scholarly journals Inadequate Sars-Cov-2 Vaccine Effectiveness in Patients with Multiple Myeloma: A Large Nationwide Veterans Affairs Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 400-400
Author(s):  
Nathanael R Fillmore ◽  
Jennifer La ◽  
Julie Tsu-Yu Wu ◽  
Westyn Branch-Elliman ◽  
Linden Huhmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cancer Survivors ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Disease Process ◽  
Veterans Affairs ◽  
Vaccine Effectiveness ◽  
Cancer Type ◽  
Matched Cohort ◽  
Treatment Timing

Abstract Introduction Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, is particularly serious in patients with multiple myeloma (MM), with estimated mortality of over 30% in several studies. In the general population, SARS-CoV-2 vaccination has been demonstrated to be an effective approach to preventing infection. However, patients with MM were not included in vaccination trials. Recent studies suggest that patients with compromised immune systems exhibit reduced antibody response to SARS-CoV-2 vaccination, and MM patients are often immunocompromised both due to MM itself and due to MM treatment. Thus, the objective of this retrospective cohort study in the national Veterans Affairs (VA) healthcare system was to evaluate the real-world effectiveness of SARS-CoV-2 vaccination to prevent COVID-19 infection in MM patients during the 140-day period following initial vaccine availability. Methods This is a multicenter study of SARS-CoV-2 infection among vaccinated and unvaccinated patients at VA hospitals nationwide during the period from 12/15/2020 to 5/4/2021. We identified a cohort of MM patients who were alive and without prior SARS-CoV-2 infection on their date of vaccination or inclusion as a control. For added comparison with a less immunocompromised population, we also identified a cohort of cancer survivors, defined as patients with any solid or hematologic malignancy who had been treated with systemic cancer-directed therapy subsequent to 8/15/2010, but had not been treated with such therapy in the 6 months prior to vaccination or inclusion as a control, and were alive and without prior SARS-CoV-2 infection on that date. Vaccinated patients were exactly matched 1:1 to unvaccinated controls on race, VA facility, rurality of home address, cancer type, and treatment timing and modality with minimum distance matching on age. The primary exposure was receipt of a SARS-CoV-2 vaccine. The primary outcome was laboratory-confirmed SARS-CoV-2 infection. Vaccination effectiveness was defined as 1 minus the risk ratio of SARS-CoV-2 infection for vaccinated individuals compared to unvaccinated controls. Results 6,891 MM patients met eligibility criteria and 4,367 were vaccinated during the study period. Of those, 1,606 vaccinated MM patients were matched 1:1 to 1,606 unvaccinated or not yet vaccinated controls. In addition, for comparison, 2,476 vaccinated cancer survivors were matched 1:1 to 2,476 unvaccinated or not yet vaccinated controls. Median follow-up was 44 days among MM patients and 46 days among cancer survivors. Vaccine effectiveness in the matched cohort of MM patients was 22.2% (95% CI, -133 to 82.7%) starting 14 days after the second dose. In contrast, effectiveness was 82.3% (95% CI 16.4 to 100%) starting 14 days after the second dose in the matched cohort of cancer survivors. Among vaccinated MM patients in the matched cohort, 14 (8.7 per 1000 patients) were infected with SARS-CoV-2 subsequent to vaccination. Among vaccinated cancer survivors in the matched cohort, 10 (4.0 per 1000 patients) were infected subsequent to vaccination. Conclusion Vaccination is an effective strategy for preventing SARS-CoV-2. However, effectiveness may be reduced in patients with MM, likely due to a co-existing immunosuppression both due to the disease process as well as associated therapy. Future studies are needed to evaluate the relationship between MM disease states, types of therapy used and treatment timing that may impact vaccine effectiveness, and to also determine if MM patients would benefit from post-vaccination serologies or a booster vaccination. Disclosures Branch-Elliman: Gilead Pharmaceuticals: Research Funding. Brophy: Novartis: Research Funding. Munshi: Pfizer: Consultancy; Legend: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy.

scholarly journals Prevalence and Outcome of COVID-19 Infection in Cancer Patients: A National Veterans Affairs Study

2020 ◽  
Author(s):  
Nathanael R Fillmore ◽  
Jennifer La ◽  
Raphael E Szalat ◽  
David P Tuck ◽  
Vinh Nguyen ◽  
...  
Keyword(s):  
African American ◽  
Cancer Patients ◽  
Hematologic Malignancy ◽  
Statistical Tests ◽  
Veterans Affairs ◽  
Attributable Mortality ◽  
Cancer Type ◽  
The Us ◽  
Charlson Comorbidity Score ◽  
Cancer Types

