bluuebunny/crossref_metadata_2025 huggingface dataset:
Fixed-duration (FD) ibrutinib (I) + venetoclax (V) for first-line (1L) treatment (tx) of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Three-year follow-up from the FD cohort of the phase 2 CAPTIVATE study.
Authors: Wierda William G. , Barr Paul M. , Siddiqi Tanya , Allan John N. , Kipps Thomas J. , Trentin Livio , Jacobs Ryan , Jackson Sharon , Tedeschi Alessandra , Opat Stephen , Bannerji Rajat , Kuss Bryone J. , Moreno Carol , Croner Lisa J. , Szafer-Glusman Edith , Zhou Cathy , Szoke Anita , Dean James P. , Ghia Paolo , Tam Constantine Si Lun
Published: June 2022

7519

Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of 1L I+V in CLL. The primary analysis (PA) evaluating FD tx with I+V was previously presented (Ghia et al., ASCO 2021). Here we present 3-y follow-up results from the FD cohort. Methods: Patients (pts) aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; <10-4) was measured by 8-color flow cytometry. Serious AEs (SAEs) deemed related to I reported >30 d after last dose of study drug were collected. Results: 159 pts were enrolled (median age 60 y), including pts with high-risk features of del(17p)/ TP53 mutation (17%), unmutated IGHV (uIGHV; 56%), and complex karyotype (19%). 147 (92%) and 149 (94%) pts completed tx with I and V, respectively. With 1 y of additional follow-up since PA, median time on study was 39 mo (range 1-41). ORR was 96% and was consistent (96%-97%) in pts with high-risk features (Table).The primary endpoint of complete response (CR) including CR with incomplete bone marrow recovery (CRi) rate in pts without del(17p) (n=136) increased nominally from 56% (95% CI, 48-64) to 58% (95% CI 50-66); in all pts, CR rate increased from 55% (95% CI 48-63) to 57% (95% CI 50-65). In pts achieving CR, 93% had durable responses lasting ≥12 mo post-tx. Of pts with uMRD in peripheral blood at 3 mo post-tx, 66/85 (78%) evaluable pts maintained uMRD through 12-mo post-tx. At 36 mo, PFS was 88% (95% CI 82‒92) and OS was 98% (95% CI 94‒99); similar rates were seen in pts with high-risk features (Table). All pts are off tx; no new SAEs of any kind have occurred since the PA. Available data on relevant mutations in BTK, PLCɣ2, or BCL-2 at time of PD will be presented. As of January 2022, 12 pts were retreated with single-agent I after PD (tx duration range 3-29 mo); of evaluated pts, 7/9 had partial responses and 2/9 had stable disease. Conclusions: Fixed duration I+V continues to provide deep, durable responses and clinically meaningful PFS, including in pts with high-risk disease features, representing an all-oral, once-daily, chemotherapy-free FD regimen for previously untreated pts with CLL/SLL. With an additional 1 y of follow-up, no OS events or SAEs occurred. Manageable safety profile is unchanged as previously reported. To date, successful single-agent I retreatment responses are observed. Clinical trial information: NCT02910583. [Table: see text]
Molecular disease monitoring in patients with relapsed/refractory B-cell non-Hodgkin lymphoma receiving anti-CD19 CAR T-cell therapy.
Authors: Colton Meryl D. , Purev Enkhtsetseg , Haverkos Bradley , Bair Steven Michael , Jasem Jagar , Schliekelman Mark Jason , Kamdar Manali K.
Published: June 2022

7531

Background: Chimeric antigen receptor (CAR) T-cell therapy has improved the historically poor outcomes for relapsed and refractory (R/R) B-cell non-Hodgkin’s lymphoma (NHL). However, nearly 60% of patients will either fail to respond or relapse after CAR T-cell therapy. Currently, PET/CT scans are used to assess response. Cell-free circulating tumor DNA (ctDNA) is released by tumor cells into the peripheral blood and can be measured for minimal residual disease (MRD) assessment. Methods: In this retrospective, IRB approved pilot study, archived lymphoma tissues and ctDNA from peripheral blood samples on day 0, 14, 28, 56, 80, 180, and 365 after CAR T-cell infusion from 10 patients with R/R NHL were collected for next-generation sequencing (NGS) of clonal variable-diversity-joining (VDJ) rearrangements [Adaptive biotechnologies (Seattle, WA)]. Response was assessed by PET/CT on days 30, 60, 90, 180 and 365 and graded according to the Lugano 2014 criteria. The primary endpoint was to determine the feasibility of detecting ctDNA to monitor disease response after anti-CD19 CAR T-cells. The secondary endpoint was to compare the sensitivity/specificity of MRD assessment from ctDNA to PET/CT imaging. Results: Nine out of 10 patients with a trackable sequence [median age 69 (range: 56-76); 55.6% male; median LDH 224], were included in this study. Each received tisagenlecleucel CAR T-cell therapy after median two prior treatments (range: 2-4). 7/9 patients had R/R diffuse large B-cell lymphoma (DLBCL), and 2/9 had transformed follicular lymphoma. At a median follow up of 12.7 months (range: 1.5-30 months), four patients were alive. By day 90, three patients (33.3%) achieved a radiographic complete response (CR) whilst six patients (66.6%) had progressive disease (PD). MRD and radiographic response are outlined in the Table. Detectable MRD on day 14 or day 28 had 83% sensitivity and 100% specificity for radiographic progression at any time before one year. For patients with PD, the median (interquartile range) MRD at day 0, 14, and 28 were 17.31 (1.01, 96.84), 9.12 (0.30, 18.8), and 23.77 (8.01, 137.53) copies per milliliter (mL), respectively. For patients with detectable MRD at day 28, mOS and mPFS were 205 and 38 days, respectively. Conclusions: Our pilot study demonstrated that monitoring MRD was a sensitive and specific method to detect disease response and relapse. In addition, MRD can be monitored more frequently, thus allowing for earlier detection of relapse. MRD and PET/CT identified progressive disease (PD) or complete response (CR) by day 90 in nine patients (A-I) with R/R NHL post CAR T-cell infusion.[Table: see text]
Cost-effectiveness of CD19 chimeric antigen receptor T-cell (CAR-T) therapy versus autologous stem cell transplantation (ASCT) for high-risk diffuse large B-cell lymphoma (DLBCL) in first relapse.
Authors: Kelkar Amar Harry , Cliff Edward Robert Scheffer , Jacobson Caron Alyce , Abel Gregory A. , Redd Robert , Dijk Stijntje , Krijkamp Eline , Hunink M. G. Myriam , Cutler Corey S.
Published: June 2022

