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  • 1
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    Trends in Incidence and Survival of Multiple Myeloma with Second Primary Malignancy,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3958-3958
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3958-3958
    Abstract: Abstract 3958 Introduction: Recent advances in the treatment of multiple myeloma (MM) have lead to improved patient outcomes and significant improvement in MM survival. Reports from ongoing randomized clinical trials have suggested that there may be an association between the types of treatment received, particularly certain novel therapeutic agents, and a higher incidence of second primary malignancies (SPM) among MM patients. In this analysis, we explored current patterns and trends in incidence and survival of MM between 1973–2008 to better characterize MM patients with second primary malignancies. Methods: We used data from the National Cancer Institute Surveillance Epidemiology and End Results Program (SEER) to examine the incidence and survival trends in MM by SPM status between 1973–2008. We included all cases with MM as the first primary malignancy and calculated the age-adjusted annual incidence rates (AIR per 100,000) stratified by those with single primary (SP) MM and those with MM as the first of multiple primaries (FMP). All cases that were not microscopically confirmed or those with an MM diagnosis coded only from autopsy- or death certificates were excluded from the analysis. We used joinpoint regression models to calculate the annual percent change (APC) and to determine the best fitting line or set of lines that describes the MM temporal trends. A Monte Carlo permutation method was used to test for significance. We used multivariate Cox proportional hazard models to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI) for MM by SPM status, and all analyses were further stratified by year of diagnosis, age, sex, and race/ethnicity. Results: A total of 61,411 cases of MM were recorded in all SEER registries between the years 1973 and 2008. The final analysis included 49,801 SP and 3090 FMP cases. Overall, the AIR of MM was 5.31 (95% CI 5.26–5.36). The AIR of SP MM was 4.33 (95% CI 4.28–4.38) and 0.28 (95% CI 0.27–0.29) for FMP MM. Compared to women, men were 1.41 times (95% CI 1.38–1.44) and 1.95 times as likely to develop SP MM and FMP MM, respectively. African-Americans had the highest rate of SP MM (AIR 9.09; 95% CI 8.85–9.34) and FMP MM (AIR 0.69; 95% CI 0.62–0.76). We observed no significant trend in AIR of SP MM between 1973–2008 (APC 0.03). The rate of FMP MM was relatively stable, however we observed a small but statistically significant increasing trend in incidence between 1973 and 1992 (APC 2.9), followed by a decreasing trend between 1992 and 2008 (APC −3.2). The rate ratio of FMP to SP MM has remained stable at approximately 6% from 1973–2008. The overall hazard ratio of mortality was 0.59 (95% CI 0.56–0.61) with a median survival of 3.6 years in the FMP MM versus 1.7 years in the SP MM patients. There was a statistically significant improvement in the survival of SP MM patients over the past three decades (P for trend 〈 0.001), with the most prominent increase in the 2002–2008 period with a HR of 0.67 (95% CI 0.64–0.69) when compared to those diagnosed in the 1973–1981 period. In contrast, the survival of FMP MM patients remained constant (P for trend=0.39). Although SP MM patients show a significant increase in survival over time, FMP MM survival remained stable and significantly higher. We further stratified the survival analysis by age, sex, and race/ethnicity. In all stratified analyses, FMP MM patients had a significantly better outcome compared to SP MM patients. Conclusions: Although there has been significant improvement in survival for patients with SP MM in recent years, our results provide an epidemiologic evidence suggestive of a subtype of MM with a better outcome, yet a higher risk of secondary primary malignancies. The incidence rate and outcome of this possible subtype has remained unchanged over the last three decades. These findings are replicated when stratified by gender, race, age, and year of diagnosis. Recent advancements of MM treatment have seemed to only increase the survival of SP MM patients, while the survival of FMP MM patients remained stable. Further studies are needed to explore the potential genetic heterogeneity between MM with and without second primary malignancies. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3958.3958