Abstract Background Emerging data suggest variability in susceptibility and outcome to coronavirus disease 2019 (COVID-19) infection. Identifying risk factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. Methods We analyzed electronic health records of the US Veterans Affairs Healthcare System and assessed the prevalence of COVID-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for COVID-19 who were positive, as well as outcome attributable to COVID-19, and stratified by clinical characteristics including demographics, comorbidities, cancer treatment, and cancer type. All statistical tests are 2-sided. Results Of 22 914 cancer patients tested for COVID-19, 1794 (7.8%) were positive. The prevalence of COVID-19 was similar across age. Higher prevalence was observed in African American (15.0%) compared with White (5.5%; P < .001) and in patients with hematologic malignancy compared with those with solid tumors (10.9% vs 7.8%; P < .001). Conversely, prevalence was lower in current smokers and patients who recently received cancer therapy (<6 months). The COVID-19–attributable mortality was 10.9%. Higher attributable mortality rates were observed in older patients, those with higher Charlson comorbidity score, and in certain cancer types. Recent (<6 months) or past treatment did not influence attributable mortality. Importantly, African American patients had 3.5-fold higher COVID-19–attributable hospitalization; however, they had similar attributable mortality as White patients. Conclusion Preexistence of cancer affects both susceptibility to COVID-19 infection and eventual outcome. The overall COVID-19–attributable mortality in cancer patients is affected by age, comorbidity, and specific cancer types; however, race or recent treatment including immunotherapy do not impact outcome.

scholarly journals Clonal Hematopoiesis Prevalence Increases throughout Treatment of Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1091-1091
Author(s):  
Tarek H. Mouhieddine ◽  
Chidimma Nzerem ◽  
Robert A. Redd ◽  
Andrew Dunford ◽  
Matthew Joseph Leventhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
First Time ◽  
Time Point

Abstract Background: Recent studies have identified clinical and genomic factors contributing to worse clinical outcomes in patients with multiple myeloma (MM). Clonal hematopoiesis (CH) reflects the presence of somatic driver mutations in the blood or marrow of otherwise asymptomatic individuals. Using a variant allele frequency (VAF) cutoff of 2%, we recently reported CH in 21.6% of MM patients at the time of autologous stem cell transplant (ASCT) and found it was associated with shorter overall survival (OS) and progression-free survival (PFS) in those who did not receive maintenance therapy with an immunomodulatory drug (IMiD). However, this finding was based on a single tertiary center and only included MM patients who received ASCT. Methods: We studied a larger cohort of 986 newly diagnosed MM cases. Whole-exome sequencing (WES) data of peripheral blood and bone marrow samples of 986 MM patients (523 transplanted and 463 non-transplanted) from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study were analyzed. Both peripheral blood and tumor samples were analyzed to filter out myeloma mutations that could be contaminating the peripheral blood. Given the lower depth of coverage compared to prior targeted sequencing studies, small clones with a VAF below 2% were not detected. Altogether, the WES samples had a total depth of coverage of 117.68X. All data were analyzed using R version 3.5.0 (R Core Team). Results: Among the total cohort, 113 CH mutations were detected in 101/986 (10.24%) patients. CH was detected in 42/523 (8.03%) transplanted patients, compared to 59/463 (12.74%) non-transplanted patients. The most commonly mutated genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. The median age of the cohort was 63 years (range: 27 - 93), 60% were male, and median follow-up was 3.9 years (95% CI: 3.7 - 4.0). The presence of CH was associated with age (69 vs. 62 years, P < 0.001). As expected, the median age of transplanted patients was lower (60 vs. 67 years) than in the non-transplanted group, which likely explains the higher prevalence of CH detected in the non-transplanted group. CH was associated with recurrent bacterial infections (P = 0.01) and increased cardiovascular disease (P = 0.006), but not with cerebrovascular disease (P = 0.74) or coagulopathies (P = 0.65). There was a trend towards worse PFS in non-ASCT patients with CH who were not treated with IMiDs (1.8 years) compared to non-CH IMiD-treated patients (2.7 years) (P < 0.001). A CH effect on PFS was not detected in ASCT patients. OS was not different in those with or without CH in both ASCT and non-ASCT groups. 8 (0.8%) patients developed a second hematologic malignancy. CH at the time of MM diagnosis was not associated with an increased risk of developing a second hematologic malignancy (P = 0.58). To determine whether CH clones emerged or evolved during treatment, we examined serial samples from 52 patients (36 ASCT patients and 16 non-transplanted patients) with sequential samples. The median time between the first and second time point was 3.1 years (range: 1.0 - 5.4 years). At the first time point, only 3/52 (5.8%) patients had CH, but that number increased to 13/52 (25.0%) at the second time point. Five out of the 13 (38%) were non-transplanted patients. All but 1 patient were exposed to IMiDs. The most common emerging mutated gene was DNMT3A, found in 7 patient samples at the second time point, compared to 2 patients at the first time point. Conclusion: Using WES in a large cohort of newly diagnosed MM patients, we detected CH in 10.2% (VAF ≥ 2%) of patients. CH and non-IMiD treatment confers a shorter PFS in non-transplanted MM patients. However, throughout IMiD-based treatment, MM patients tend to acquire and/or expand previously undetected CH clones, particularly DNMT3A. The clinical significance of this clonal expansion during therapy is yet to be elucidated, and for now, this observation does not yet change clinical management. Figure 1 Figure 1. Disclosures Steensma: Novartis: Current Employment. Ebert: Deerfield: Research Funding; GRAIL: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees. Soiffer: NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Gilead, USA: Other: Career Development Award Committee; Rheos Therapeutics, USA: Consultancy; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Precision Biosciences, USA: Consultancy; Jazz Pharmaceuticals, USA: Consultancy; Jasper: Consultancy; Takeda: Consultancy. Sperling: Adaptive: Consultancy. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals An Ongoing, Observational Cohort Study in Multiple Myeloma (PREAMBLE): Preliminary Efficacy Analyses in Patients with 1 Line of Prior Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2403-2403
Author(s):  
Brian Durie ◽  
David J Kuter ◽  
Catherine Davis ◽  
Teresa Zyczynski ◽  
Hartmut Goldschmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Treatment Outcomes ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Research Assessment ◽  
Advisory Committees ◽  
Prior Therapy