7537

Background: The recently reported ZUMA-7 and TRANSFORM trials demonstrate superior event-free survival among patients with primary refractory or early relapsed DLBCL compared to salvage chemotherapy with ASCT. However, given a cost of >$370,000, it is not known whether second-line CAR-T is cost-effective compared to ASCT. Thus, we developed a state-transition microsimulation model to simulate clinical outcomes and costs associated with therapy for DLBCL patients in first relapse, using ZUMA-7 and TRANSFORM data. Methods: The model begins at initiation of second-line therapy comparing salvage chemotherapy with ASCT or CAR-T therapy. We examined a three-year time horizon, including crossover to the alternative strategy therapy in the third line, as well as subsequent lines of therapy, using open-source Amua 0.3.0 software. Base case analysis was performed using 1000 first-order Monte Carlo simulations and probabilistic sensitivity analysis (PSA) was performed with 1000 simulations to test model uncertainty. Conditional probabilities of survival and disease progression were extracted from Kaplan-Meier curves from pivotal clinical trials using the WebPlotDigitizer tool. Costs were estimated from public sources in US Dollars ($) and effects were estimated in quality-adjusted life years (QALY) using published utility values. Results: Median overall survival was 15 months (95% confidence interval [CI] 13-19 months) with ASCT and 21 months (95% CI 17-29 months) with CAR-T. The PSA demonstrated costs and effectiveness per patient of $243,581 and 1.06 QALYs with ASCT and $470,150 and 1.22 QALYs with CAR-T with an incremental cost-effectiveness ratio (ICER) of $1,383,320/QALY. Incremental net monetary benefit of CAR-T versus ASCT, based on a willingness-to-pay (WTP) threshold of $200,000/QALY, was -$193,812. The break-even price for CAR-T and all subsequent therapies, based on a one-way sensitivity analysis, was $170,489. Conclusions: The model demonstrated improved survival and QALYs for the second-line CAR-T therapy, but was not cost-effective, as the ICER exceeded $1,000,000/QALY, which is higher than most accepted WTP thresholds. A limitation of these early data is that they only assess outcomes over three years. To estimate the full effect of these therapies, we will extrapolate the Kaplan-Meier curves for additional analyses. Clinical outcomes of second-line CAR-T are promising, but prices would need to be considerably lower to enable equitable access and affordability.[Table: see text]
Asia subpopulation analysis from the phase III POLARIX trial.
Authors: Song Yuqin , Jin Jie , Tilly Herve , Zhang Huilai , Cao Junning , Feng Jifeng , Zhang Liling , Rai Shinya , Goto Hideki , Terui Yasuhito , Kim Won Seog , Shin Ho-Jin , Gau Jyh-Pyng , Tsai Cheng-Hong , Sharman Jeff Porter , Bu Lilian , Hirata Jamie , Lee Calvin , Izutsu Koji , Zhu Jun
Published: June 2022

7558

Background: In the pivotal Phase III POLARIX trial, Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP, with a similar safety profile in patients with previously untreated DLBCL (Tilly et al. 2022). An Asia subpopulation analysis was included as part of the trial design; patients enrolled in Asia were analyzed for the purpose of registration in China of POLARIX (NCT03274492). Methods: Patients from mainland China, Hong Kong, Japan, South Korea, and Taiwan (enrolled during the global phase), and from the China extension cohort were included in the Asia subpopulation. POLARIX methods were previously described (Tilly et al. 2022). Briefly, patients with untreated DLBCL were randomized 1:1 using the same stratification factors to receive six cycles of Pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The purpose of this analysis was to evaluate consistency of PFS (defined as ≥50% risk reduction in PFS) in the Asia subpopulation with the global population. Results: Overall, 281 patients (intent-to-treat population; 150, 85, 31 and 15 patients in mainland China, Japan, South Korea and Taiwan, respectively) were analyzed (141 received Pola-R-CHP and 140 received R-CHOP); 160 patients from the global population and 121 from the China extension cohort. Median age was 63 (range 19–79) years, and most patients had an International Prognostic Index of 3–5 (61.9%). At the data cut-off of June 28, 2021, (median follow-up of 24.2 months) PFS was superior with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.40–1.03) and met the consistency definition with the global population. The 2-year PFS rate was 74.2% (95% CI: 65.7–82.7) with Pola-R-CHP vs 66.5% (95% CI: 57.3–75.6) with R-CHOP. Other key efficacy results were similar to the global study results (Table). The safety profile was generally comparable for Pola-R-CHP vs R-CHOP, including rates of grade 3–4 adverse events (AEs; 72.9% vs 66.2%), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to discontinuation of any study treatment (5.0% vs 7.2%), and incidence of peripheral neuropathy (all grades, 44.3% vs 50.4%), respectively. Key efficacy results. CR, complete response. Conclusions: The results from the Asia subpopulation of POLARIX were consistent with the global study, with a clinically meaningful improvement in PFS (risk of disease progression, relapse or death reduced by 36%) following treatment with Pola-R-CHP vs R-CHOP, and a comparable safety profile in Asian patients with previously untreated DLBCL. Clinical trial information: NCT03274492. [Table: see text]
Association of socioeconomic status with adherence to oral agents in patients with multiple myeloma.
Authors: Rutter Wilbur , Prakash Shivaani , Cavers William , Avalos-Reyes Elisea , Johnson Kjel Andrew , Bernal-Mizrachi Leon
Published: June 2022

