) and 65.13% (155) patients respectively (p=0.650). The PFS at 24 months was 83% (CI 71-90) with VTD vs 72% (CI 66-78) [(HR 0.92 (CI 0.59 - 1.42) p 0.715] and OS 96% (CI 87-99) vs 91% (86-94) respectively [(HR 1.2 (CI 0.62 - 2.32) p 0.587]. Conclusions: VTD has better CR and VGPR compared to CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina based on safety profile. The optimal number of induction treatment cycles remains to be determined. Disclosures Schutz: Takeda: Honoraria, Research Funding; Sanofi Aventis: Research Funding; Roche: Research Funding; Glaxo: Research Funding; Janssen: Honoraria, Research Funding; Varifarma: Honoraria. Shanley:Brystol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Fantl:Janssen: Consultancy, Honoraria, Research Funding; Varifarma/Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Roche: Research Funding; Tecnofarma: Honoraria; BMS: Consultancy, Honoraria; Glaxo: Research Funding.

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High Glycine Promotes Proliferation and Progression Though Increase of Glutathione Synthesis in Multiple Myeloma

Blood ◽

10.1182/blood-2019-125452 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1791-1791

Author(s):

Jiliang Xia ◽

Jingyu Zhang ◽

Bin Meng ◽

Xuan Wu ◽

Qian Lei ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Cell Lines ◽

Peripheral Blood ◽

Colony Formation ◽

Clinical Characteristics ◽

Metabolic Flux ◽

Conflicts Of Interest

Background: Metabolites in tumor microenvironment have been confirmed to contribute to cancer progression. Our previous untargeted metabolomics study has indicated that glycine was significantly increased in bone marrow and peripheral blood derived from Multiple Myeloma(MM) patients compared with health donors(HD). However, the role of glycine in MM progression and its underling mechanisms remain unclear. Materials and Methods: Liquid chromatography-mass spectrometry (LC-MS) was used to detect the concentration of glycine in peripheral blood derived from (25) MM patients and (21) HD. Metabolic flux experiment was performed to explore the distribution of exogenous glycine in MM cell lines ARP1 and 5TGM1. Soft agar colony formation and cell cycle assay were performed to detect MM cells proliferation. 5TGM1 MM mouse models were prepared to examined the effect of glycine on MM in vivo. The unpaired t test was used to evaluate the difference between two different groups. Two-sided Fisher's exact tests were used to assess the associations between glycine abundance and clinical characteristics in MM patients, with a confidence coefficient (confidence interval, CI) of 95%. Results: Targeted metabolic assay of glycine in peripheral blood confirmed that glycine was significantly higher in MM patients than HD(HD vs. MM patients, 14000 vs. 15200, p=0.047). To explore the role of high glycine in MM progression, the associations between glycine abundance and clinical characteristics were investigated. We found that MM patients with high glycine had significantly higher plasma cells percentage(High glycine vs. Low glycine, 11.00% vs. 27.95, p=0.039) and lower hemoglobin concentration(High glycine vs. Low glycine, 96g/l vs. 77g/l, p=0.016). Moreover, high glycine was found to associate with bone damage(p=0.031). Additionally, colony formation and cell cycle assay results showed Glycine-free RPMI 1640 media inhibited MM cells proliferation. Furthermore, 5TMG1 MM mouse fed with glycine-deficiency fodder had slower progression as compared with 5TMG1 MM mouse fed with normal fodder(p=0.0007). These data suggested that exogenous glycine contributes to MM progression. To characterize how exogenous glycine is metabolized in MM cells, MM cell lines ARP1 and 5TGM1 were cultured in the presence of uniformly labeled 13C-glycine for 2, 4, and 6 hours, then the concentration of glycine metabolism related metabolites in conditional media and MM cells were tested by using LC-MS. As a result, 13C-glycine derived GSH was observed in ARP1 as well as 5TGM1, accounting for 37.2% and 52.7% of total GSH after 6 hours of culture, respectively, alternatively, the levels of 13C-GSH in both cell lines were up-regulated with the extension of culture time, indicating that exogenous glycine was involved in GSH synthesis in MM cells. Furthermore, addition of GSH(10 uM) to glycine-free RPMI 1640 media recover the proliferation ability of ARP1 and 5TGM1. Interestingly, betaine, a competitive similar of glycine, was found to suppress MM cell proliferation, and addition of GSH partially counteracted the effect of betaine on MM cells. Conclusion: These findings thus indicate that glycine promotes MM proliferation in vivo and in vitro, and GSH synthesis is the main metabolic pathway contributing to proliferation. Pharmacological blockage of glycine uptake and utilization shows therapeutic potential in MM treatment. Disclosures No relevant conflicts of interest to declare.