Abstract Introduction: Multiple myeloma (MM) is an incurable hematologic malignancy associated with high disease burden and relapse rates. In recent years, several treatment options for MM have become available that have improved patient outcomes. However, robust data on real-world treatment outcomes associated with these MM treatments are sparse. PREAMBLE (Prospective REsearch Assessment in Multiple myeloma: an oBservationaL Evaluation; NCT01838512) is an ongoing multinational observational study that aims to increase understanding of real-world clinical effectiveness of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and combination therapy for relapsed/refractory MM (RRMM). Here, we present preliminary efficacy analyses on data from patients with 1 line of prior MM therapy both with and without prior transplantation experience. Methods: Eligible patients had a confirmed diagnosis of RRMM with 1 prior treatment and started treatment with an IMiD, PI, or IMiD+PI 90 days prior/30 days following study enrollment. Patient data were collected at each healthcare provider visit for a follow-up period of 3 years. Vital status was recorded every 6 months for all patients. Response rates (defined as minimal response or better) were assessed using cumulative incidence function, with progression as competing risk. Time in response, progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan-Meier method. Results: Of 855 treated patients, 367 (43%) had 1 prior line of therapy (median age 70 years, 56% male). In this group, 71 (19%) had refractory disease, with even distribution among International Staging System stages I, II, and III. Index therapy was IMiD (n=193, 53%), PI (n=148, 40%), or IMiD+PI (n=26, 7%). At data cut-off (April 2016), median (Q1-Q3) follow-up was 16.7 (9-27) months, and 225 (61%) patients were still on study; the most common reasons for discontinuation were death or entering into a randomized clinical trial. Discontinuation was attributed to death for 92 (25%) patients; 69 (75%) of these deaths were due to disease progression. Approximately one-third of patients (128/367; 35%) had prior transplantation experience: 5% of patients had 2 prior transplantations, 99% of transplantations were autologous, and 83% were received after frontline (first) therapy. In patients without transplantation experience (n=238), the response rate (95% CI) was 46% (39-53) at 6 months, 58% (50-65) at 12 months, and 60% (53-67) at 18 months, versus 43% (34-53), 60% (50-70), and 60% (50-70), respectively, in those with prior transplantation. Median time in response was 14.6 months in patients without prior transplantation versus 20.3 months in those with prior transplantation. In patients with and without prior transplantation, time in response was longer in patients who had received an IMiD as index therapy (Table). Median PFS was 11.5 months in patients without transplantation and 14.1 months in those with transplantation; PFS rates (with/without prior transplantation) was: 6 months, 71%/67%; 12 months, 56%/49%; 18 months, 41%/32%. OS rate at 12 months was 81% in patients without prior transplantation and 82% in those with prior transplantation. In patients (≥6 months on study) who responded within 6 months, OS rate (IMiD/PI cohorts) was: 6 months, 100%/100%; 12 months, 93%/91%; 18 months, 85%/78%. In patients (≥6 months on study) who progressed within 6 months, OS rate (IMiD/PI cohorts) was: 6 months, 100%/100%; 12 months, 84%/69%; 18 months, 56%/64%. Conclusions: In patients with MM and 1 line of prior therapy either with or without prior transplantation experience, approximately 45% achieved a response, with approximately 40% of these patients maintaining their response at 18 months. Regardless of index therapy type or prior transplantation experience, loss of response was observed over time, highlighting the continuing unmet medical need in RRMM. Collectively, these data exemplify the importance of novel therapies that have potential to provide durable responses and improve treatment outcomes for patients with RRMM. Further analyses exploring any impact of prior transplantation and type of frontline therapy on treatment outcomes with subsequent lines of therapy are ongoing, and will be included in the final presentation. Study support: Bristol-Myers Squibb (BMS). Medical writing assistance was provided by K Rees, of Caudex, funded by BMS. Disclosures Durie: Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Kuter:Amgen: Consultancy; Eisai: Consultancy; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Shionogi: Consultancy; Shire: Consultancy; 3SBios: Consultancy; Bristol-Myers Squibb: Research Funding; Protalix: Research Funding; Rigel: Research Funding. Davis:Bristol-Myers Squibb: Employment. Zyczynski:Bristol-Myers Squibb: Employment. Goldschmidt:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Vij:Amgen: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Karyopharm: Honoraria. Popov:Bristol-Myers Squibb: Consultancy. Cella:Abbvie, Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bayer Pharmaceuticals, Inc.: Consultancy, Research Funding; Alexion, Inc., Astellas, Biogen Idec, Celgene, Clovis Oncology, Inc., Daiichi Sankyo, Eli Lilly, Evidera, Inc., Exelixis, Fiborgen, Genetech, Helsinn Therapeutics, Inc., Immunogen, Ipsen Pharma, Janssen, Lexicon Pharmaceuticals, Inc., Merck, Novartis, Onc: Consultancy, Research Funding; Facit.org: Other: President; Bristol-Meyers Squibb: Consultancy, Research Funding. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Lower Dose Lenalidomide and Dexamethasone for Patients with Relapsed/Refractory Multiple Myeloma Who Are Aged 60 Years or over and/or at Risk of Myelosuppression: Final Analysis of the Revlite Trial and Matched Comparison to the MM009 and MM010 Trials

