Racial and Ethnic Differences in Clonal Hematopoiesis, Tumor Markers, and Clinical Outcomes of Patients with Multiple Myeloma

Abstract Background: Multiple myeloma (MM) is twice as common in Blacks compared to Non-Hispanic (NH) Whites and Hispanics. While treatment and mortality differences have been reported for Black patients with MM compared to NH White patients, there is limited data on Hispanic populations. Furthermore, the factors driving observed differences in MM presentation and treatment responses by race and ethnicity are largely unknown. We investigated demographic, clinical, and molecular features, including tumor mutations and clonal hematopoiesis (CH), in a diverse population of patients with MM to elucidate mechanisms driving clinical disparities. Methods: Patients diagnosed with MM who consented to our institutional biorepository protocol were eligible for inclusion. Demographic and clinical data were obtained from cancer registry and abstracted from electronic medical records. MM tumor cells were purified from bone marrow aspirates by CD138 affinity chromatography. DNA was isolated from tumor cells and whole blood for each patient, and whole exome sequencing (WES) data was generated. Tumor somatic mutations were characterized using paired tumor-normal (blood) WES. CH was classified based on blood-derived somatic mutations, using paired tumors and reference populations as germline comparators. Outcomes included overall survival (OS; date of diagnosis to death/last contact) and progression-free survival (PFS; 1 st-line treatment start to 1 st disease progression/death). Results: A diverse group of MM patients (n=496) were included: NH White (80%), NH Black (10%) and Hispanic (9%). NH Black and Hispanic MM patients had a younger median age at diagnosis (57 and 53 yrs, respectively) compared to NH Whites (63 yrs, p = 0.0001; Fig A). There was no statistical difference in treatment categories received by race/ethnicity. NH Black patients had a longer time to hematopoietic cell transplant (HCT; 376 days) than NH White or Hispanic patients (248 and 270 days, respectively, p = 0.011). There was an improvement in OS for NH Black (HR 0.49, 95% CI 0.30-0.81) and Hispanic (HR 0.66, 95% CI 0.37-1.18) patients compared to NH White patients, but the association was not statistically significant in Hispanics. In univariable analysis, OS was also associated with age at diagnosis, International Staging System (ISS), treatment with HCT, and treatment regimen category. In multivariable analysis, after adjusting for age, ISS, HCT, and treatment category there was no longer a statistically significant association between OS and race/ethnicity. Although a worse PFS was present among Hispanic patients (adjusted HR 1.45, 95% CI 0.99-2.13), there was no statistically significant difference in PFS by race/ethnicity. The most mutated genes in MM tumors were KRAS (24%), NRAS (17%), TP53 (11%), DIS3 (9%), and BRAF (9%) (Fig B). Genes with significantly higher tumor mutation rates in Black compared to NH White patients were SP140 (12% v 4%, p = 0.026), AUTS2 (8% v 2%, p = 0.04), and SETD2 (6% v 1%, p = 0.037). IRF4 was most commonly mutated in Hispanics (11% v 3% in NH White and 0% in Black, p = 0.019). We identified CH using WES in 60 (12%) patients. The most CH mutations were in ASXL1, DNMT3A, and TET2. There was no difference in the prevalence of CH by race/ethnicity (p=0.8). There was a statistically significant difference in OS by race/ethnicity and CH status (Fig C). For NH Black patients, CH (HR 4.36, 95% CI 1.36-14.0) and age at diagnosis (HR 1.08, 95% CI 1.03-1.14) were associated with inferior OS (Fig C). After adjusting for age in multivariable analysis, the positive association with CH status among Black patients was no longer statistically significant (HR 2.72, 95% CI 0.48-15.4). A positive, but not statistically significant, association for PFS in NH White patients with CH was also noted (adjusted HR 1.38, 95% CI 0.95-2.0). Conclusions: This is the first study to examine differences in tumor mutation profiles, CH, and treatment among different racial and ethnic groups of patients diagnosed with MM. Our data suggest that age at diagnosis, tumor mutations, and CH may all contribute to clinical disparities observed in patients with MM. Efforts to expand our cohort and incorporate additional molecular biomarkers, epidemiologic characteristics, and clinical parameters are ongoing with the ultimate goal of elucidating targetable biological mechanisms to personalize management and optimize outcomes for diverse patients diagnosed with MM. Figure 1 Figure 1. Disclosures Hampton: M2Gen: Current Employment. Blue: WebMD: Consultancy; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Siqueira Silva: AbbVie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Research Funding. Baz: GlaxoSmithKline: Consultancy, Honoraria; BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Oncopeptides: Consultancy; Merck: Research Funding. Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Shain: Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Sanofi Genzyme: Consultancy, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Racial and Age-Related Differences in Impacts of High-Risk Cytogenetic Abnormalities on Survival in Multiple Myeloma in a Nationwide Electronic Health Record-Derived Database

