Shi, Min Yan

7533 Background: Maintenance treatment (rx) with lenalidomide (R) improves overall survival (OS) in multiple myeloma (MM). We report a retrospective cohort of patients (pts) with second primary B-cell acute lymphoblastic leukemia (ALL) diagnosed after R-rx for MM. Methods: We included pts who were exposed to at least 1 yr of R for MM rx prior to ALL dx. After approval by institutional review board, data were collected by chart review at participating centers using Redcap. OS was the primary endpoint. We used BlueSky statistics v10.3.1 for analysis. Results: Analysis included 33 ALL pts diagnosed from 2014-2022 at 7 sites. 52% pts were female. Median follow up was 9.6 yrs (95%CI,7.6-11.8) from MM dx and 3.2 yrs (CI, 2.1-4.7) from ALL dx. Pt characteristics at MM dx are given in Table. Induction rx included: proteasome inhibitor (PI) +immunomodulatory drug (IMiD) (43%), PI+alkylator (24%), IMiD (18%) & others (15%). 50% pts received autologous stem cell transplantation (ASCT). Median OS from MM dx was 11.2 yrs (CI, 8.9-NR). Time from MM dx and initial R rx to ALL dx were 5.0 yrs (range, 2.4-18.5) and 4.4 yrs (2.2-10.6) respectively. Median duration of R exposure before ALL dx was 3.8 yrs (1.6-10.4). Table shows characteristics of pts at B-ALL dx and genetic classification based on karyotyping (n=30), ALL FISH (n=28), chromosomal microarray (n=5) and next-generation sequencing (n=5). 31 pts received ALL-directed rx while 1 pt was initially managed with close observation as the pt attained CR on stopping R ( Lakshman et al; ASH 2019 ). Rx was unknown in 1 pt. Initial rx included: hyper-CVAD+/- rituximab- 49%, pediatric inspired protocols-18%, reduced intensity rx for frail pts- 21% and others- 12%. Response to first line rx were: CR- 56%, CRi- 28%, induction failure- 16%. 32% pts attained measurable residual disease (MRD) negativity. 48% pts underwent SCT for ALL. 14 pts died during follow up. 3-yr OS from ALL-dx was 50% (CI, 33%-76%). 3 pts required rx for MM after ALL diagnosis (2 had allo-SCT for ALL before MM relapse). Conclusions: Most pts had standard risk MM and were exposed to R for several years prior to dx of B-ALL, characterized by high incidence of hypodiploid karyotype; IKZF1 loss and TP53 deletions/mutations were detected in a subset of pts.MRD-adapted timely discontinuation of R in standard risk MM may decrease risk of second primary ALL. [Table: see text]

Abstract Background: Prospective validation of breast cancer risk models integrating classical risk factors and genetic variants is required for risk-stratified prevention and screening strategies. The objective of this study was to validate a breast cancer risk model integrating classical risk factors and a 313-variant polygenic risk score (PRS) in multiple prospective cohort studies, and to project five-year risk of breast cancer in six different countries. Methods: The study population included 7,529 cases and 230,103 controls from 14 prospective cohort studies in Australia, Germany, the Netherlands, Sweden, UK, and USA. We used the Individualized Coherent Absolute Risk Estimator (iCARE) tool for risk model building, validation, and risk projection. Expected five-year risk of invasive or in situ breast cancer was compared to observed risk, overall and within deciles of expected risk using goodness of fit statistics. We evaluated calibration of the relative risk through meta-analysis across cohorts, and of the absolute risk within each cohort. Model discrimination was evaluated using the area under the curve (AUC), and percentages of women crossing risk thresholds. Projections of five-year risk distributions were estimated for women of European ancestry aged 50-70 years in the general populations of these six countries. Results: Analysis showed overall good calibration of the integrated iCARE-based model relative risk for both women younger than 50 years (χ2=14.9, P=0.09) and aged 50 years or older (χ2=14.6, P=0.10), with a small overestimation of risk for women in the highest decile of expected risk (RR = 3.5 expected vs 2.3 (95% CI 1.6 to 3.2) observed for women <50 years; and 2.8 expected vs 2.3 (95% CI 2.0 to 2.7) observed for women 50+ years). The age-adjusted AUCs for the integrated model were 63.1 (95% CI 60.9 to 65.3) and 62.9 (95% CI 61.8 to 64.0), for the two age groups respectively. The calibration of absolute risk showed substantial variation across cohorts, particularly for the older group, but had no systematic bias. Model based projections in the general populations showed that compared to the population average, women in the 1st and 99th percentiles of the integrated risk score had relative risks 0.19 and 3.56 respectively. The proportion of women of European ancestry aged 50-70 years with a five-year risk greater than 3% (threshold for consideration of risk-lowering drugs by U.S. Preventive Services Task Force) ranged from 7.1% in Germany to 18.2% in the US, which corresponds to ~5.5 million women in the US. Conclusions: Five-year risk predictions from a model with classical risk factors and PRS are well calibrated and provide substantial risk stratification across multiple cohorts in six different countries. Further studies are needed to evaluate the clinical utility of the validated model for risk stratified screening and prevention of breast cancer. Citation Format: Parichoy Pal Choudhury, Amber Wilcox, Chi Gao, Brian Carter, Anika Husing, Mark Brook, Mikael Eriksson, Kara Martin, Chris Scott, Min Shi, Thomas Ahearn, Michael Jones, Nick Orr, Minouk Schoemaker, Kamila Czene, Jenny Chang-Claude, Jacques Simard, Doug Easton, Marjanka K. Schmidt, Dale Sandler, Clarice R. Weinberg, Celine Vachon, Roger Milne, Per Hall, Anthony Swerdlow, Rudolph Kaaks, Myrto Barrdahl, Mia Gaudet, Antonis Antoniou, Peter Kraft, Montserrat Garcia-Closas, Nilanjan Chatterjee. Validation of breast cancer risk model incorporating classical risk factors and polygenic risk scores in 14 prospective cohort studies in 6 countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 962.