8023

Background: The introduction of novel oral immunomodulatory drugs has improved the overall survival rates of patients with multiple myeloma (MM). Poor adherence to oral therapies may lead to drug resistance, poor response to treatment and other downstream effects. It is unknown if socioeconomic status (SES) mediates adherence to oral MM agents. Methods: This is a retrospective review of newly diagnosed adult patients with MM with drug coverage through a large pharmacy benefit manager (PBM) who received oral MM agents between September 1, 2016 and September 1, 2020. Patients were excluded if they were not eligible for PBM benefits for the 6 months prior to or the 12 months after the index date and if they had a stem cell transplant based on a proxy signal. Adherence was defined as an annual medication possession ratio between 0.8 and 1.2. An SES composite index was developed using ZIP code level factors in a K-means clustering algorithm. Multivariable logistic regression for adherence was conducted using the SES-index and controlled for other patient-specific demographics. Results: In total, 6,602 patients were enrolled in the study, of which, 4,211 (64.5%) were defined as adherent. There were significant unadjusted differences in age (67.89 vs 64.06, p<0.00001), ZIP code-based SES index (p=0.00049), census region (p<0.00001) and insurance plan type (p<0.00001). Results from multivariable logistic regression are shown in table. Patients residing in Very Low SES ZIP codes were significantly less likely to be adherent to oral MM agents compared to those residing in Very High SES locations. Odds of adherence increased as patient’s age increased. Increasing polypharmacy was negatively associated with oral MM agent adherence. Conclusions: Aside from patients residing in Very Low SES ZIP codes, ZIP code-based SES measures were not associated with worse adherence. Other mediating factors include younger age and number of co-prescribed medications. Further investigations of adherence to oral MM agents with clinically relevant outcomes are warranted. [Table: see text]
Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): Interim phase 1b study results.
Authors: Quach Hang , Parmar Gurdeep , Ocio Enrique , Prince H. Miles , Oriol Rocafiguera Albert , Tsukada Nobuhiro , Sunami Kazutaka , Bories Pierre , Karanes Chatchada , Madan Sumit , Semiond Dorothee , Inchauspe Marlene , Macé Sandrine , Musholt Petra B. , Suzan Florence , Moreau Philippe
Published: June 2022

8025

Background: Intravenous (IV) isatuximab (Isa) + Pd is approved for the treatment of RRMM patients (pts). SC delivery would optimize convenience of administration. Prior results showed that SC Isa administered by syringe pump has efficacy and safety profiles comparable to IV Isa; the recommended Phase 2 dose (RP2D) was 1400 mg (IMW21 P-207). Methods: This multicenter Phase 1b study evaluated safety, PK and efficacy of SC vs IV Isa + Pd in RRMM pts after ≥2 prior treatment lines. Pts were randomized 2:1 to SC1000 mg or IV 10 mg/kg and to SC1400 mg or IV. An expansion cohort was later implemented with SC Isa administered at the RP2D via OBDS, a wearable bolus injector applied to the abdomen by a healthcare professional. Primary endpoints (EPs) were safety, including injection site reactions (ISRs), and PK. Main secondary EPs were overall response rate (ORR) and progression-free survival (PFS). Results: 56 pts were randomized and treated: 12 Isa IV, 12 Isa SC1000, 10 Isa SC1400 and 22 OBDS pts. At study entry, ISS stage II–III was 67% in IV, 33% in SC1000, 60% in SC1400 and 50% in OBDS pts. On Jan 20, 2022, 33% IV, 25% SC1000, 50% SC1400 and 86% OBDS pts remained on treatment. Due to sequential accrual, median follow-up (FU) was longer in IV (20.6 mo) and SC1000 (23.8 mo) than SC1400 (18.1 mo) and OBDS (6.5 mo) pts. Infusion reactions (IRs) were infrequent (≤10% in each cohort, all Grade [G] 2), only at first IV or SC infusion/injection, with no IRs in OBDS. Local tolerability of OBDS was very good, with 5 (22.7%) pts experiencing 7 ISR episodes, all G1, out of 305 administrations (2.3%): 5 injection site erythemas, 1 injection site hemorrhage, and 1 injection site induration. Median duration of OBDS injection was 10 min. Incidence of G4 neutropenia was lower in SC1000 (42%) vs the other cohorts (55–60%). The lower % of ≥G3 treatment-related AEs in OBDS (77%) vs the other cohorts (≥80%) may be due to shorter FU. Best overall responses are shown in table; longer FU is needed for OBDS pts. Median PFS was 22 mo in IV, 12.5 mo in SC1000 and not reached in SC1400 and OBDS pts. PK and CD38 receptor occupancy results in OBDS pts are consistent with those observed in SC1400 with pump. Conclusions: SC Isa administered by OBDS shows a safety profile consistent with IV administration with no IRs and excellent local tolerability. Efficacy in the SC cohorts was comparable to the Phase 3 ICARIA results. Isa SC administration by OBDS is well tolerated, requires a short duration of injection and provides a convenient hands-free option. Clinical trial information: NCT04045795. [Table: see text]
Safety and efficacy of daratumumab use in patients with renal impairment and hemodialysis.
Authors: Niewinski Mateusz , Chin-Hon Jamie , Akerman Meredith , Davies Faith , Morgan Gareth , Braunstein Marc Justin
Published: June 2022