Blood ◽

10.1182/blood-2021-152774 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4121-4121

Author(s):

Gregory S Calip ◽

Mustafa S Ascha ◽

Xiaoliang Wang ◽

Amy E Pierre ◽

Kathleen Maignan ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Age Related ◽

Black Patients ◽

Double Hit ◽

White Patients

Abstract Background: The incidence of multiple myeloma (MM) and enrichment of cytogenetic abnormalities differ significantly between racial/ethnic groups in the US, and their significance in determining myeloma progression and survival is not well understood. Whole genome sequencing has identified unique mutational signatures in MM, including an age-related process common in hyperdiploid myeloma. Our purpose was to describe racial and age-related differences in the impact of high-risk cytogenetic abnormalities (HRCAs) on survival in MM. Methods: We conducted a retrospective cohort study of adult MM patients starting first-line therapy between January 2011 and May 2021 using the nationwide Flatiron Health electronic health record-derived de-identified database. Patient-level demographic and clinical characteristics were ascertained using structured and unstructured data, curated via technology-enabled abstraction. Patients who had documented fluorescence in situ hybridization testing within 30 days prior to or 90 days following the start of first-line treatment were included. HRCAs, including gain or amplification 1q21, deletion 17p, t(4;14), t(14;16) and t(14;20), were identified and categorized as 0, 1, or 2+ HRCAs. Our outcomes of interest were real world progression free survival (rwPFS) and overall survival (rwOS). Cox proportional hazards models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI), adjusted for demographic and clinical characteristics and treatment including time-dependent receipt of autologous stem cell transplantation. Results: From a cohort of 4889 MM patients, there were 790 (16%) Black and 2995 (61%) White patients with median ages at diagnosis of 68 and 70 years, respectively. Compared to White patients, a higher proportion of Black patients had IgG M-protein (61% vs 55%) and a lower proportion had 1+ HRCAs identified (31% vs 34%). Among all racial groups, compared to patients aged <65 years (N=1771), a higher proportion of patients aged 65+ years (N=3118) had IgA M-protein (21% vs 17%) and 1+ HRCAs identified (35% vs 33%). Multivariable models showed evidence of significant statistical interaction between age and prevalence of HRCA for rwPFS (P-int: 0.02). Among White patients, having 2+ HRCAs ("double-hit MM") compared to no HRCAs was associated with worse rwPFS in both younger and older patients (<65 years: HR 2.88, 95% CI 1.93-4.32, P<0.01; 65+ years: HR 1.51, 95% CI 1.18-1.94, P<0.01). Among Black patients, associations between double-hit MM and rwPFS were attenuated and not statistically significant regardless of age (<65 years: HR 1.81, 95% CI 0.69-4.74, P=0.23; 65+ years: HR 1.61, 95% CI 0.92-2.81, P=0.09). Similarly, we also found evidence of statistical interaction between age and prevalence of HRCA for rwOS (P-int: 0.02). Among White patients, double-hit MM was significantly associated with worse rwOS but the magnitude of increased risk differed for younger (HR 3.39, 95% CI 2.24-5.14, P<0.01) and older (HR 1.61, 95% CI 1.27-2.05, P<0.01) patients. Double-hit MM was significantly associated with worse rwOS among older Black patients (HR 1.78, 95% CI 1.03-3.06, P=0.04), but not younger Black patients (HR 1.60, 95% CI 0.58-4.40, P=0.36). Conclusions: In this cohort of newly diagnosed MM patients treated in routine practice, having double-hit MM was differentially predictive of poor survival across age groups. Double-hit MM was associated with worse rwPFS and rwOS among White patients, but these trends were less consistent among Black patients. Our current understanding of cytogenetic risk stratification of MM requires further study and additional data for identifying low- and high-risk subsets of patients across different ages and racial groups. Figure. Kaplan-Meier survivor functions for rwPFS in White (Panel A) and Black (Panel B) patients by age group and number of HRCAs Figure 1 Figure 1. Disclosures Calip: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Ascha: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wang: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Pierre: Flatiron Health, Inc: Current Employment; Roche: Current holder of stock options in a privately-held company. Maignan: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wadé: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Leng: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Seymour: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current equity holder in publicly-traded company; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Flatiron Health Inc: Current Employment. Patel: Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding.