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 2
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    Genetic Susceptibility Markers of Multiple Myeloma in African-Americans
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2030-2030
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2030-2030
    Abstract: Multiple myeloma (MM) is 2-3 times more common among African-Americans compared to non-Hispanic whites. The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in populations of European ancestry have identified seven novel risk loci at 2p23.3 (rs6746082), 3q26.2 (rs10936599), 3p22.1 (rs1052501), 6p21.32 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077) and 22q13.1 (rs877529) (Broderick, et al. Nat Genet, 2011, Chubb, et al. Nat Genet, 2013), three of which were replicated in another European series (Martino et al., Br J Haematol, 2012). Here we examined the index signals and conducted fine-mapping for each locus in a case-control study of 1,049 multiple myeloma cases and 7,084 controls of African ancestry to identify better markers of risk and novel independent loci in seven previously reported regions in this high risk population. Incident cases were recruited from 10 clinical centers and SEER cancer registries from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from previous genome-wide studies of breast and prostate cancer, genotyped using the Illumina 1M-Duo in 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies). Imputation to 1000 Genomes (March 2012 release) was conducted for regions around six of the previously identified single nucleotide polymorphisms [SNPs] (the HLA region harboring rs2285803 is still being imputed, results will be presented). A case-control analysis of SNPs/indels 〉 1% frequency within 250 kb of each index variant was conducted using unconditional multivariable logistic regression adjusting for age, sex and five leading principal components. Region-specific alpha levels were determined through permutation tests. The minimum alpha level across the six regions was α=0.002. All previously reported risk variants were common in African-Americans (minor allele frequency [MAF] 〉 0.05). For five of the six SNPs, we had ≥94% power to detect the same effect observed in non-Hispanic whites, and 64% power for the less common variant rs10936599 (MAF=0.07). We observed directionally consistent effects (odds ratio [OR] 〉 1) for the six risk variants tested, with three replicating at p≤0.05 (7p15.3, p=1.4x10-7; 17p11.2, p=0.05; 22q13.1, p=0.02). For three of the six regions, we observed better markers of risk in African-Americans that were correlated with the index SNP in Europeans (7p15.3, rs56333627, p=1.5x10-5, r2=0.89; 17p11.2, rs34562254, p=2.9x10-3, r2=0.90; 22q13.1, rs2092410, p=1.1x10-4 r2=.71). The missense variant identified in the 17p11.2 region (rs34562254, Pro251Leu) is located in TNFRSF13B, which encodes the protein TACI, a B cell surface receptor which plays a role in B cell maturation, apoptosis and antibody production by inducing activation of transcription factors including NFAT and NFκβ. In addition, there is evidence suggesting that TACI is involved in MM pathogenesis. Our results demonstrate that many of the risk loci for MM found in European ancestry populations are also risk loci in men and women of African ancestry and that by fine-mapping, we are able to identify variants that better capture risk in populations of African ancestry. Disclosures Terebelo: Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2030.2030
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 3
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    Current State of Patient Awareness and Participation in Care for Multiple Myeloma and the Psychophysical Impact of Treatment: An International Internet-Based Study
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1294-1294
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1294-1294