8026

Background: Targeting CD38 in multiple myeloma (MM) using daratumumab-based regimens can prolong remission in both the newly diagnosed and relapsed settings. However clinical trials have excluded patients with creatinine clearances (CrCl) <30 mL/min, warranting real-world analysis of daratumumab use in MM patients with renal insufficiency. Methods: Following IRB approval, we performed a retrospective chart review of relapsed MM patients at our institution who had reduced CrCl and received at least one dose of either daratumumab between October 2018 and January 2022. All subjects received IV daratumumab, 52% went on to receive SQ. Outcomes included change in CrCl during treatment, adverse events, and survival. Survival was estimated using product-limit estimates. CrCl groups at daratumumab initiation of more or less than 30 were compared using the chi-square test or Fisher’s exact test, as deemed appropriate, for categorical variables and the two-sample t-test or Mann-Whitney test for continuous data (SAS Institute Inc., Cary, NC). Results: 101 MM patients were included, with median age of 74 (54-92); 46 (45.5%) were female. 14% were on hemodialysis. Patients had a median of 2 prior lines of therapy. Distribution of R-ISS stages were I (20%), II (35%), and III (45%). High-risk cytogenetics were present in 20%. A median of 23 daratumumab infusions (1-60) were delivered over a median of 18 months (median IV=16, SQ=10). Daratumumab regimens included DRD (32%), DPD (35%), DKD (13%), and DVD (35%). Median CrCl at MM diagnosis and at daratumumab initiation was 45 (7.3-101) and 40 (5.3-107), respectively, with 33% having CrCl <30. Following 3, 6, and 12 months (n = 95, 89, 69) on daratumumab-based regimens, median CrCl were 45, 43, and 41, respectively. There were no differences in renal function in patients who went on to receive SQ daratumumab. 16 patients had died at the time of data collection, and the median survival was 63 months. Of the 101 patients, 16 subjects were deceased at the time of data collection, and 23% of subjects had gone on to subsequent treatments. Analysis showed that there was a progression-free survival of 54% at 5 years. The most common adverse events reported were anemia (37%) and neutropenia (15%). Infusion-related reactions were reported in 19% of patients. Conclusions: This is the largest real-world assessment of outcome for MM patients treated with daratumumab-containing regimens in the setting of renal insufficiency. There was no significant impact of the treatment on renal function at 12 months. Compared to published data on patients treated with CrCl>30, there does not appear to be a detriment to survival or an increase in adverse events when using daratumumab regimens in patients with more advanced renal insufficiency.
Subgroup analyses in patients with relapsed/refractory multiple myeloma (RRMM) receiving real-life current standard of care (SOC) in the LocoMMotion study.
Authors: Einsele Hermann , Moreau Philippe , De Stefano Valerio , Dytfeld Dominik , Angelucci Emanuele , Benjamin Reuben , Goldschmidt Hartmut , van de Donk Niels W.C.J. , Besemer Britta , Scheid Christof , Vij Ravi , in ’t Groen-Damen Ester , Semerjian Maria , Strulev Vadim , Schecter Jordan Mark , Roccia Tito , Nesheiwat Tonia , Wapenaar Robert , Weisel Katja , Mateos Maria-Victoria
Published: June 2022

8031

Background: Patients (pts) with RRMM who are triple-class exposed (proteasome inhibitor [PI], immunomodulatory drug [IMiD], and anti-CD38 monoclonal antibody [mAb]) have an urgent and currently unmet clinical need. LocoMMotion (NCT04035226) is the first prospective multinational study of real-life SOC in triple-class exposed pts with RRMM. Here we present efficacy in subgroups of pts treated with SOC therapies in the LocoMMotion study. Methods: LocoMMotion is a noninterventional study across 76 sites (63 European; 13 US). Eligible pts had received ≥3 prior lines of therapy (LOT) or were double refractory to a PI and an IMiD; received a PI, an IMiD, and anti-CD38 mAb; and had disease progression during/after their last LOT. Real-life SOC treatments were defined as those used in local clinical practice. Responses and disease progression were assessed by response review committee, per IMWG criteria. Subgroups were defined by baseline (BL) characteristics: age, Eastern Cooperative Oncology Group performance status (ECOG PS), renal function, ISS stage, presence of extramedullary plasmacytoma, LDH level, % of bone marrow plasma cells, number of prior LOT, triple-class or penta-drug exposure, and refractoriness. Results: As of May 21, 2021 (median follow-up 11.0 mo), 248 pts were enrolled and treated with median 4.0 (range, 1–20) cycles of SOC therapy. Evaluation of efficacy outcomes in subgroups demonstrated that refractoriness to 3 classes of antimyeloma therapy, presence of extramedullary plasmacytomas, high LDH, and ECOG PS ≥1 were associated with generally worse outcomes, compared with pts who did not have these characteristics (Table). Overall response rate (ORR) ranged from 20.0–43.1% across all subgroups. Age and number of prior LOT did not have an impact on efficacy outcomes. Conclusions: Subgroup analyses of this first prospective study of real-life SOC tx in triple-class exposed pts with RRMM indicate that specific pt and disease characteristics were associated with poor outcomes. Triple-class refractory and non-triple-class refractory pts had poor outcomes, although the latter had longer median progression-free survival (PFS). These findings should be considered when planning bridging strategy for CAR-T therapy. Clinical trial information: NCT04035226. [Table: see text]
Demographic disparities in genomic data and clinical trials for multiple myeloma.
Authors: Aggarwal Nidhi , Ahluwalia Pankaj Kumar , Kolhe Ravindra B. , Cortes Jorge E.
Published: June 2022