Download Full-text

Racial, Ethnic, and Socioeconomic Factors Result in Disparities in Outcome Among Children with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease Prognosticators: A Children's Oncology Group (COG) Study

Blood ◽

10.1182/blood-2021-147386 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 211-211

Author(s):

Sumit Gupta ◽

David T. Teachey ◽

Meenakshi Devidas ◽

Yunfeng Dai ◽

Richard Aplenc ◽

...

Keyword(s):

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Black Patients ◽

Increased Risk ◽

Hispanic Patients ◽

Race Ethnicity ◽

Racial Ethnic ◽

Subsequent Addition ◽

Hispanic White ◽

White Patients

Abstract Introduction: Health disparities are major issue for racial, ethnic, and socioeconomically disadvantaged groups. Though outcomes in childhood acute lymphoblastic leukemia (ALL) have steadily improved, identifying persistent disparities is critical. Prior studies evaluating ALL outcomes by race or ethnicity have noted narrowing disparities or that residual disparities are secondary to differences in leukemia biology or socioeconomic status (SES). We aimed to identify persistent inequities by race/ethnicity and SES in childhood ALL in the largest cohort ever assembled for this purpose. Methods: We identified a cohort of newly-diagnosed patients with ALL, age 0-30.99 years who were enrolled on COG trials between 2004-2019. Race/ethnicity was categorized as non-Hispanic white vs. Hispanic vs. non-Hispanic Black vs. non-Hispanic Asian vs. Non-Hispanic other. SES was proxied by insurance status: United States (US) Medicaid (public health insurance for low-income individuals) vs. US other (predominantly private insurance) vs. non-US patients (mainly jurisdictions with universal health insurance). Event-free and overall survival (EFS, OS) were compared across race/ethnicity and SES. The relative contribution of disease prognosticators (age, sex, white blood cell count, lineage, central nervous system status, cytogenetics, end Induction minimal residual disease) was examined with Cox proportional hazard multivariable models of different combinations of the three constructs of interest (race/ethnicity, SES, disease prognosticators) and examining hazard ratio (HR) attenuation between models. Results: The study cohort included 24,979 children, adolescents, and young adults with ALL. Non-Hispanic White patients were 13,872 (65.6%) of the cohort, followed by 4,354 (20.6%) Hispanic patients and 1,517 (7.2%) non-Hispanic Black patients. Those insured with US Medicaid were 6,944 (27.8%). Five-year EFS (Table 1) was 87.4%±0.3% among non-Hispanic White patients vs. 82.8%±0.6% [HR 1.37, 95 th confidence interval (95CI) 1.26-1.49; p<0.0001] among Hispanic patients and 81.9%±1.2% (HR 1.45, 95CI 1.28-1.56; p<0.0001) among non-Hispanic Black patients. Outcomes for non-Hispanic Asian patients were similar to those of non-Hispanic White patients. US patients on Medicaid had inferior 5-year EFS as compared to other US patients (83.2%±0.5% vs. 86.3%±0.3%, HR 1.21, 95CI 1.12-1.30; p<0.0001) while non-US patients had the best outcomes (5-year EFS 89.0%±0.7%, HR 0.78, 95CI 0.71-0.88; p<0.0001). There was substantial imbalance in traditional disease prognosticators (e.g. T-cell lineage) across both race/ethnicity and SES, and of race/ethnicity by SES. For example, T-lineage ALL accounted for 17.6%, 9.4%, and 6.6% of Non-Hispanic Black, Non-Hispanic White, and Hispanic patients respectively (p<0.0001). Table 2 shows the multivariable models and illustrates different patterns of HR adjustment among specific racial/ethnic and SES groups. Inferior EFS among Hispanic patients was substantially attenuated by the addition of disease prognosticators (HR decreased from 1.37 to 1.17) and further (but not fully) attenuated by the subsequent addition of SES (HR 1.11). In contrast, the increased risk among non-Hispanic Black children was minimally attenuated by both the addition of disease prognosticators and subsequent addition of SES (HR 1.45 to 1.38 to 1.32). Similarly, while the superior EFS of non-US insured patients was substantially attenuated by the addition of race/ethnicity and disease prognosticators (HR 0.79 to 0.94), increased risk among US Medicaid patients was minimally attenuated by the addition of race/ethnicity or disease prognosticators (HR 1.21 to 1.16). OS disparities followed similar patterns but were consistently worse than in EFS, particularly among patients grouped as non-Hispanic other. Conclusions: Substantial disparities in survival outcomes persist by race/ethnicity and SES in the modern era. Our findings suggest that reasons for these disparities vary between specific disadvantaged groups. Additional work is required to identify specific drivers of survival disparities that may be mitigated by targeted interventions. Figure 1 Figure 1. Disclosures Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Teachey: NeoImmune Tech: Research Funding; Sobi: Consultancy; BEAM Therapeutics: Consultancy, Research Funding; Janssen: Consultancy. Zweidler-McKay: ImmunoGen: Current Employment. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Racial Disparities in Telemedicine Uptake during the COVID-19 Pandemic Among Patients with Hematologic Malignancies in the United States