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Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy for Chinese Relapsed or Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.4948.4948 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4948-4948

Author(s):

Yongqing Zhang ◽

Guangxun Gao ◽

Jishi Wang ◽

Xiequn Chen

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Partial Response ◽

Combination Therapy ◽

Response Rate ◽

Conflicts Of Interest ◽

Complete Response ◽

Extramedullary Plasmacytoma ◽

Refractory Multiple Myeloma ◽

Progression Of Disease

Abstract Abstract 4948 Objective To investigate the efficacy and safety of PAD (bortezomib, doxorubicin and dexamethasone) combination therapy for Chinese relapsed or refractory multiple myeloma (MM). Methods 31 patients with relapsed or refractory MM received two to eight 21-days cycles of PAD: comprising an intravenous bolus of bortezomib 1.3 mg/m2 (P1,N=13) or 1.0 mg/m2 (P2,N=18) on days 1, 4, 8, and 11, doxorubicin 10mg per day on days 1 to 4, along with dexamethasone 40mg on days 1-4. Response to PAD was evaluated according to International Myeloma Working Group Criteria (IMWG 2006), toxicity was graded according to NCI CTCAE v3.0. Results 25 patients (80.6%) achieved at least a partial response (PR), including complete response (CR) in 9 patients (29%), very good partial response (VGPR) in 7 patients (22.6%), PR in 9 patients (29%) and stable disease (SD) in 4 patients(12.9%), progression of disease (PD) in 2 patients (6.5%); median time to progression was 9.2 months, the median courses to achieve at least PR was 1.6(1-3) cycles, all of 7 patients with extramedullary plasmacytoma achieved at least PR after the first cycle of PAD, extramedullary plasmacytoma disappeared with 1-2 cycles of PAD. The efficacy was independent of traditional prognostic factors such asβ2-MG, Albumin,LDH and Hemoglobin which have previously influenced response to traditional chemotherapy. 1.5 year OS (Overall survival)of CR+VGPR group and PR group were 87.5% vs 46.7% (P=0.09). ≥PR response rate (CR +VGPR +PR) of P1AD and P2AD were 84.6% VS 77.8% (P= 0.501), CR+VGPR rate of P1AD and P2AD were 53.8% vs 50.0% (P=0.561 ). 1 year PFS(Progession-free survival) of P1AD and P2AD were 61.2% vs 55.6%(P=0.638), there were not difference between P1AD and P2AD in response rate(P= 0.501) and 1 year OS (P=0.872). Adverse events included thrombocytopenia in 15 patients ( 48.4% ), leukopenia in 8 patients(25.8%), peripheral neuropathy in 6 patients (19.4% ), varicella herpes zoster in 7 patients (22.6%), fatigue in 11 patients (35.5%) and diarrhea in 5 patients (16.1%), Thrombocytopenia and peripheral neuropathy of P1AD and P2AD were 46.2% vs 11.1%( P=0.037)and 53.8% vs 11.1%(P= 0.014).Common adverse reactions could be controlled with routine supportive treatmemt, one patient (3.2% ) died from respiratory failure during his fifth P1>AD. Conclusions PAD should be considered an appropriate treatment for Chinese relapsed or refractory MM, especially for MM with extramedullary plasmacytoma, its efficacy were independent of traditional prognosis factors, bortezomib dose reduction may reduce toxicities of PAD while retaining the efficacy. Disclosures No relevant conflicts of interest to declare.

