Marinac, Catherine R.

Abstract Background Multiple myeloma (MM) evolves from monoclonal gammopathy of undetermined significance (MGUS), a clinically detectable but asymptomatic premalignant phase seen in ~3% of the general population 50 years of age or older. The prevalence of MGUS has not been described in a population at high risk of developing MM, specifically Black/African American (AA) individuals or first-degree relatives of patients with hematologic malignancies (HM). In 2019, we launched the first nationwide US screening study for individuals at high risk of MM to help better identify what population would benefit most from screening and early intervention for precursor MM stages. We aim to assess the prevalence of MGUS in a population at high risk of MM and characterize clinical variables of individuals who screen positive. Here, we report interim screening data on the first 2,960 participants. Methods Individuals aged 40 or older with an additional MM risk factor are eligible to be screened in the PROMISE Study. High-risk individuals include Black/AAs and those with a first-degree relative diagnosed with a hematologic malignancy or a precursor condition to MM. Blood from all participants was analyzed via serum protein electrophoresis, immunofixation, and Optilite® to measure the serum free light chains (sFLC), IgG, IgA and IgM. Results were returned to all participants, and those who tested positive for a monoclonal gammopathy (MGUS/SMM) were referred to a hematologist for clinical follow-up and invited to periodically complete epidemiologic exposure and psychosocial questionaries, including a 4-item cancer worry questionnaire and the RAND 36-item Short Form Survey (SF-36). To investigate the use of the higher-sensitivity matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) with the Optilite® IgG, IgA, IgM and sFLC results as a screening test for all participants, we rescreened 1,092 samples from PROMISE. The Binding Site Group proprietary software was used for the analysis of the combined MS/Optilite® results, allowing for the detection and quantification of M-protein. Heavy-Chain MGUS (HC-MGUS) was defined by the presence of one or more paired heavy and light chain monoclonal peaks detected by MS. Pairing was based on mass to charge ratio of identified peaks. To enrich the PROMISE cohort with Black/AA individuals, we identified and screened 1,868 Black/AA additional individuals from the Mass General Brigham (MGB) Biobank who met the PROMISE enrollment criteria. Screening was performed by MS/Optilite®, and results have not been returned to participants. Results We screened 2,960 participants with the combined MS/Optilite® approach. We report here the prevalence of HC-MGUS and plan on presenting the estimated rate of light chain MGUS in our cohort, at the meeting. We detected HC-MGUS in 9.6% (95% CI: 8.6-11%) of our cohort, with a prevalence of 10% (95% CI: 8.3-12%) in the PROMISE cohort and 9.4% (95% CI: 8.1-11%) in the MGB cohort (Table 1 and Figure 1). HC-MGUS prevalence increased with age in high-risk individuals from 4.9% (CI: 3.3-6.9%) for participants aged 40-49 to 13% (CI: 10-17%) in the 70-79 range (P < 1.2E-5). Among monoclonal HC-MGUS, we found 65% IgG, 18% IgM, and 18% IgA. M-spike was quantified in 97% of samples. Median M-spike concentration was, 0.058g/dL (max. 2.6g/dL) for IgG, 0.0043g/dL (max. 0.6g/dL) for IgM, and 0.067g/dL (max. 0.8g/dL) for IgA. In the Promise cohort, no significant change in cancer worry was observed across the pre- and post-screening interval among participants who screened positive (P = 0.52). Health-related quality of life, as measured by the SF-36, was not significantly different in screen-positive vs. screen-negative individuals for any of the eight subscales (all P > 0.20). Conclusions We present the largest dataset on monoclonal gammopathy prevalence and screening in individuals at high risk for MM, and more specifically the largest cohort of Black/AA, using a novel high-sensitivity testing approach. Our results confirm that older adults who are Black/AA or have a first-degree relative with an HM have a high prevalence MGUS and may benefit from precision screening approaches to allow for early detection and clinical intervention. Preliminary data on cancer worry and quality of life indicates that the psychosocial burden of screening in this population is likely minimal. Figure 1 Figure 1. Disclosures Sakrikar: The Binding Site: Current Employment. Krause: The Binding Site: Current Employment. Barnidge: The Binding Site: Current Employment. Bustoros: Takeda: Consultancy, Honoraria; Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau. Perkins: The Binding Site: Current Employment. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kapoor: Ichnos Sciences: Research Funding; Amgen: Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi: Consultancy; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; BeiGene: Consultancy; Sanofi: Research Funding; Karyopharm: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Murray: The Binding Site: Patents & Royalties: Potential Royalties for use of mass spectrometry in M-protein detection. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Marinac: JBF Legal: Consultancy; GRAIL Inc: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

To examine the extent of the evaluation required to achieve diagnostic resolution and the test performance characteristics of a targeted methylation cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test, ~6200 participants ≥50 years with (cohort A) or without (cohort B) ≥1 of 3 additional specific cancer risk factors will be enrolled in PATHFINDER (NCT04241796), a prospective, longitudinal, interventional, multi-center study. Plasma cfDNA from blood samples will be analyzed to detect abnormally methylated DNA associated with cancer (i.e., cancer “signal”) and a cancer signal origin (i.e., tissue of origin). Participants with a “signal detected” will undergo further diagnostic evaluation per guiding physician discretion; those with a “signal not detected” will be advised to continue guideline-recommended screening. The primary objective will be to assess the number and types of subsequent diagnostic tests needed for diagnostic resolution. Based on microsimulations (using estimates of cancer incidence and dwell times) of the typical risk profiles of anticipated participants, the median (95% CI) number of participants with a “signal detected” result is expected to be 106 (87–128). Subsequent diagnostic evaluation is expected to detect 52 (39–67) cancers. The positive predictive value of the MCED test is expected to be 49% (39–58%). PATHFINDER will evaluate the integration of a cfDNA-based MCED test into existing clinical cancer diagnostic pathways. The study design of PATHFINDER is described here.