    Abstract: Background: Outcomes in multiple myeloma (MM) have significantly improved, leading to higher prevalence of this disease. Increasing efforts have been made by various agencies to educate patients (pts), manage quality of life (QoL) and survivorship. A global impact of these efforts including pt awareness, disease knowledge and participation in their care, as well as the physical and emotional impact of MM and its treatments (Rx) has not been assessed. We undertook an international, pt-reported survey to investigate these factors and understand any underlying disparities. Methods: A 61-question patient-reported questionnaire (MM-Q), addressing global aspects of MM pts care (components in Figure 1) was used. MM-Q was administered in collaboration with the International Myeloma Foundation (IMF). To limit responses by MM pt only, SmartPatient MM community members and IMF Support Group Leader list were invited to complete the survey. Some of the questions were mandatory, and those with missing responses were withdrawn from the final analysis of that pts MM-Q. Categorical and continuous variables were compared among groups using the Chi-square and Kruskal-Wallis tests, respectively using SAS software (v9.3) with a two-sided significance level of 0.05. Results: Survey responses are available from 894/1240 (72%) individuals thus far. Average survey completion time was 16 minutes. Data from 746 MM-Q was included in this analysis with 466 (62.5%) complete responses. Pts from United States (US) represented 85.7% of the responders (majority from New York State). Ethnicity (n=590) was reported as non-Latino by 97%, race (n=580) was reported as White by 95%, family history of MM was reported by 19 pts and 81 reported prior history of a primary malignancy (most common, 37% non-melanoma skin cancer). Living situation questions (n=538) revealed majority were in a household of 2 (62%), were unemployed/on public assistance (53.5%), travelled alone to medical appointments (74%), with travel times varying from 〈 30 min (55%) to 〉 1 hr (17%). Majority (83%) had no prior knowledge of MM, 63% were patient support group members, and 92% did MM-related research on internet. With respect to MM Rx (n=524), 70% had been on Rx within 3 months and 12% reported non-compliance. Prior Rx included thalidomide (30%), lenalidomide (66%), pomalidomide (11.5%), bortezomib (63.5%), carfilzomib (11%), steroids (100%), and clinical trial participation in 25% pts. Side effects from Rx/QoL in prior 3 months (n=403) are summarized in figure 2. Pts satisfaction with Rx/treating staff (n=378) revealed majority felt their Rx to be effective (92%), right for them (87%) and side effects were as expected (84%). In general, pts acknowledged positive attributes of the Rx staff (worked towards same goal; 91%, participated in decisions; 81%, honesty 89%, confidence; 92%), and their doctor's explanations regarding Rx (benefits; 84%, side effects; 74%, test results; 83%), with the exception of emotional effects of Rx (48%). 94% pts rated their care as good/excellent and 95% were willing to participate in a follow-up survey. Stratification of statistically significant responses by geographical categories, age and time since diagnosis are shown in table 1 and analysis by occupation and educational status is ongoing. Conclusions: We conducted a large patient-reported survey to understand the current state of awareness among MM pts and a global impact of the diagnosis and its Rx on them. We showed that majority of pts who accessed the survey responded (72%), which may be a product of literacy, education and access to technology. Majority of the pts were White and non-Latino, highlighting the possible role of access and awareness in ethnic minorities. We report the large prevalence of psychophysical burden of MM and its Rx in MM pts. In general, MM pts had a high rate of satisfaction related to the Rx and their healthcare providers, but the frequency of discussion regarding emotional effects of Rx between doctors and pts was conspicuously low (48%) and the more recently diagnosed pts were less likely to be satisfied with their treating staff. We also demonstrated significant behavioral pattern differences in geographical, age and time-since-diagnosis subgroups, some of which may be sociocultural, while others may be a result of more patient awareness and understanding of the disease. This knowledge will be very helpful in devising MM survivorship strategies. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1294.1294
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
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    Treatment options for multiple myeloma patients with high-risk disease