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4236-4236 ◽  
Author(s):  
Hang Quach ◽  
Simon Harrison ◽  
Liam J. Fernyhough ◽  
Ross Alistair Henderson ◽  
Gillian Corbett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Standard Dose ◽  
Survival Outcome ◽  
Phase Iii ◽  
High Dose ◽  
Matched Cohort ◽  
Pivotal Phase ◽  
Multicentre Phase ◽  
Refractory Multiple Myeloma

Abstract Background: The pivotal phase III MM009 and MM010 trials have established standard dose lenalidomide (len; 25mg daily, days 1-21 of 28 day cycle) and high-dose dexamethasone (dex; 40mg daily, days 1-4,9-12,17-20) [RD] as effective treatment for patients with relapsed/refractory multiple myeloma (RRMM). However, moderate toxicities were seen with RD that necessitated dose reduction in 76% and treatment cessation in 20% of patients. We prospectively investigated lower dose len-dex (rd) in a group of patients who were deemed at higher risk of myelosuppression and compared this to a matched cohort of patients who received RD in the MM009 and MM010 trials. Methods: RevLite was a multicentre phase II single-arm study across 12 centres in Australia and New Zealand of patients with RRMM, who were aged ≥60 years and/or with CrCL 20-59ml/min and/or platelets ≤75x109/L. Patients received rd (len 15mg daily, day 1-21 of a 28 day cycle and dex 20mg daily, days 1-4,9-12,17-20) until disease progression. The primary end point was overall response rate (ORR) and secondary endpoints were progression free survival (PFS) and adverse events (AE). A matched cohort of patients who received RD was extracted from the MM009/010 trials. Toxicities and survival outcome were compared between the cohort of patients receiving rd and RD. Results: A total of 149 patients (median age 69 years; male 60%) received rd in the RevLite trial. 65% of patients had prior thalidomide and 49% had at least 3 prior lines of treatment. ORR was 69.1% with CR 14.1%. With a median follow up of 28.4 months (0.2-63.5), median PFS was 8.9 months (95% confidence interval (CI): 6.9-11.5) and median OS was 30.5 months (20.0-36.2). Data of a total of 255 patients were extracted from the RD cohort in the MM009 and MM010 trials. Patients from the rd vs. RD cohort were similar in age, sex, ISS stage and CrCL. There was a higher prior exposure to thalidomide in the rd cohort (65% vs. 36% (RD)). ORR was similar between rd (69%; CR 14.1%) and RD (60%; CR 13.7%). No difference was seen in PFS (p=0.34) and OS (p=0.21). On multivariate analysis, after adjusting for other baseline prognostic factors, there was a trend for better OS with RD (HR 0.76 (95%CI 0.57-1.01), p=0.058). Grade 3-4 toxicities were lower with rd, mainly lower neutropenia (29 vs. 41%), infections (23.3 vs. 31.4%), and VTE (3 vs. 13%). Patients who were still on treatment after 3 years were on an average daily dose of 15mg in both groups. Conclusion: Lower dose len-dex is less toxic but remains efficacious in patients with RRMM who are at higher risk of myelosuppression. While this trial was not powered to detect non-inferiority of rd vs RD with respect to PFS and OS, rd was shown to induce a meaningful depth of response and PFS that was comparable to that seen with standard dose len-dex in patients who are aged ≥60 years and/or with renal impairment and/or with thrombocytopenia. These results reinforce the growing recognition of treatment attenuation in elderly or frail patients, and confirm that such practice with len-dex will not likely compromise patient response or survival outcome. Disclosures Quach: Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Harrison:Celgene: Honoraria, Research Funding. Li:Celgene Corp: Employment, Equity Ownership. Dimopoulos:Amgen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Prince:Celgene Corp, Amgen, Janssen: Honoraria, Research Funding.