Blood ◽

10.1182/blood-2021-153787 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1973-1973

Author(s):

Natalia Neparidze ◽

Krystal W. Lau ◽

Xiaoliang Wang ◽

Amy J. Davidoff ◽

Scott F. Huntington ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Visit Rate ◽

Black Patients ◽

Monthly Visit ◽

All Diseases ◽

Privately Held ◽

White Patients

Abstract Background/objectives: The COVID-19 pandemic impacted healthcare visit trends, propelling healthcare systems to reduce in-person visits and hospital admissions and increasingly rely on telemedicine; whether there are differences in these trends across racial groups is unknown. This study investigated potential racial disparities in visits during the pandemic for patients with documented active treatment for hematologic malignancies. Methods: We used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to select patients with confirmed diagnosis of AML, DLBCL, FL, MCL, CLL or MM, at least 18 years old at initial diagnosis, and documented race in the EHR as Black/African American or White were included. Patients were categorized into treatment types within lines of therapy: Orals (orals + outpatient infusions with orals) vs. Inpatient treatments (chemotherapy, hematopoietic transplants & CAR-T cell therapy). Monthly visit rates were calculated as the number of visits (telemedicine or in-person [in-clinic treatment administration, vitals, and/or labs]) per active patient per 30-day standardized month, except for months in which the patient was considered not active (e.g. no documented therapy, surveillance). We used time-series forecasting methods on pre-pandemic monthly visit rate data (March 2016 - February 2020) to estimate projected counterfactual monthly visit rates (expected rates if the pandemic did not occur) between March 2020 - February 2021 for all diseases combined, for each disease, each treatment type, and each race. Differences between projected and actual monthly visit rates during the pandemic period were considered significant and related due to the pandemic if the actual visit rate was outside of the 95% prediction interval (PI) surrounding the projected estimate. We used cross-correlation analysis to test for significant differences in visit rates between Black and White patients. Results: The analysis included 17,621 patients (2,225 Black, 15,396 White): 3,041 AML, 2,715 DLBCL, 1,558 FL, 1,511 MCL, 3,813 CLL and 5,244 MM (1,166 Black, 4078 White). Across all diseases and treatment categories, Black patients had no significant reductions in in-person visit rates throughout the pandemic period compared to the projected rates. There was, however, an 18% statistically significant reduction (95% PI 9.9% - 25%) in in-person visit rates for White patients on orals during early pandemic months (March - May 2020) from a projected visit rate of 2.0 (95% PI 1.8 - 2.2) visits per patient per month to an actual visit rate of 1.61. There was no significant reduction in in-person visit rates for White patients on inpatient treatments. Telemedicine uptake was significantly higher for White patients compared with Black patients for all diseases combined across all treatment categories (Figure A & B) (t = 9.5, p < 0.01), AML inpatient treatments (t = 2.4, p = 0.04), MM orals (Figure C) (t = 6.0, p < 0.01) and MM inpatient treatments (Figure D) (t = 2.3, p = 0.04). Conclusions: A tradeoff in reductions in in-person visits and uptake of telemedicine use was observed overall. White patients had significantly higher telemedicine uptake compared with Black patients for both oral and inpatient treatments. In-person visit rates for Black patients were unchanged regardless of treatment category. These in-person visit rates reflect documented telemedicine use disparities, which requires further study into possible compound causes, including economic and societal factors. Figure. Trends over time in telemedicine visit rates for White patients (blue line) and Black patients (black line) Figure 1 Figure 1. Disclosures Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding. Lau: Flatiron Health Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Wang: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Davidoff: Amgen: Consultancy; AbbVie: Other: Family member consultancy. Huntington: Bayer: Honoraria; Servier: Consultancy; Pharmacyclics: Consultancy, Honoraria; Thyme Inc: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; SeaGen: Consultancy; Celgene: Consultancy, Research Funding; Flatiron Health Inc.: Consultancy; DTRM Biopharm: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Novartis: Consultancy. Calip: Flatiron Health Inc: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Shah: AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Epizyme: Research Funding. Stephens: Adaptive: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Abbvie: Consultancy; CSL Behring: Consultancy; Novartis: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; JUNO: Research Funding; Mingsight: Research Funding; AstraZeneca: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding. Miksad: Flatiron Health Inc: Current Employment, Current holder of individual stocks in a privately-held company; Roche: Current equity holder in publicly-traded company. Parikh: Onc.AI: Current holder of individual stocks in a privately-held company; Humana: Honoraria, Research Funding; Flatiron Health Inc: Honoraria; Thyme Care: Honoraria; Nanology: Honoraria; GNS Healthcare: Current holder of individual stocks in a privately-held company. Takvorian: Genentech: Consultancy; Pfizer: Research Funding. Seymour: Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Current equity holder in publicly-traded company; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Flatiron Health Inc: Current Employment; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Patient Characteristics, Treatment Patterns and Outcomes Among Black and White Patients with Multiple Myeloma Initiating Daratumumab: A Real-World Chart Review Study

Blood ◽

10.1182/blood-2021-145941 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1965-1965

Author(s):