    Springer Science and Business Media LLC ; 2010
    In:  Medical Oncology Vol. 27, No. S1 ( 2010-6), p. 53-61
    Details
    In: Medical Oncology, Springer Science and Business Media LLC, Vol. 27, No. S1 ( 2010-6), p. 53-61
    Type of Medium: Online Resource
    ISSN: 1357-0560 , 1559-131X
    URL: Article
    DOI: 10.1007/s12032-010-9521-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
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  • 5
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    Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Lenalidomide Refractory Myeloma: Long Term Follow up and Comparison of 2 Mg Vs 4 Mg Doses
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 4780-4780
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4780-4780
    Abstract: Background: Pomalidomide has demonstrated excellent activity in patients with relapsed, lenalidomide refractory, multiple myeloma (MM). Between November 2007 and March 2012, we enrolled 285 patients with relapsed MM on 5 sequential phase 2 trials; patients received pomalidomide at 2mg or 4 mg daily with weekly dexamethasone (Pom/dex). The approved dose of pomalidomide is 4 mg for 21 of 28 days. We wished to compare efficacy, tolerability and long-term outcomes between cohorts treated with 2 mg or 4mg daily continuously and 4mg daily for 21/28 days. Methods: After excluding two ineligible patients, 283 patients with lenalidomide refractory, relapsed MM from 5 sequential cohorts were analyzed. These patients were divided into 3 groups: Group1 received Pom 2mg for 28/28 day cycle (N= 69), Group 2 received Pom 4 mg for 28/28 day cycle (N= 95) and Group 3 received Pom 4mg for 21/28 day cycle (N= 119). All patients received oral dexamethasone given 40 mg daily on days 1, 8, 15, and 22. Response was assessed by the IMWG Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis or full dose anticoagulation. Results: The median age was 63 years (32-85); 35% were female. The median time from diagnosis was 53 months and the median number of prior regimens was 4. 127 (46%) had high-risk molecular markers. Prior therapies (% received) included lenalidomide (100%), thalidomide (46%), bortezomib (78%), autologous stem cell transplant (71%), and allogeneic transplant (4%). The median follow-up is 16.4 months (3.2-64.4). Forty eight percent are alive and 26% remain progression free; 15 patients are continuing to receive treatment. Frequency of AEs by groups are shown in Table 1. The most notable difference is grade 3+ neutropenia seen in 39% of group 1 and 56% and 57% of groups 2 and 3. Confirmed responses of PR or better were seen in 29% (group1), 35% (group2) and 24% (group3). Median duration of response (DOR) was 14.1 months (group1), 14.5 months (group2) and 10.2 months (group3). Median PFS was 5.5 months (group1), 6.9 months (group2) and 4.3 months (group3). Although the dose level cohorts were sequential rather than randomized, we compared OS between the dose levels in an exploratory manner. There was no significant difference in OS between dose levels (p=0.26). Median overall survival (OS) was 16.6 months (group1), 21.9 months (group2) and 16.0 months (group3). Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients Responses are durable. Response rates and overall toxicity are similar between the 2 mg and 4 mg doses. Neutropenia is more common in those receiving doses of 4mg daily or for 21/28 days compared to those receiving 2 mg daily. Table 1. All Grades Grade 3+ 2mg 28 Day 4mg 28 Day 4mg 21 Day 2mg 28 Day 4mg 28 Day 4mg 21 Day Anemia 68% 58% 74% 14% 15% 27% Lymphopenia 22% 51% 11% 16% 32% 8% Neutropenia 71% 82% 77% 39% 57% 56% Thrombocytopenia 51% 61% 63% 10% 9% 23% Leukopenia 59% 77% 72% 26% 38% 39% Pneumonia 7% 11% 12% 6% 7% 11% Fatigue 51% 65% 60% 9% 5% 8% Neuropathy 28% 32% 28% 0% 3% 0% Elevated Blood Glucose 10% 21% 8% 4% 6% 3% Pneumonitis 3% 2% 3% 3% 1% 1% VTE (Thrombosis) 3% 3% 3% 1% 3% 3% Secondary Malignancy 0% 2% 1% 0% 2% 1% Figure1. Kaplan Meier Overall Survival Curves Figure1. Kaplan Meier Overall Survival Curves Disclosures Lacy: Celgene: Research Funding. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Stewart:Novartis: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Array BioPharma: Consultancy; Sanofi: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.4780.4780
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 6