scholarly journals Ticagrelor Modulates Proliferation in Multiple Myeloma Via P1 and P2 Receptor-Mediated Mechanisms

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5694-5694
Author(s):  
Elan Meltzer ◽  
Aranzazu Mediero ◽  
Carl Whatling ◽  
Jeffrey S Berger ◽  
Bruce Cronstein
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Research Funding ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Bone Destruction ◽  
Extracellular Adenosine ◽  
Myeloma Cells ◽  
Platelet Releasate

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy involving uncontrolled proliferation of plasma cells and is particularly trophic to bone where it induces osteoclast-mediated bone destruction. Ticagrelor is a platelet inhibitor that blocks P2Y12 receptors and inhibits ENT1-mediated adenosine uptake, thereby increasing extracellular adenosine, which activates P1 receptors. Prior studies demonstrate that ticagrelor increases life span in a murine model of MM via its effect on extracellular adenosine. Prior studies also demonstrate an increase in proliferation, in vitro, and tumor growth, in vivo, of MM cells in the presence of platelet releasate. Ticagrelor blocks in vitro platelet-stimulated myeloma proliferation, suggesting a positive relationship and interaction between active platelets and multiple myeloma. We therefore determined whether the effect of ticagrelor on myeloma cells was mediated by extra-cellular adenosine or/and inhibition of platelet function. Methods:Human primary myeloma cells (KMS) were incubated with ticagrelor (10-9-10-4 M) in the presence of 5ng/ml IL-6 in the absence/presence of an A2AR antagonist (ZM241385 10-6M) and platelets (1:500 myeloma cell:platelets). In other experiments MM cells were incubated in the presence of platelet releasate, releasate from platelets treated with ticagrelor, or ticagrelor alone. Proliferation was assayed by Cell Titer MTS assay (Promega). Results: Ticagrelor inhibited MM cell proliferation by 20% (p<0.0001, IC50=0.5µM). This effect was abrogated by ZM241385 (48±6% increased vs. ticagrelor, p<0.0001). Platelet releasate increased MM proliferation by 33±6% (p<0.05) and ticagrelor inhibited the effect of platelet releasate on MM cell proliferation (IC50=0.12µM). Conclusions:These results suggest that ticagrelor inhibits proliferation of malignant plasma cells by a mechanism dependent on both adenosine A2A and platelet P2Y12 receptors. Moreover, platelet releasate intensifies proliferation, and this effect is reversed when the P2Y12 receptor is blocked by ticagrelor. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Meltzer: NIH: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding. Mediero:AstraZeneca: Research Funding; Celgene: Research Funding; NIH: Research Funding. Whatling:AstraZeneca: Employment. Berger:Merck: Membership on an entity's Board of Directors or advisory committees; AZ: Research Funding. Cronstein:AstraZeneca: Consultancy, Research Funding; CanFite: Equity Ownership; Gizmo Therapeutics: Consultancy; Eli Lilly & Co.: Consultancy; NIH: Research Funding; Celgene: Research Funding.

scholarly journals The Role of Proteasome Activator PA28α in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5499-5499
Author(s):  
Yanyan Gu ◽  
Benjamin G Barwick ◽  
Mala Shanmugam ◽  
Craig C Hofmeister ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
The United States ◽  
Myeloma Cell ◽  
Advisory Board ◽  
20S Proteasome ◽  
Advisory Committees