8043

Background: There are considerable outcome disparities among patients with multiple myeloma (MM). African-Americans have higher risk of developing MM, earlier age at diagnosis, and higher mortality compared to Whites. While outcomes have multifactorial socioeconomic etiologies, race and ethnicity (R&E) correlate with genomic ancestry, and any role of genetics should be explored. This requires equitable representation in biological databases like The Cancer Genome Atlas (TCGA). Here, we characterize disparities in MM cases of TCGA and clinical trials (CT). Methods: MM incidence was obtained from North American Association of Central Cancer Registries (NAACCR) for R&E, sex and age ( < 50, 50-64, 65+ years). Race includes White, Black, and Asian, along with Hispanic ethnicity, as TCGA MM is limited to these groups. Genes with oncogenic potential and > 5% mutation were stratified by R&E and age. TCGA MM cases are from USA, Canada, Italy, and Spain. On ClinicalTrials.gov, completed MM CT limited to these countries were identified. Student’s t-test and chi-square test were used to analyze disparities and gene mutations. Kaplan-Meier curve was generated to evaluate survival. Results: TCGA MM representation is in Table, calculated as (demographic TCGA cases divided by total TCGA cases) divided by (demographic incidence divided by total incidence). Race was not reported in 20% of TCGA, 4% of CT, and 3% of NAACCR. Of cases reporting R&E, Hispanics are underrepresented by 26% in TCGA and 47% in CT relative to incidence, Blacks by 22% in TCGA and 41% in CT, and Asians by 40% in TCGA and 10% in CT. Whites are overrepresented, by 8% in TCGA and 7% in CT. More men are in TCGA than women, in all R&E. Less than 25% of patients age < 50 relative to incidence are in TCGA, in all R&E. BCL7A is mutated more in Blacks age < 50 (n = 20, 50%) than Whites (n = 39, 10%) (p < 0.01). FAT4 is mutated in Whites age 65+ (n = 31, 10%) but not Blacks. In all ages, KRAS is mutated more in Blacks than Whites (31-35% vs. 20-25%, p < 0.05). Black patients have lower survival than Whites (p < 0.02). In patients age 65+, KRAS mutation is associated with 10% lower 4.5-year survival. Conclusions: Substantial disparities in Black, Hispanic, women, and age representation exist for MM cases in TCGA and CT. This stratification by R&E and age offers new insight on BCL7A, FAT4, and KRAS mutation in MM. Mutation status is associated with survival in older patients. Equitable demographic representation should be pursued to improve quality of available data and access to medical resources for all populations. [Table: see text]
The association of agent orange (AO) exposure with monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) progression: A population-based study.
Authors: Liu Lawrence , Wang Mei , Schroeder Mark A. , Thomas Theodore Seth , Kumar Akhil , Vargo Kristin , Gao Feng , Sanfilippo Kristen Marie , Chang Su-Hsin
Published: June 2022

8050

Background: With limited evidence from a single center study [n=211 (11 with AO exposure)] reporting AO exposure as a risk factor for transformation, whether or not AO exposure increases the rate of transformation from MGUS to MM is unclear. Thus, we aimed to conduct a nation-wide study to determine the association between AO exposure and the risk of MGUS to MM progression. Methods: A retrospective, matched cohort study using data from the U.S. Veterans Health Administration system was conducted. Based on a power calculation, a random sample of MGUS patients with AO exposure was selected and 1:1 matched to those with MGUS without AO exposure (matching factors: age at MGUS diagnosis, race, body mass index categories). Data abstraction confirmed MGUS and MM diagnoses. In addition, information on date of diagnosis, MGUS subtype, and monoclonal protein (M-protein) values was performed. Patients were considered to have MGUS if they had M-protein detected on serum protein electrophoresis (SPEP) with immunofixation confirmation. The association of AO exposure with progression from MGUS to MM was examined using a multivariable Fine-Gray subdistribution hazard model with death as the competing event. The covariates included M-protein at MGUS diagnosis (>1.5, ≤1.5 g/dL [reference]), MGUS subtype (Immunoglobulin A, light chain, and Immunoglobulin G [reference]), and Charlson comorbidity score at MGUS diagnosis. A sensitivity analysis was conducted using inverse probability treatment weighted survival analysis to evaluate the robustness of the conclusion. Results: After excluding individuals with no confirmed MGUS or M MGUS subtype, a total of 563 MGUS patients with AO exposure and 563 matched controls were included. No statistically significant difference was observed in the progression of MGUS to MM between the AO exposed group and control group (adjusted hazard ratio (aHR) 0.78, 95% confidence interval (CI) 0.53 to 1.17). The sensitivity analysis demonstrated consistent results. Conclusions: Our carefully designed study does not show an association between AO exposure and progression of MGUS to MM in a national cohort of Veterans. [Table: see text]
Outcomes for transplant-eligible, newly diagnosed Black patients (Pts) with multiple myeloma (MM): The Levine Cancer Institute (LCI) experience.
Authors: Paul Barry , Atrash Shebli , Robinson Myra M. , Jagosky Megan , Bhutani Manisha , Varga Cindy , Pineda-Roman Mauricio , Friend Reed N. , Foureau David , Cassetta Kristen , Usmani Saad Zafar , Voorhees Peter M.
Published: June 2022