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    A steroid-independent regimen of bortezomib, liposomal doxorubicin and thalidomide demonstrate high response rates in newly diagnosed multiple myeloma patients : VDT Regimen in Newly Diagnosed Multiple Myeloma
    Wiley ; 2011
    In:  British Journal of Haematology Vol. 154, No. 1 ( 2011-07), p. 104-110
    Details
    In: British Journal of Haematology, Wiley, Vol. 154, No. 1 ( 2011-07), p. 104-110
    Type of Medium: Online Resource
    ISSN: 0007-1048
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.2011.154.issue-1
    DOI: 10.1111/j.1365-2141.2011.08703.x
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    Language: English
    Publisher: Wiley
    Publication Date: 2011
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  • 7
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    Combination Therapy with BCNU/Etoposide/Melphalan (BEM) as Conditioning Regimen for Autologous Stem Cell Transplant In Multiple Myeloma.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4587-4587
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4587-4587
    Abstract: Abstract 4587 Background: High-dose chemotherapy and autologous stem cell transplant (ASCT) remains an important therapeutic modality for MM patients. Traditionally high-dose single agent melphalan (200 mg/m2; Mel-200) has been used as the conditioning regimen prior to ASCT for MM. We investigated the combination regimen of BCNU, etoposide and melphalan (BEM) in this setting at our center. Methods: All patients who had undergone ASCT for MM utilizing BEM conditioning regimen at Norris Cancer Center, University of Southern California, Los Angeles were eligible. BEM consisted of BCNU 12 mg/kg (actual body weight or ideal body weight whichever was lower) iv on day -5, etoposide 60 mg/Kg iv on day -3, and melphalan 140 mg/m2 iv on day -1, prior to stem cell reinfusion on day 0. Overall survival (OS) was defined as time from MM diagnosis to death, or in patients still alive, the date of last follow-up. Progression-free survival (PFS) was defined as time from ASCT to date of relapse, or in patients without documented relapse, date of death or last follow up, whichever was sooner. Survival for patients with different clinical and disease-specific characteristics was explored using logrank test. Response was assessed according to International Uniform Response Criteria for MM. Results: A total of 44 MM patients underwent ASCT utilizing the BEM conditioning regimen. Of these, evaluable data was available for 42 patients (25 males; 60%, 17 females; 40%) with a median follow up of 27.6 mths. Median age at diagnosis was 54.5 yr (range 34–68) while median time from MM diagnosis to ASCT was 10.5 mths (range 2.8–47.8). MM subtypes included IgA (n=5, 12%), IgG (n=30, 71%) and light chain-only (n=7, 17%). Median bone marrow (BM) plasmacytosis at diagnosis was 42.5% (range 0%-100%). Durie-Salmon (DS) stages included stage I (12%), II (36%) and III (52%), while 4 patients (10%) had renal dysfunction at the time of initial MM diagnosis. Majority of the patients (71%) had lytic bone lesions at the time of diagnosis and 86% (n=36) hade secretory disease. Patients had received a median of 1 prior treatment (range 1–5), while 23 (55%) patients had received novel agents (proteasome inhibitors or IMiDs) prior to the BEM regimen. Response rates prior to and after the regimen are summarized in Table 1. After BEM-ASCT an additional 16 (38%) patients achieved a CR. Median duration of hospitalization and time to engraftment were 19 days (range 15–41) and 10.5 days (range 7–19), respectively. One patient died prior to discharge from the hospital post ASCT (Day 36 post ASCT) for a treatment related mortality of 2%. CR rate post BEM-ASCT was 64% with an ORR of 97%. Relapses have been noted in 25 patients to date. Median OS for all patients was 4.9 yrs (5.6 yrs for patients in CR and 6.6 yrs for patients in PR after BEM-ASCT). Median PFS was 23.9 mths for all patients (25 mths for patients in CR and 21.8 mths for those in PR after BEM-ASCT). No statistically significant differences were noted in OS based on patient gender (p=0.47), age at diagnosis ( 〈 or ≥60 yr), MM subtype (p=0.52), DS stage at diagnosis (0.09), patients without lytic bone lesions at diagnosis (p=0.054), secretor status (p=0.2), response status at the time of BEM-ASCT (p=0.9) or prior exposure to novel agents (p=0.62). Conclusions: BEM is a well-tolerated conditioning regimen prior to ASCT in MM and has efficacy comparable to Mel-200. BEM can be effectively employed in patients where Mel-200 is not feasible. We are particularly intrigued by its ability to deliver high CR rates (64%) compared to 〈 30% (historical control). Very encouraging median OS (4.9 yr) and PFS (23.9 mth) rates were noted which were even better in patients who had a measurable response after this regimen. Further investigations will be needed to optimally define its potential as standard conditioning regimen in MM patients undergoing ASCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4587.4587
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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    Methylation Patterns in Waldenströms Macroglobulinemia Cells That Are Inherently Resistant or Have Acquired Resistance to Bortezomib, Converge on the TP63 and Cepba Family of Transcription Factors
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3551-3551
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3551-3551
    Abstract: Background: Waldenstrms macroglobulinemia (WM) is an indolent B-lymphoplasmacytic lymphoma, which is highly sensitive to 20S proteasome inhibitors such as bortezomib. However, clinical resistance to the drug can be observed early at onset of therapy (primary or inherent resistance) or develop over time, through repeated exposure to the drug (acquired resistance). Although prior investigations into the biological mechanisms associated with bortezomib resistance (BR) have identified aberrations at the genomic (PSMB5 mutation) and transcriptional level (loss of XPB-1), there is limited data on the epigenetic abnormalities that support resistance to 20S proteasome inhibition. With this in mind, we conducted a comprehensive methylation and mRNA expression analysis in WM cells focusing on the molecular patterns that characterize inherent BR (iBR) as well as acquired BR (aBR). Materials and Methods: Bortezomib sensitive (BS) human WM cell lines, BCWM.1 and MWCL-1, the iBR WM cell line RPCI-WM1 (developed from a bortezomib-refractory WM patient) as well as aBR subclones (BCWM.1/BR, MWCL-1/BR) were used in the study. Methylation status of WM cells was profiled by Illumina Infinium 450k methylation array. Methylation IDAT files were background subtracted using GenomeStudio v1.9. Beta mixture quantile dilation (BMIQ) method in R watermelon package was used to adjust type II probes into distribution characteristic of type I probes. For each gene, probes were partitioned into 6 regions using R IMA package and the ones belonging to the same region were averaged, including transcription start sites (TSS; both 200 bp and 1500 bp upstream), 5' untranslated region (UTR), and 3'UTR, the first exon, and genebody. Gene regions showing a significant adjusted p-value and a beta difference of 〉 0.1 or 〈 -0.1 were selected for differential hypermethylation and hypomethylation, respectively. Correlation with gene expression was conducted only on genes showing 〉 1.5 fold change in expression. Overview of methodology is shown in Figure 1. Results: We first assessed the differential methylation pattern (TSS, 200bp upstream of gene body) of bortezomib-sensitive (BS, BCWM.1, IC50 6nM) and iBR cells, (RPCI-WM1). A total of 3,801 hypermethylated and 1,865 hypomethylated DNA regions were observed in iBR cells relative to BS cells (Figure 2A). In iBR cells, a negative correlation between hypermethylated DNA and corresponding gene expression was found in 1,039 genes (Spearman r = -0.12) (Figure 2B). In parallel, we compared the methylation pattern (TSS 200bp) of BS WM cells (BCWM.1 and MWCL-1) with their aBR derivatives, which display ~20 – 50 fold resistance to bortezomib. aBR subclones showed differential hypermethylation of 1,521 DNA regions and hypomethylation of 651 genomic regions relative to BS WM cells. These findings were not unexpected as aBR cell lines, being derivatives of BS WM cells, are clonally related to the former, whereas iBR cells are derived from a different clone. Meta-analysis of iBR and aBR followed by pathway enrichment (NextBio, Illumina Inc), revealed a significant clustering of commonly hypermethylated genes within the Validated Transcriptional Targets of TP63 isoforms Canonical Pathway (p 〈 1.9-E5, Figure 2C) and the CEBPA binding site Geneset 2 (p 〈 8.2-E9, Figure 