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The Difference of Macrophage Involvement in Multiple Myeloma Patients with Distinct Prognosis

Blood ◽

10.1182/blood.v120.21.4979.4979 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4979-4979

Author(s):

Wu Yu ◽

Huangling Zhu ◽

Li Xiang Long ◽

Ting Liu

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Therapeutic Response ◽

Conflicts Of Interest ◽

Hot Spot ◽

Staging System ◽

Female Ratio ◽

International Staging System ◽

The Difference ◽

Male To Female

Abstract Abstract 4979 Recently the essential role of macrophages in the drug resistance or pathogenesis of plasma cell myeloma has gradually been identified and investigated. Here we analyzed patients diagnosed as multiple myeloma in West China Hospital, Si Chuan University, China in the past 3 years. The study involved 156 patients, aged 34–81 year old, mean age 60. 4 year old, male to female ratio is 1. 47:1, including 2 and 3 stages of myeloma according to International Staging System. The therapeutic response was evaluated on the basis of criteria of International Myeloma Working Group Uniform Response Criteria in patients who had completed 3 therapeutic dexamethasone- containing cycles. We observed the involvement of macrophages in bone marrow by immunohistochemical staining of anti-CD68 monoclonal antibody (DAKO). During the observation, two pathologists without any knowledge of clinical data find the “hot spot ” of myeloma cells and then enumerated the number of macrophage in “ hot spots ” under 400 magnification. Interestingly, patients with more macrophage involvement (>40/hp) in bone marrow showed poorer response (including PR, VGPR and CR after 3 cycles of chemotherapy) (31. 2%) to Dexamethasone-containing chemotherapy and higher incidence of disease progression-related deaths. On the contrary, the patients with lower macrophage involvement demonstrated much better response (91. 6%) to chemotherapy and persistent remission (figure 1 the response rate analyzed by macrophage involvement). In summary, the difference of macrophage involvement in bone marrow of multiple myeloma patients with distinct prognosis suggested the macrophage inside bone marrow play a role in myeloma pathogenesis and therapeutic response. Disclosures: No relevant conflicts of interest to declare.

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The Distinct Clinical Features and Prognosis of the CD10+MUM1+ and CD10-Bcl6-MUM1- Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.3895.3895 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3895-3895

Author(s):

Tingxun Lu ◽

Yi Miao ◽

Jia-Zhu Wu ◽

Qi-Xing Gong ◽

Jin-Hua Liang ◽

...

Keyword(s):

Clinical Features ◽

Clinical Characteristics ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Positive Staining ◽

Double Positive ◽

Dual Color ◽

The Difference

Abstract Introduction: Based on combination of the three markers (CD10, Bcl6 and MUM1), Hans algorithm could divide DLBCL into two groups (GCB and non-GCB subtype). Although MUM1 is used as a post GC marker, cases with coexpression of CD10 and MUM1 (CD10+ MUM1+, double positive or DP), which was classified as GCB subtype according to Hans algorithm, do exsit. However, the differences of clinical characteristics and prognosis between DP and other GCB (GCB excluding DP) is unknown. Additionally, DLBCL without any positive staining of these three markers (CD10¨C Bcl6¨C MUM1¨C, triple negative or TN) were also noted. These cases, based on Hans algorithm, are classified as non-GCB subtype. However, little was known about the difference between TN cases with GCB or other non-GCB (non-GCB excluding TN). Patients and methods: Immunohistochemistry was appiled in this study with the antibodies as follows. CD10 (clone 56C6, Dako), CD20 (clone L26, Abcam), Bcl6 (clone LN22, Dako), and MUM1 (clone MUM1p, Dako), FOXP1 (clone JC12, Abcam), GCET1 (clone RAM341, Abcam), LMO2 (clone 1A9-1, Santa Cruz), Myc (clone Y69; Abcam, cut-off: 40%) and Bcl2 (clone 124; Dako, cut-off: 50%). Fluorescence in situ hybridization (FISH) was carried out according to manufacturer¡¯s instructions on with the following probes: MYC dual-color, break apart translocation probe (Vysis LSI) and IGH/BCL2 dual-color, and dual fusion translocation probe (Vysis LSI). For cases with MYC translocation, BCL6 dual-color break apart rearrangement probe (Vysis LSI) wasfurtheranalyzed. A total of 601 cases were included in the study. Among these, 306 cases were treated with rituximab based chemoimmunotherapy and well follow up. The median follow up time was 24.3 months (1 to 115.4 months).We analyzed the clinical features of different groups: GCB vs. non-GCB; DP vs. other GCB (GCB*) or non-GCB; TN vs. other non-GCB (non-GCB*) or GCB. Besides, we further analyzed the survival differences among above groups in patients who were treated with rituximab based chemoimmunotherapy and well followed up. Results: The incidence of the DP patients was 13.3% (80/601, 95%CI: 10.7%-16.3%). The DP phenotype was more likely to occur in elderly patients (P =0.0432) and associated with poor PS status (P =0.0192) than GCB* phenotype. Additionally, although not statistically significant, the DP group showed higher incidence of double hit lymphoma (DHL) than GCB* patients (10.7% vs 2.9%, P =0.139). However, the DP group showed more frequent incidence of double expression lymphoma (DEL, Myc and Bcl2 coexpression) (P =0.044), MYC rearrangement (P =0.016) and DHL (P =0.029) than non-GCB group. The incidence of the TN patients was 8.8% (53/601, 95%CI: 6.7%-11.4%). There was no difference in any of clinical characteristics between the TN and GCB group. However, advanced Ann Arbor stage (III or IV) (P =0.0442), better PS status (P =0.0321), high-risk IPI (P =0.0042) Myc expression as well as BCL2 rearrangement were significantly more common in the non-GCB* group than the TN group. The DP group showed similar overall survival (OS) (median OS: both not reached, P =0.3650) and progression-free survival (PFS) (median PFS: 47.0 vs. 32.7 months, P =0.0878) with the non-GCB group while the TN group showed similar OS (median OS: both not reached, P =0.9278) and PFS (median PFS: both not reached, P =0.9420) with the GCB group (Fig 1-2). Conclusion: Cases in the DP and TE group might hinder the intrinsic power of Hans algorithm in other studies. More detailed classification of DLBCL based on Hans algorithm may help to identify patients with distinct clinical characteristics and prognosis, thereby improving the stratification of patients for risk-adjusted therapies. Disclosures No relevant conflicts of interest to declare.