8053

Background: Studies have revealed disparities for Black (B) pts with MM, including more advanced disease at presentation, delayed therapy with novel agents such as immunomodulatory drugs (IMIDs) and proteasome inhibitors (PIs), reduced access to autologous stem cell transplant (ASCT), and under-representation in clinical trials. However, B pts tend to be younger at diagnosis and less likely to harbor high risk disease biology, suggesting outcomes could be better relative to their White (W) counterparts. To better understand outcomes by race in the setting of more optimal treatment access, we pursued a retrospective analysis of pts treated at LCI undergoing ASCT as part of first line therapy. Methods: 255 pts (181 W pts, 74 B pts) transplanted between 3/2014 – 12/2018 were included. Analysis was restricted to pts with MM who underwent a single ASCT as part of first line therapy. Pts with < 1 year of follow-up and no overall survival (OS) events were excluded. Proportions were compared between groups with Fisher’s exact tests; OS and progression free survival (PFS) were evaluated with Kaplan Meier methods and compared between groups with log-rank tests. Results: Median follow-up for B and W pts was 5.0 yrs (0.9 – 7.8 yrs) and 4.1 yrs (0.5 – 8.0 yrs). At initial presentation, median age was 59 yrs (24 – 76 yrs) and 61 yrs (35 – 78 yrs, P= 0.038), anemia was present in 81.3% and 64.6% ( P= 0.020), renal impairment in 41.3% and 33.1% ( P= 0.335), and high-risk cytogenetics [gain 1q21, t(4;14), t(14;16) or del(17p)] in 25.4% and 35.9% ( P= 0.162) of B and W pts, respectively. Median time from diagnosis to ASCT was 0.6 yrs (0.3 – 2.4 yrs) and 0.5 yrs (0.3 – 2.0 yrs) for B and W pts. 35.2% of all B pts and 43.9% of all W pts treated at LCI during the study period underwent ASCT (48.3% and 64.4% of pts ≤70 yrs of age, P= 0.002), while 63.5% and 80.1% received PI/IMID-based induction therapy ( P= 0.009) and 90.5% and 93.4% received maintenance therapy post-ASCT ( P= 0.438), respectively. Although ≥very good partial responses were achieved in fewer B pts than W pts after induction (65.8% and 80.7%,( P= 0.014), there was no difference after ASCT (95.8% and 93.9%, P= 0.759). Median PFS was 5.9 yrs (95% CI 3.4 – 6.6) and 3.6 yrs (95% CI 3.0 – 4.5) for B and W pts ( P= 0.039). Median OS trended in favor of B pts ( P= 0.163) with 5-year OS of 83.0% (95% CI 71.2% - 90.3%) and 74.2% (95% CI 65.8% - 80.9%), respectively. Conclusions: Despite disparities in optimal induction therapy, Black pts with MM who underwent frontline ASCT enjoyed better PFS relative to W pts. Optimizing access to PI/IMID-based induction therapy and ASCT will be necessary to further improve OS.
Prognostic impact of t(11;14) on PFS1 among patients with myeloma receiving triplet induction therapy.
Authors: Pirmohammed Shama , Joseph Nisha , Hofmeister Craig C. , Heffner Leonard T. , Gupta Vikas Anand , Boise Lawrence , Dhodapkar Madhav V. , Lonial Sagar , Nooka Ajay K. , Kaufman Jonathan L.
Published: June 2022

8064

Background: Presence of t(11;14) on plasma cells by FISH or metaphase cytogenetics is considered a standard-risk prognostic factor per IMWG risk-stratification. However, recent studies suggest inferior PFS and OS observed among t(11;14) patients relative to the standard-risk myeloma patients. In the context of the ongoing trials of BCL-2 inhibitors (venetoclax) among t(11;14) relapse/refractory myeloma patients yielding response rates closer to 90%, we review the prognostic impact of t(11;14) on PFS. These results may have implications for earlier incorporation of BCL-2 inhibitors among t(11;14) myeloma patients. Methods: Among the 1000 consecutive newly diagnosed myeloma patients uniformly treated with RVD induction therapy from January 2008 until August 2016, we have information on FISH probes for t(11;14) tested for 869 patients [121 - t(11;14) and 748 – no t(11;14)]. First, we explore the frequency of IMWG defined concomitant high-risk cytogenetic characteristics [del 17p, t(4;14), t (14;16)]. Next, we create a synthetic control cohort that received maintenance, and excluded patients exhibiting high-risk features to evaluate the relative prognostication conferred by presence of t(11;14). Median follow up was 91 months. Demographic and outcomes data were collected from IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age is 61.2 years (range 16.3-79.83). 34% of the patients are above the age of 65. Men (14.1% vs 11.7%, p = NS) and blacks had higher rates of t(11;14) (16.1% vs 11.1%, p = 0.028). 17 (14%) had concomitant high-risk features – 4 (3.3%) had t(4;14), 3 (2.5%) had t(14;16) and 11 (9.1%) had del17p. Interestingly, the rates of amplification of 1q (26.1% vs 14.9%, p = 0.002), and del13 (34.7% vs 24.4%, p = 0.015) were higher among t(11;14) patients. Compared to the synthetic cohort, the post-induction and post-transplant responses were lower for t(11;14) patients as summarized in table 1. ≥VGPR for t(11;14) vs no t(11;14) post-induction were 48.2% vs 71.5% p < 0.001 and post-transplant were 83.1% vs 92.8% p = 0.001, respectively. The median progression-free survival for the t(11;14) and non-t(11;14) groups were 61.4 months (95% confidence interval (CI), 49.13-73.67) and 82.56 months (95% CI, 70.47-94.65) months, respectively (p = 0.002). Conclusions: Even with the use of modern day induction regimens and transplant, patients with t(11;14) seem to have inferior response rates compared to the other standard-risk myelomas. The lower rates of ≥VGPR post-induction and the shorter median PFS suggests BCL-2 inhibitors such as venetoclax may be incorporated earlier in myeloma treatments to improve the outcomes of t(11;14) patients on par with the other standard-risk myeloma patients.
Immune cell differences between patients in different stages of monoclonal plasma cell disorders.
Authors: Ho Christine , Wallace Paul K. , Attwood Kristopher , Parker Sarah , Mohammadpour Hemn , Herr Megan , Chen George , Tario Joseph , McCarthy Philip L. , Hillengass Jens
Published: June 2022