Shebli Atrash ◽

Philippe Thompson-Leduc ◽

Ming-Hui Tai ◽

Shuchita Kaila ◽

Kathleen Gray ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Index Date ◽

Patient Characteristics ◽

Treatment Patterns ◽

Advisory Committees ◽

New Therapies ◽

Black Patients ◽

Line Of Therapy ◽

White Patients

Abstract Background and Objective: Daratumumab, a CD38 monoclonal antibody, was approved for the treatment of multiple myeloma (MM) among previously treated patients in 2015, and among newly diagnosed patients in 2018. While the safety and efficacy of daratumumab has been well documented in clinical trials, there is limited real world information on the use and outcomes of daratumumab in patients of different races. This is of particular relevance for potential health care disparities, as evidence suggests that African American patients with MM receive new therapies later in their disease and may experience different outcomes than White patients (Blood Adv. 2019;3:2986-94, Cancer Med. 2017;6: 2876-85). Therefore, we sought to describe patient characteristics, treatment patterns and outcomes of patients with MM who received daratumumab. Results were stratified by race (i.e., Black vs. White). Methods: We conducted a retrospective chart review of patients with MM initiating daratumumab between 1/2018 and 5/2020. De-identified data were retrieved from two U.S. clinical sites, Levine Cancer Institute (Atrium Health) and Weill Cornell Medicine. Patients were included if they had a confirmed diagnosis of MM and were at least 18 years old at the time of daratumumab initiation (index date). Patients who accessed daratumumab through interventional clinical trials were excluded. Patients were followed from the index date until death, loss to follow-up, or date of chart abstraction, whichever occurred first. Patient characteristics included age, sex, body mass index, MM stage at diagnosis, cytogenetic profile as of the index date, and number of prior regimens. Treatment patterns included type and duration of daratumumab-based regimen. Treatment outcomes included treatment response (as per physician notes and guided by the International Myeloma Working Group consensus criteria) and time to next line of therapy (TTNT; the time between the index date and the initiation of the following line of therapy, censoring at the end of follow-up). All analyses were descriptive and stratified by race. Results: A total of 252 patient charts were extracted: 89 Black (35.3%) and 163 White (64.7%). Black patients were, on average, younger at diagnosis (61.7 years old vs. 67.0) and at the index date (Table 1). The proportion of females was similar across both races (Black: 44.9%, White: 46.6%), and mean body mass index was slightly higher in Black patients (28.7 vs. 26.8). Black patients had longer time between initial MM diagnosis and initiation of daratumumab (43.2 vs. 34.1 months). MM stage at diagnosis, cytogenetic profile at index, and prior regimens were similar between White and Black patients (Table 1). While unknown cytogenetics were most common for both White (45.4%) and Black (59.6%) patients, White patients (20.2%) were twice as likely as Blacks (9.0%) to have high-risk cytogenetics. Black patients received more lines of treatment prior to the initiation of daratumumab (mean 2.9 vs. 2.3), with 55.1% of Black patients receiving 3 or more prior lines. The most common regimen was daratumumab with pomalidomide and dexamethasone (DPd) for both races (Table 1), with use of DPd being particularly common (51.7%) in Black patients. Duration of treatment with daratumumab was similar across races (Table 1). Treatment response was similar across races: among patients initiating daratumumab in first, second and third line or after, respectively, overall response rate was 100.0%, 90.9% and 67.6% for Black patients and 100.0%, 82.9% and 65.4% for White patients. Among patients initiating daratumumab in third line or after, median TTNT was 12.3 months among Black patients and 10.4 months among White patients. Conclusions: Black and White patients had similar overall response rate and comparable TTNT. However, Black patients initiated daratumumab later in their treatment, with more than half of Black patients initiating daratumumab in fourth or later line of therapy, and a lower percentage of Black patients had high-risk cytogenetics, suggesting a potential discrepancy in access to new therapies for MM. These findings were observed in a relatively modest sample size, and therefore interpretation warrants caution. Future studies should investigate whether such a discrepancy in treatment access exists, potential reasons for this discrepancy, and strategies to mitigate the effect of race on access to new therapies in MM. Figure 1 Figure 1. Disclosures Atrash: GSK: Research Funding; AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau. Thompson-Leduc: Biogen: Consultancy; Novartis: Consultancy; Shire/Takeda: Consultancy; Regeneron: Consultancy; Janssen Scientific Affairs, LLC: Consultancy; BioMerieux: Consultancy; Merck: Consultancy; GlaxoSmithKline: Consultancy; BioFire Diagnostics: Consultancy. Tai: Janssen Scientific Affairs, LLC: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment. Gray: Janssen Scientific Affairs, LLC: Current Employment, Current holder of individual stocks in a privately-held company. Ghelerter: Janssen Scientific Affairs, LLC: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Novartis: Consultancy. Lafeuille: Pharmacyclics: Consultancy; Pfizer: Consultancy; Janssen Scientific Affairs, LLC: Consultancy; GlaxoSmithKline: Consultancy. Lefebvre: Regeneron: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Janssen Scientific Affairs, LLC: Consultancy; GlaxoSmithKline: Consultancy. Rossi: Janssen Scientific Affairs, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

Download Full-text

Older Age and Increased Neutrophil-to-Lymphocyte Ratio (NLR) Are Predictors of Mortality in a Multiethnic Urban Cohort of Hematologic Neoplasms and COVID-19 Patients

Blood ◽

10.1182/blood-2020-138842 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Angelica D'Aiello ◽

Sumaira Zareef ◽

Kith Pradhan ◽

Amanda Lombardo ◽

Fariha Khatun ◽

...