Multiple myeloma (MM) is a commonly occurring hematologic malignancy in the United States with poor prognosis. Among all treatments, proteasome inhibitor (PI) based regimens have been a major breakthrough for patients' outcomes. Available PIs all target 20S proteasome core complex, and the duration of response is limited by toxicity and resistance development. Until now, the underlying mechanism of drug resistance remains unclear. The proteasome is the major proteolytic machinery in protein homeostasis which is pivotal for myeloma cell survival. A functional proteasome consists of 20S proteasome core particle with regulatory particle on one or both ends. There are 3 types of proteasome regulators that could activate a 20S proteasome, PA700 (19S), 11S REG (PA28) and PA200. The 11S REG (PA28) protein family consists of three members, α, β, and γ. PA28 α/β are IFN-γ inducible and with higher expression in antigen presenting cells. Currently, the function of 11S subunit remains largely unknown. Our analysis of plasma cells from MM patients and healthy donors has demonstrated that expression of 11S proteasome is higher in myeloma cells than normal plasma cells and progressively upregulated with disease progression. To further identify the function of 11S proteasome especially PA28α in MM, we generate PA28α knockdown stable MM cell lines. We have found that knockdown of PA28α inhibits MM cell growth and proliferation, also induces myeloma cell resistance to PIs. The mechanism of PI resistance is different from knocking down of 19S or 20S proteasome subunits. Silencing of PA28α inhibits proteasome activity and decreases proteasome work load concurrently, resulting in a favorable proteasome load vs capacity ratio. Altogether, in this report, we describe the function of PA28α in MM cells, also provide novel insights into regulating PIs sensitivity through modulation of the 11S proteasome subunit PA28α. Disclosures Hofmeister: Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kaufman:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; AbbVie: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy. Nooka:Amgen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation. Boise:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Lonial:Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy, Research Funding.

scholarly journals Pathogenic Germline Variants in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 399-399
Author(s):  
Santiago Thibaud ◽  
Aaron Etra ◽  
Ryan Subaran ◽  
Zachry Soens ◽  
Scott Newman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Survival Analysis ◽  
Family History ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Hematologic Malignancy ◽  
European Ancestry ◽  
Germline Variants ◽  
High Prevalence ◽  
History Of

Abstract BACKGROUND: There is growing evidence supporting inherited predisposition to multiple myeloma (MM). Epidemiologic studies have shown that 1st-degree relatives of MM patients (pts) have a 2-4 fold increase in risk of developing MGUS or MM. Genome-wide association studies (GWAS) have identified common SNPs as well as rare high-penetrance variants that collectively explain ~16% of the estimated heritability of multiple myeloma (PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer patients (~8%, PMID 29625052), but prevalence in MM is not known. The aim of our study is to investigate the occurrence of PGV in newly-diagnosed MM (NDMM), and to describe clinical characteristics & outcomes of carriers. METHODS: We analyzed MMRF CoMMpass data (version IA16) and identified 895 NDMM pts for whom whole-exome sequencing of germline DNA was available. We used the clinical annotation pipeline from Sema4, a CLIA/CAP certified genetic testing laboratory, to identify pts with PGV according to ACMG variant classification guidelines. We compared clinical characteristics & disease phenotypes of PGV carriers vs non-carriers. We used Chi-Square and Fisher's Exact tests to assess statistical significance, which we defined as a two-sided p value &lt; 0.05. Logistic regression models were used for multivariate analyses. Kaplan-Meier method and Cox proportional-hazards models were used for uni- and multivariate survival analysis, respectively. Bonferroni method was used to account for multiple testing. RESULTS: We identified 83 PGV in 31 distinct HCG in 79 (8.8%) of 895 NDMM pts (83% European ancestry) [Figure 1A]. Most PGV involved DNA damage repair (DDR) genes (78%), and homologous recombination (HR) genes were the most commonly mutated (34%). PGV in CHEK2 were the most common (n=10, 1.1% of all MM pts). 2 pts carried PGV in TP53 and reported extensive family history of Li-Fraumeni-associated cancers (breast, sarcoma, gastric & melanoma). 6 pts had germline mismatch repair (MMR) gene defects (1:149, considerably higher than the estimated prevalence of Lynch syndrome in Western populations). 4 pts carried PGV in BRCA2 (previously identified in a family study as a potential MM predisposition gene, PMID 11904319). MM pts with a family history of hematologic malignancy (leukemia, lymphoma or MM) in a 1st or 2nd-degree relative were significantly more likely to carry PGV (22 vs 7.6%, OR=3.3, p&lt;0.001), an association that remained significant in MVA (OR=4.1, p&lt;0.001). CHEK2 variants emerged as leading drivers of this correlation (OR 18.2, 95% CI 4.1-75, adjusted p&lt;0.01), & especially protein-truncating founder variant c.1100delC. Likelihood of being diagnosed w/ MM before age 40 was significantly higher in PGV carriers (6.3 vs 1.8%, OR=3.7, p=0.025). 25% of those younger than 40 y/o carried PGV, but none of these were in DDR-HR genes, a notable difference with other age groups (0 vs 41%, p=0.02). 2/6 MMR PGV were detected in pts diagnosed before age 40. In univariate survival analysis, DDR-PGV carriers had a significant PFS1 advantage over non-carriers (median 52 vs 35 months, p=0.008), as well as a non-significant OS advantage (p=0.08). PFS1 difference remained significant in MVA after adjusting for age, ISS stage, high-risk cytogenetics, treatment type & transplant status (OR 0.65, 95% CI 0.44-0.97, p=0.03) [Figure 1B]. CONCLUSIONS: PGV in HCG were common (8.8%) in this large cohort of NDMM pts of predominantly European ancestry, especially in those with a family history of hematologic malignancy (1:4, with high prevalence of CHEK2 variants & particularly protein-truncating founder variant c.1100delC), and in those diagnosed before age 40 (1:4). Routine screening in high-prevalence subgroups might be warranted, as carriers may benefit from counseling and enrollment in early cancer detection programs. We observed a clinically and statistically significant PFS1 advantage in carriers of PGV in DDR genes, possibly due to increased sensitivity to MM therapies, a well-described phenomenon in other cancer types (PMID 33158305). Prospective validation of these findings is needed to better understand prognostic & therapeutic implications of PGV in MM. Figure 1 Figure 1. Disclosures Chari: Karyopharm: Consultancy; Takeda Pharmaceutical Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Richter: Sanofi: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