8065

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy. Precursor conditions include monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM). Immune surveillance is paramount for keeping the malignancy in check, whereas a dysfunctional immune system is suspected to promote disease progression. Methods: We performed flow cytometric immune panel analyses including T-cell, B-cell, natural killer (NK) cell and dendritic cell (DC) subsets in MGUS, SMM, and MM patients between 2018-2021. Immune panels were analyzed on fresh peripheral blood samples drawn at diagnosis. The patient population were MGUS (n=28), SMM (n=19) and MM (n=94). Samples from MGUS and SMM patients were combined into a single group (asymptomatic) and were compared to MM patients (symptomatic). Lymphocytes were identified by CD45+ expression resolving against side-scattered light on a bivariate plot. B cell and NK cell antigen expression profiles were assessed from this lymphocyte population. T cell subsets were further determined by CD3+. The percent gated for each marker was summarized by cohort using the appropriate descriptive statistics and compared using the Mann-Whitney U exact test. Analyses were performed in SAS v9.4 (Cary, NC) using a two-sided α=0.05. Results: Compared to MGUS/SMM patients, MM patients had a significant lower proportion of naive B cells, NK cells, and cytolytic NK cells, and a significant higher proportion of cytolytic T cells at diagnosis (Table). Consistent with prior studies, we demonstrated an increase in exhaustion markers. There was a trend toward a higher population of CD8+ exhausted T cells in MM patients compared to MGUS/SMM patients. Since the follow up for this study was short, survival data is not mature. Conclusions: This study demonstrates the immune imbalance that occurs between myeloma precursor conditions and MM. There is a shift in certain cell subsets in the immune microenvironment that alters tumor immunosurveillance and tumor cell killing favoring disease progression. In data not shown, we are currently analyzing the bone marrow microenvironment and its relation to disease progression. Follow up studies could assess if therapeutic intervention could reverse the imbalance, restore homeostatic equilibrium with the goal of controlling disease long-term. [Table: see text]
Primary analysis from the phase 2 study of continuous talazoparib (TALA) plus intermittent low-dose temozolomide (TMZ) in patients with relapsed or refractory extensive-stage small cell lung cancer (ES-SCLC).
Authors: Goldman Jonathan W. , Cummings Amy Lauren , Mendenhall Melody A. , Velez Maria A , Babu Sunil , Johnson Tirrell T. , Alcantar Juan M. , Dakhil Shaker R. , Kanamori David E. , Lawler William E. , Anand Sidharth , Chauv James , Garon Edward B. , Slamon Dennis J.
Published: June 2022

8517

Background: TALA exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. TMZ has been shown to increase antitumor response when combined with TALA in SCLC models (Wainberg AACR 2016). TALA plus TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes. Methods: This is a phase 2, open-label, single-arm study of the safety and efficacy of TALA plus TMZ in patients with ES-SCLC, relapsed or refractory to a first-line platinum-based regimen. Participants receive TALA 0.75 mg (or 0.5 mg if creatinine clearance < 60 mL/min) po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria, versus a historical control of 15% ORR in second-line topotecan, with the null hypothesis rejected for 8 or more confirmed responses among 28 evaluable subjects (29% ORR). Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as status of DNA damage response genes (DDR) and patient reported outcomes. A Simon two-stage design was utilized to reach a total accrual of 28 evaluable patients. Results: Thirty-one subjects were enrolled, of which 3 were non-evaluable due to ineligibility (1) or early withdrawal of consent prior to first disease assessment (2). Eleven of 28 evaluable subjects (39.3%) achieved a confirmed partial response. The ORR was similar among platinum-refractory (3/6), -resistant (4/9), and -sensitive subgroups (4/13). The median time to response was 1.8 months (m), duration of response 5.8 m, progression free survival 4.5 m, and overall survival 11.9 m. Adverse events (AEs) were manageable, with grade ≥ 3 AEs being thrombocytopenia (61.3%), anemia (54.8%), neutropenia (41.9%), and atypical pneumonia (3.2%), which responded well to dose-hold or dose-reduction and transfusion or growth factor support as needed. Cell free DNA and tissue analysis demonstrated no germline DDR mutations among the trial subjects, but somatic DDR mutations at baseline and acquired during treatment were common. Three subjects remain on study treatment. Conclusions: The study exceeded its target response rate. This is the second trial to demonstrate a benefit of PARP inhibition with low-dose TMZ in SCLC (see Farago Cancer Discovery 2019). A phase 3 study is appropriate to confirm the benefit of this approach compared to currently approved options. Clinical trial information: NCT03672773.
Adjuvant icotinib versus observation in patients with completely resected, EGFR-mutated, stage IB non–small cell lung cancer (GASTO1003, CORIN): A randomized phase II trial.
Authors: Li Ning , Wang Bao-Xiao , Ou Wei , Shi Hena , Ji Dong , Yan Yan , Wang Shu-Quan , Chang Wu-Guang , Zhu Teng-Fei , Wang Si-Yu
Published: June 2022