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Thalidomide Based Regimens for Treatment of Unfit Patients with Relapsed and Refractory Multiple Myeloma: a Monocentric Experience

Blood ◽

10.1182/blood.v116.21.5048.5048 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5048-5048

Author(s):

Alessandro Moscetti ◽

Francesca Saltarelli ◽

Maria Paola Bianchi ◽

Bruno Monarca ◽

Giacinto La Verde

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Response Rate ◽

Conflicts Of Interest ◽

Therapeutic Option ◽

Alkylating Agents ◽

High Dose ◽

Refractory Multiple Myeloma ◽

Unfit Patients

Abstract Abstract 5048 Thalidomide, an immunomodulating drug with antiangiogenic activity, is an efficacious therapeutic option for unfit patients with multiple myeloma. Its efficacy may be increased by the addiction of steroids or other cytotoxic drugs such melphalan or cyclophosphamide. In this study we assessed the efficacy and toxicity of thalidomide based regimens as savage therapy in a series of elderly patients with relapsed/refractory multiple myeloma. Previous treatments included at least one therapy (range 1–4), such as high dose dexamethasone, alkylating agents, anthracyclines, IFN-α and autologous graft. Thalidomide 50–200 mg/die was administered orally in a total of 16 patients (median age 73.8 years, range 59–84) with relapsed/refractory multiple myeloma observed in our Hematology Department between May 2004 and January 2010. Oral dexamethasone or prednisone was added to the treatment. All patients continued therapy until relapse or progression and were prospectively followed-up including accurate monitoring of side effects. Response to thalidomide was assessed according to the European Group for Blood and Marrow Transplantation criteria. The median follow-up time was 25.6 months (range 8 – 68). Overall response rate was 81.2% (13/16 patients) with a median duration of response of 26.7 months (range 7 – 67): 3 patients showed a very good partial remission, 10 partial response, 1 stable disease and 2 progression of disease. During follow-up, 6 patients died (3 due to progression, 2 due to other neoplasm, 1 due to heart failure), 10 patients are still alive (2 VGPR and 7 PR in continuous therapy, 1 PD in third line therapy). No response was observed in 3/16 patients (18.7%). Despite the following side effects, mild to moderate bradycardia (25%, 1 needed PMK positioning and 1 dose reduction), peripheral sensitive polyneuropathy (18.7%) and constipation (6%), no patient discontinued therapy. This study shows that thalidomide based regimens are an effective therapy with a high response rate and manageable side effects when used in patient with multiple myeloma with relapsed/refractory disease. Disclosures: No relevant conflicts of interest to declare.

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