Keyword(s):

Cancer Treatment ◽

Board Of Directors ◽

Median Time ◽

Lymphocyte Count ◽

Research Funding ◽

Hematologic Neoplasms ◽

Private Company ◽

Advisory Committees ◽

Treatment Status ◽

Race Ethnicity

Introduction: We sought to compare outcomes among patients with hematologic neoplasms diagnosed with COVID-19 infection in a multiethnic urban academic medical center. Methods: A retrospective analysis of patients with hematologic neoplasms diagnosed with COVID-19 from March 17th to June 8th2020 was conducted. Subjects included were censored at last point of contact. Variables collected included age, gender, race/ethnicity, hematologic diagnosis, cancer treatment status, baseline and follow-up COVID-19 testing, neutrophil count, and lymphocyte count at time of diagnosis. Associations between hematologic diagnosis, cancer treatment status, age, gender, race/ethnicity, neutrophil-to-lymphocyte ratio (NLR), and overall survival (OS) were assessed using the Kaplan-Meier method with logrank test. Results: A total of 102 subjects with hematologic neoplasms and COVID-19 infection treated in Montefiore Health system were identified (Table 1). Thirty-nine (38%) subjects were undergoing active treatment, including 17 (16%) receiving conventional chemotherapy agents, 12 (12%) targeted therapy, and 10 (10%) combination therapy. Of those subjects, twenty (50%) experienced delay or discontinuation of treatment due to COVID-19 infection. Four subjects (4%) showed persistent infection by PCR at median duration of 25.1 days after initial diagnosis. Ten subjects (9.8%) showed clearance of the virus by PCR with median time-to-clearance of 51.8 days. Of 9 subjects with serologic testing, 8 tested positive for COVID-19 IgG antibody at median time of 62 days after initial COVID-19 diagnosis. Forty-seven (47%) subjects expired as a result of COVID-19 disease at the time of analysis. Disease type, treatment status, race/ethnicity, age, and gender showed no significant association with mortality. Patients older than 70 had worse outcomes than the younger population (p = 0.0082). Median neutrophil and lymphocyte count at time of diagnosis was 4500 and 900, respectively. NLR greater than 9 was associated with worse survival when compared to NLR less than 9 (p=0.0067). Conclusions: COVID-19 infection has adverse effects on patients with hematological neoplasms. Subjects older than 70 years had a significantly worse prognosis. Notably, subjects actively being treated with chemotherapy did not have worse outcomes than those not being treated in our cohort, supporting the notion than active COVID-19 infection per se should not result in treatment delays. In addition, high NLR correlates with worsened survival, suggesting that this could be a potential prognostic factor for COVID-19 mortality in the hematologic neoplasms population. Disclosures Steidl: Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Research Funding; Pieris Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:stelexis: Current equity holder in private company; BMS: Consultancy, Research Funding; Medpacto: Research Funding; Janssen: Research Funding; acceleron: Consultancy, Honoraria.

Download Full-text

Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽

10.1182/blood.v128.22.3306.3306 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3306-3306

Author(s):

Yi L. Hwa ◽

Qian Shi ◽

Shaji Kumar ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Research Funding ◽

Beta Blockers ◽

Multivariable Analysis ◽

Advisory Committees ◽

Risk Of Death ◽

Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: 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.

Download Full-text

Outcomes of Patients with Relapsed or Refractory Acute Myeloid Leukemia Receiving Hypomethylating Agent and Venetoclax

Blood ◽

10.1182/blood-2019-128958 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1357-1357 ◽

Cited By ~ 2

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Groups ◽

Initial Therapy ◽

Intermediate Risk ◽

Advisory Committees ◽

Significant Difference ◽

Frontline Therapy ◽

Refractory Aml

Background: Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML. Methods: We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided. Results: Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009). At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97). The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07). Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted. Conclusion: Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML. Disclosures Padron: Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: 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; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. OffLabel Disclosure: Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.

Download Full-text

Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-122291 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4396-4396

Author(s):

Patrick Mellors ◽

Moritz Binder ◽

Rhett P. Ketterling ◽

Patricia Griepp ◽

Linda B Baughn ◽

...