8519

Background: The role of adjuvant therapy in patients with completely resected stage IB non-small-cell lung cancer (NSCLC) remains to be determined. Icotinib is standard-of-care therapy for patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutation. This phase II study investigated whether adjuvant therapy with icotinib improves the clinical outcome compared with observation in patients with EGFR mutation-positive resected stage IB NSCLC. Methods: This phase II, open-label, randomized study (GASTO1003, CORIN) was conducted at Sun Yat-sen University Cancer Center. From May 2013 to December 2020, patients with completely resected, EGFR mutation-positive, stage IB (7th TNM staging for NSCLC) NSCLC without adjuvant chemotherapy according to physician and patient choices were enrolled. The patients were assigned in a 1:1 ratio to receive adjuvant therapy with icotinib (125mg, three times daily) for 12 months or to undergo observation. Therapy continued until disease progression or intolerable toxicity. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Survival endpoints were assessed in the intention-to-treat population. Results: Three patients withdrew consent and were excluded. A total of 128 patients were enrolled and randomized, with 63 patients in the icotinib group and 65 patients in the observation group. Baseline characteristics were well balanced between the groups. The median duration of follow-up was 34.9 months. A total of 13 recurrence events occurred, including 2 in the icotinib arm and 11 in the observation arm. DFS was significantly longer among those in the icotinib arm than among those in the observation arm (hazard ratio: 0.20, 95% confidence interval, 0.04-0.89; P = 0.018). The 3-year DFS for the icotinib and observation arms were 95.3% and 86.7%, respectively. The OS data were immature with 3 deaths in the observation arm. The safety profile was consistent with the known safety profile of icotinib. Icotinib was well tolerated with no unexpected adverse events. No treatment-related death occurred. Conclusions: Adjuvant icotinib shows prolonged DFS and acceptable toxicity in patients with completely resected EGFR-mutated stage IB NSCLC. Ajuvant icotinib provides a treatment option for these patients. Clinical trial information: NCT02264210.
Patients' preferences for adjuvant osimertinib in non–small cell lung cancer (NSCLC) after complete surgical resection: What makes it worth it to patients? (PATT)—The Roswell Park (RP) Comprehensive Cancer Center experience.
Authors: Mier-Hicks Angel , Attwood Kristopher , Catalfamo Kayla , Jain Prantesh , Chen Hongbin , Yau Edwin , Early Amy P. , Dy Grace K.
Published: June 2022

8520

Background: There are clinical controversies surrounding the US FDA approval of Osimertinib in December 2020 as adjuvant therapy, based on disease-free survival (DFS) improvement in patients (pts) with surgically resected stage IB-IIIA EGFRm NSCLC. We initiated a survey study to investigate our hypothesis that DFS benefit alone even without significant OS maybe deemed a valuable endpoint to pts after considering trade-offs. Methods: Participants were recruited from pts seen at the RP Thoracic Clinic from 01/21 to 12/21. Eligible pts who were being evaluated for adjuvant systemic therapy following surgical resection were given a self-administered survey based on the validated questionnaire by Blinman et al, which was modified to provide explanation of the differences between OS and DFS and the ADAURA trial results. Survey responses were collected in an online repository. Associations between survey responses and demographics were assessed using Fisher’s exact test. Changes in preference responses were assessed using McNemar’s test. Results: A total of 524 pts with NSCLC were screened, of which 101 pts were eligible to receive the survey. 51 pts (50%) responded to the survey. Median age of respondents was 69yrs (37-83), majority were female (69%, n = 35,), married (61%, n = 31), retired ( 63%, n = 32), had at least some college or higher education level(54%, n = 28), with history of smoking (84%, n = 43) and with stage IIIA (43%, n = 22) adenocarcinoma (80%, n = 41). To evaluate toxicity-related tradeoffs (Q1), a ≥12 mo. improvement in OS benefit was needed for 66% of pts to consider adjuvant Osi. However, an increase of ≥ 6 mo. of DFS was enough for 66% of pts to justify taking a daily medication (Q2). One mo. increase in DFS or OS was not enough for 60% and 78% of pts respectively to justify taking the medication. A threshold 1% increase in 5-year OS was sufficient to persuade patients to take Osi for three years, even with respect to toxicity side effects (p = 0.023). (Q3). Finally, in the hypothetical cost-based scenario (Q4), there was no indication that pts were willing to pay more for each incremental increase in OS. There appears to be some association between employment status (p =.033) or educational degree (p =.049) for tolerance of side effects if there is at least 1 additional year of DFS or OS. Conclusions: We observed that the value patients ascribe to adjuvant Osimertinib is influenced by factors besides efficacy. Knowing pts' preferences for cancer treatments can better inform regulatory bodies in formulating cost-sharing structure for cancer therapies. Our study highlights the importance of shared decision making based on individual pts' preferences.