2D); pathways whose genes are actively involved in suppression of cell growth and differentiation. Further validation and functional relevance of candidate gene targets from this analysis, which are relevant to WM pathobiology, are currently being investigated. Conclusion: This is the first study to examine and correlate the global methylation and gene expression profiles in WM tumor cells that are inherently wired to resist 20S proteasome inhibition as well as tumor cells, which have acquired resistance through continuous exposure to bortezomib. Although considerable differences were observed in the methylation profiles of WM cells displaying inherent vs. acquired resistance, a number of common genes emerged and pointed towards transcriptional repressors, whose inactivation through methylation has been linked to other cancers. Altogether, these findings uncover cellular systems in WM cells, which are affected by DNA methylation, subsequent mRNA suppression and which may be associated as a whole with both inherent and acquired forms of bortezomib resistance. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3551.3551
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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    Phase I Study of Lorvotuzumab Mertansine (LM, IMGN901) in Combination with Lenalidomide (Len) and Dexamethasone (Dex) in Patients with CD56-Positive Relapsed or Relapsed/Refractory Multiple Myeloma (MM)
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 728-728
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 728-728
    Abstract: Abstract 728 Background: LM, an antibody-drug conjugate (ADC), is designed to specifically kill CD56+ cancer cells and contains a potent maytansinoid cytotoxic agent (DM1) attached to a CD56-targeting antibody. MM shows CD56 expression in 〉 70% of cases. LM has demonstrated single agent clinical activity and an acceptable safety profile in relapsed/refractory (rel/ref) MM patients. Preclinical studies showed enhanced anti-MM activity when LM was combined with Len/Dex. To further study the safety and efficacy of LM in combination with Len/Dex, a phase I study was conducted in rel/ref patients. This abstract reports updated results on the safety and efficacy of LM/Len/Dex and preliminary results on the pharmacokinetics (PK) and immunogenicity studies. Methods: Primary study objectives were to determine the safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), anti-MM activity and PK of LM in combination with standard oral (PO) doses of Len (25 mg po, daily on days 1–21) and Dex (40 mg po on D 1, 8, 15, and 22) in CD56+ rel/ref MM patients who have received at least 1 prior therapy. LM was given intravenously (IV) on D 1, 8, and 15 on a 28-day cycle. Dose escalation was conducted in new cohorts of patients to define the MTD, which was then further evaluated in a dose-expansion cohort. Adverse events (AEs) were assessed using CTCAEv3 criteria, and dose-limiting toxicity (DLT) determination was based on the occurrence of AEs that were probably or definitely attributed to the study regimen. Efficacy was assessed using the International Myeloma Working Group (IMWG) criteria. Enrollment has completed and 16 patients remain on study. Results: Forty-four patients were enrolled, 41 are currently evaluable for safety and 32 are evaluable for efficacy. The median number of prior therapies was 2 (range 1–11), 62% of patients had prior Len exposure and 33% were Len refractory. LM doses of 75 (N = 11), 90 (N=4), and 112 (N =6) mg/m2 were evaluated in the dose-escalation phase. The most common AE was peripheral neuropathy (PN), which occurred more frequently at higher LM doses (55% at 75 mg/m2 and 100% at 90 and 112 mg/m2); Grade 3 PN was seen only in patients treated at 90 mg/m2 or above. PN emerged, in most cases, in cycles 〉 3 and was manageable with LM dose modification. During dose escalation, 1 patient experienced Grade 4 neutropenia and hyperuricemia. The 75 mg/m2 LM dose was considered the MTD based on overall tolerability and the lower incidence of PN observed, and was further tested to determine its suitability as the RP2D in the dose expansion portion of the study (N=23 patients, 19 patients available for safety evaluation). Grade 1–2 PN occurred in 8 patients (42%) and grade 3 PN was observed only in 1 pt in the dose-expansion cohort. Two patients developed grade 3 tumor lysis syndrome (TLS). Other