scholarly journals Characteristics Associated with Disparities in Survival between Hispanic and Non-Hispanic White Patients with Multiple Myeloma: A Matched Cohort Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4091-4091
Author(s):  
Jing Dong ◽  
Zhuping Garacci ◽  
Christopher Staffi Buradagunta ◽  
Meera Mohan ◽  
Anita D'Souza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Survival Time ◽  
Board Of Directors ◽  
Median Survival ◽  
Research Funding ◽  
Low Ses ◽  
Matched Cohort ◽  
Advisory Committees ◽  
The Difference ◽  
Medicare Database

Abstract Background: Recent treatment advances have greatly improved the survival in multiple myeloma (MM), the second most common hematologic malignancy in the US. However, large racial and ethnic disparities in MM survival still exist. Previous Surveillance, Epidemiology and End Results (SEER)-based analyses suggest Hispanics have lower utilization rate of effective antimyeloma therapies and worse overall survival than non-Hispanic whites (NHWs) with MM, but the factors associated with these disparities are not clear. To understand the nature of the disparity, we used a novel tapered matching approach to examine the sequential effects of demographics, clinical, and treatment-related factors on the disparities in survival time between Hispanic and NHW patients with MM. Methods: We identified 1,591 Hispanic and 20,831 NHW patients, 65 years or older, diagnosed with MM between 1999 and 2017 in the SEER-Medicare database (2020 release). MM diagnosis was defined by International Classification of Diseases for Oncology, Third Edition using topography codes (C42.1) and histologic codes (M9732/3). All patients have continuous enrollment in Medicare parts A and B from 12 months before MM diagnosis to at least 12 months after MM diagnosis or death, whichever occurs first. Patients were followed up until death from any cause, maximum claim date, or December 31, 2018. Four sets of 1,591 NHW patients were matched sequentially to the same set of 1,591 Hispanic patients, based on demographics (age, sex, year of diagnosis, SEER site, and marital status), socioeconomic status (SES, demographic variables plus SES), presentation (SES variables plus comorbidities) and treatment (presentation variables plus chemotherapy, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and autologous stem cell transplantation (ASCT)). All matching was performed using the OPTNET procedure in SAS 9.4 to identify the optimal 1:1 matched cohort that had the minimal total distance between Hispanic and NHW matched pairs. We used paired Cox proportional hazards models to examine survival over time and hazard ratios (HRs) and used the bootstrap method to obtain standard errors for the paired differences in survival. Results: Overall, compared to the unmatched NHWs, Hispanics were younger on average (75.8 vs. 77.1 years), more likely to be female (52.6% vs. 48.0%), to have low SES (52.6% vs. 23.1%), but less likely to be married at diagnosis (36.4% vs. 40.2%). Hispanics also had more comorbidities (Comorbidity Index = 0, 16.2% vs. 22.0%), but were less likely to receive ASCT (4.0% vs. 5.3%) than NHWs (all P &lt; 0.05, Table 1). During follow-up evaluation, 1,217 of 1,591 Hispanics (76.5%) and 16,479 of 20,831 NHWs (79.1%) died. Compared with demographics matched NHWs, Hispanics had a significantly shorter median survival (30.0 vs. 37.0 months; P=0.004). After matching on SES, the difference in median survival was no longer significant (P=0.46), neither in the matching on presentation (P=0.38) nor treatment (P=0.19). The absolute difference in 5-year survival between Hispanics (29.6%) and NHWs (33.2%) was 3.6% (95%CI, 0.1%-6.9%, P = 0.002) in the demographics match. After we matched for SES, the difference in 5-year survival was reduced to 2.2% (95%CI, -1.2%-5.7%) and was not statistically significant (P = 0.32). No 5-year survival difference was observed in the presentation or treatment match (both P &gt; 0.05) (Table 2 and Figure 1). We further conducted stratified analysis by SES and found that among those with low SES, NHWs still had a marginally significant longer median survival (30.0 vs 26.0 months, P=0.06) and better 5-year survival (28.4% vs. 25.5%, P =0.07) than Hispanics in the demographics match. Further matching on presentation and treatment eliminated the survival differences between NHWs and Hispanics who were both at low SES. However, if NHWs and Hispanics were both at high SES, they experienced similar survival across the demographics, presentation and treatment match (all P &gt; 0.1). Conclusions: In the SEER-Medicare database, SES could account for the disparities in survival time between Hispanic and NHW patients with MM. While SES is an important prognostic factor of MM, additional social, clinical, and biological factors also need to be investigated to understand the mechanisms underlying survival disparity in patients with low SES, so proper intervention and policy development could be implemented. Figure 1 Figure 1. Disclosures Mohan: Medical College of Wisconsin: Current Employment. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy. Dhakal: Fate: Research Funding; Carsgen: Research Funding; Natera: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau.

Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

2020 ◽  
Vol 27 (2) ◽  
pp. 187-215 ◽  
Author(s):  
Lavinia Raimondi ◽  
Angela De Luca ◽  
Gianluca Giavaresi ◽  
Agnese Barone ◽  
Pierosandro Tagliaferri ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Natural Products ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Signal Transduction Pathways ◽  
Pharmacologically Active ◽  
Dietary Agents

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

scholarly journals Self-reported causes of cancer among 6881 survivors with 6 tumour types: results from the PROFILES registry

2021 ◽  
Author(s):  
Carla Vlooswijk ◽  
Olga Husson ◽  
Simone Oerlemans ◽  
Nicole Ezendam ◽  
Dounya Schoormans ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Cancer Survivors ◽  
Causal Attributions ◽  
Population Based ◽  
Comorbid Conditions ◽  
Prostate Cancer Survivors ◽  
Cancer Types ◽  
External Causes ◽  
Single Question

Abstract Objective Our aim was to describe and compare self-reported causal attributions (interpretations of what caused an illness) among cancer survivors and to assess which sociodemographic and clinical characteristics are associated with them. Methods Data from five population-based PROFILES registry samples (i.e. lymphoma (n = 993), multiple myeloma (n = 156), colorectal (n = 3989), thyroid (n = 306), endometrial (n = 741), prostate cancer (n = 696)) were used. Causal attributions were assessed with a single question. Results The five most often reported causal attributions combined were unknown (21%), lifestyle (19%), biological (16%), other (14%), and stress (12%). Lymphoma (49%), multiple myeloma (64%), thyroid (55%), and prostate (64%) cancer patients mentioned fixed causes far more often than modifiable or modifiable/fixed. Colorectal (33%, 34%, and 33%) and endometrial (38%, 32%, and 30%) cancer survivors mentioned causes that were fixed, modifiable, or both almost equally often. Colorectal, endometrial, and prostate cancer survivors reported internal causes most often, whereas multiple myeloma survivors more often reported external causes, while lymphoma and thyroid cancer survivors had almost similar rates of internal and external causes. Females, those older, those treated with hormonal therapy, and those diagnosed with prostate cancer were less likely to identify modifiable causes while those diagnosed with stage 2, singles, with ≥2 comorbid conditions, and those with endometrial cancer were more likely to identify modifiable causes. Conclusion In conclusion, this study showed that patients report both internal and external causes of their illness and both fixed and modifiable causes. This differsbetween the various cancer types. Implications for Cancer Survivors Although the exact cause of cancer in individual patients is often unknown, having a well-informed perception of the modifiable causes of one’s cancer is valuable since it can possibly help survivors with making behavioural adjustments in cases where this is necessary or possible.

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