Keyword(s):

Multiple Myeloma ◽

Risk Stratification ◽

Board Of Directors ◽

Research Funding ◽

Multivariable Analysis ◽

Risk Modeling ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Download Full-text

Nilotinib in Imatinib-Resistant or -Intolerant Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): 48-Month Follow-up Results of a Phase 2 Study,

Blood ◽

10.1182/blood.v118.21.3770.3770 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3770-3770 ◽

Cited By ~ 3

Author(s):

Philipp D. le Coutre ◽

Francis J. Giles ◽

Javier Pinilla-Ibarz ◽

Richard A. Larson ◽

Norbert Gattermann ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lung Neoplasm ◽

Chronic Phase ◽

Dose Intensity ◽

Advisory Committees ◽

Imatinib Resistance ◽

Imatinib Resistant ◽

Significant Difference

Abstract Abstract 3770 Background: Nilotinib is a selective and potent BCR-ABL TKI approved for the treatment of pts with newly diagnosed Ph+ CML-CP, and for pts with CML-CP or CML-AP resistant to or intolerant of imatinib. Here, we present the 48-mo follow-up data from the 2101 trial for pts with imatinib resistance or intolerance. Methods: Pts were treated with nilotinib 400 mg twice daily (BID). Key endpoints included PFS (defined as progression to AP/BC or discontinuation due to disease progression as assessed by investigator or death from any cause) and OS (includes deaths during treatment or follow-up after discontinuation). Results: 321 pts were enrolled (70% imatinib resistant; 30% imatinib intolerant with resistance). At baseline (BL), 36% of pts were in CHR. At the time of data cutoff, 224/321 pts (70%) discontinued nilotinib therapy (Table), and 31% of all pts had at least 48 mo of treatment. The median nilotinib dose intensity was 789 mg/day (range, 151–1110) and 62% of pts received ≥ 400 mg BID nilotinib as their last dose available. Pts with BL CHR had a significantly higher PFS rate at 48 mo vs pts without BL CHR (71% vs 49%, respectively; P =.001). Only 11 (3%) pts progressed to advanced disease (AP/BC) during study. Estimated 48-mo OS rate was 78% (95% CI 74%-83%). Among resistant pts, those without BL mutations (n = 92) had a significantly higher OS rate at 48 mo vs pts with sensitive mutations at BL (n = 78) (84% vs 74%, respectively, P =.029); however, there was no significant difference in OS among pts with sensitive and insensitive mutations (Y253H, E255K/V or F359C/V, n = 27) at BL (74% vs 71%, respectively, P =.804). No new safety signals were observed, and few additional AEs were reported since 24 mo follow-up (Table). Biochemical lab abnormalities were generally mild, transient, and easily managed; grade 3/4 lipase elevation (19%), hypophosphatemia (18%), and hyperglycemia (13%) were most common. Reports of any-grade pleural effusions remained low (1%), and no new cases were reported with longer follow-up. No new cases of QTcF >500 ms and 3 new cases of QTcF increases > 60 ms from BL were reported. Nine pts died during treatment or within 28 days of discontinuation: 8 deaths were previously reported and occurred in the first 24 mo of follow-up; 1 additional death due to lung neoplasm occurred between 24 and 48 mo (35 mo). Conclusions: With longer follow up, nilotinib continues to be effective and well tolerated in pts with Ph+ CML-CP resistant to or intolerant of imatinib therapy. Nilotinib prevented progression to AP/BC in the majority of pts on treatment and was associated with high OS rates. No cumulative toxicity was observed. Data demonstrating the higher rate of PFS in pts who entered the study with a BL CHR suggest that switching pts to nilotinib prior to hematologic failure on imatinib, and according to current treatment guidelines, may maximize the efficacy of nilotinib therapy. Disclosures: le Coutre: Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Giles:Novartis: Consultancy, Honoraria, Research Funding. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis: Honoraria, Research Funding. Ottmann:Novartis: Consultancy; BMS: Consultancy, Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Radich:BMS: Consultancy; Novartis: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Müller:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shou:Novartis: Employment. Novick:Novartis: Employment, Equity Ownership. Fan:Novartis: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Baccarani:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Download Full-text