grade 3 AEs reported in 1 patient each (5%) in the dose-expansion cohort consisted of neutropenia, thrombocytopenia, anemia, hemolytic anemia, and LDH increase. Efficacy was observed across all dose levels and the overall response rate (ORR) was 59%, including 1 patient each with stringent complete response (sCR) and complete response (CR), 8 patients with very good partial remission (VGPR), and 9 patients with partial remission (PR). No immunogenicity against the antibody (HAHA) or DM1 component (HADA) of LM was detected. PK results from 18 patients treated at 75 mg/m2 indicate LM Cmax and exposure in this combination regimen is consistent with LM monotherapy. Conclusions: Based on all available safety data, 75 mg/m2 was considered the RP2D. LM at 75mg/m2 in combination with Len and Dex has shown objective evidence of clinical activity with an acceptable safety profile. Disclosures: Off Label Use: Lorvotusumab mertansine is not FDA approved for treatment of multiple myeloma alone or in combination with lenalidomide and dexamethasone as is investigated in this trial. Running:ImmunoGen, Inc.: Employment. Murphy:ImmunoGen, Inc.: Employment. Guild:ImmunoGen, Inc.: Employment. Carrigan:ImmunoGen, Inc: Employment. Ladd:ImmunoGen, Inc.: Employment. Wolf:ImmunoGen, Inc.: Employment, Equity Ownership. O'Leary:ImmunoGen, Inc.: Employment. Ailawadhi:Millenium Pharmaceuticals: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.728.728
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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    Obesity In Young Adulthood Is Associated With Early Onset Multiple Myeloma In African Americans
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1872-1872
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1872-1872
    Abstract: African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. Methods Patients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, β2 microglobulin level, Ig serotype, light vs. heavy chain disease, and presence of lytic bone lesions. BMI (ht/wt2) was categorized into 3 levels (normal 〈 25, overweight 25-29, obese 〉 30) according to World Health Organization standard. The Pearson chi-square test was used to test the association between BMI category, and risk factors and clinical characteristics. Mean ages at diagnosis across BMI categories were compared using linear regression and a t-test for trend calculated. Results To date, 1,044 African-American MM patients have been enrolled and of those, 1,014 provided a DNA sample. At present, 970 patients have completed a questionnaire, clinical records have been abstracted for 823 patients, and 509 patients have some information on gender, age at diagnosis, weight, height and clinical characteristics.The mean age at diagnosis was 59. Increasing BMI at age 20 was associated with younger age at diagnosis (p= 0.0004), whereas BMI at 5 years prior to diagnosis was not associated with age at diagnosis (p=0.9477). Among men, mean age at diagnosis decreased with increasing BMI at age 20 (p= 0.0125) (Table 1a) and at 5 years prior to diagnosis (p=0.0252) (Table 1b). Among women, the trend was signficant at age 20 (p=0.0018) (Table 1a) but not at 5 years prior to diagnosis (p= 0.7094) (Table 1b). Increasing BMI was not significantly associated with any other clinical characteristics. Conclusion/Discussion In a large collection of African-American MM patients, we observed a strong association between increasing BMI at age 20 and younger age at diagnosis. A similar trend was observed in men only at 5 years prior to diagnosis, consistent with previous reports. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. Obesity at an early age may influence MM risk through shared biological pathways such as interleukin-6 and insulin-like growth factor, by contributing to chronic B-cell activation, thereby increasing susceptibilty for MM later in life. The significance of the gender difference for the association closer to diagnosis is unclear and requires additional study. Disclosures: Terebelo: Amgen: Honoraria; Millennium: Honoraria. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Zonder:Skyline: Consultancy. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Lonial:Celgene Corporation: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.1872.1872
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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