3010 Background: PATHFINDER (NCT04241796) is an interventional, prospective study evaluating implementation of a blood-based multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA analysis to detect multiple cancer types and simultaneously predict cancer signal origin (CSO). We present a prespecified interim analysis of PATHFINDER evaluating an MCED test in a clinical setting. Methods: Participants (pts; ≥50y) were enrolled into 2 risk cohorts: non-elevated and elevated (smoking history, prior cancer [ > 3y post treatment], or genetic predisposition). MCED test results (cancer signal detected/not detected) were returned to investigators; pts with a signal detected also received a CSO prediction and underwent further diagnostic testing by their medical team. The primary objective was to assess the extent of diagnostic testing needed to achieve diagnostic resolution (eg, time to resolution, number/type of tests). Secondary endpoints included positive predictive value (PPV) and a measure of test satisfaction (following diagnostic resolution [signal detected] and post test [signal not detected]). Results: PATHFINDER consented 6796 pts before closing accrual on 12/4/20; as of October 6, 2020, 4086 consented, 4047 enrolled, and 4033 analyzable pts were included in the interim analysis (62.4% female, 92.1% white). Two study-related adverse events (anxiety of mild severity) were reported. Cancer signal was detected in 1.5% (62/4033) of pts; 40/62 reached diagnostic resolution to date. Kaplan-Meier estimate of median time to resolution was 78 (95% CI, 54-151) days. Among 40 pts that reached diagnostic resolution, ≥1 imaging test was performed in 93% (37/40); ≥1 invasive procedure was performed in 72% (13/18) versus 18% (4/22) of pts with diagnostic resolution of cancer versus no cancer, respectively. Based on results to date, PPV was 45% (95% CI, 30.7-60.2%; 18/40). Of 18 cancer diagnoses, 11 were solid tumors (3 stage IV, 6 stages I-III, 1 metastatic recurrence, 1 missing stage), and 7 were hematologic malignancies (1 stage IV, 4 stages I-III, 2 without AJCC stage). Accuracy of the top CSO prediction in true positives was 82.4% (95% CI, 59.0-93.8%; 14/17). Most pts were satisfied with the test (43.7% extremely satisfied, 30.7% very satisfied, 14.6% satisfied). Signal detection rate and test satisfaction were similar in the 2 risk cohorts; PPV tended to be higher in the elevated risk cohort, as expected. Conclusions: An interim analysis of this return of results study demonstrated promising MCED test results. Of 40 pts achieving diagnostic resolution, nearly half had a diagnostic workup confirming cancer; CSO was predicted with high accuracy for detected cancers. Taken together with the rarity of adverse events and high test satisfaction, these results support the feasibility of clinical implementation. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.

Abstract Background: Early detection decreases patient mortality for many cancers, but prevailing paradigms focus on distinct screening modalities for each cancer type. A minimally invasive test that detects multiple tumor types could substantially reduce cancer mortality and improve screening efficiency. In preliminary studies, we showed that a targeted methylation cell-free DNA (cfDNA) test can detect cancer and determine the tissue of origin (TOO) of abnormally methylated cfDNA with high sensitivity and specificity; however, blood was collected at the time of diagnosis and results were not disclosed to inform care. The current study includes disclosure of results to the study investigator to understand the care pathways prompted by a “signal detected” test result, and the benefits, harms, and burdens associated with a multi-cancer detection test. Methods: PATHFINDER (NCT04241796) is a prospective, longitudinal, multi-center clinical study. Approximately 6,200 participants with varying levels of cancer risk will be enrolled at 5-10 clinical sites in the United States. Participants must be ≥50 years of age. If participants have at least 1 of the following–a smoking history of ≥100 cigarettes, a genetic cancer predisposition, or a history of invasive or hematologic malignancy with definitive treatment completed >3 years prior to enrollment–they are eligible for the Elevated Risk Cohort (n = 4340); otherwise, they are eligible for the Non-Elevated Risk Cohort (n = 1860). Individuals being evaluated for cancer or who have a history of invasive or hematologic malignancy within 3 years of enrollment will be excluded. Blood drawn at study sites will be analyzed at GRAIL, Inc. (Menlo Park, CA). Participants and study investigators will be informed of the test results. Participants with “signal not detected” results will be advised to continue routine clinical care, including age- and risk-based cancer screening. Those with “signal detected” test results will be informed of the predicted origin and undergo diagnostic evaluation. The primary study objective is to determine the extent of diagnostic testing required to achieve diagnostic resolution following a “signal detected” test result, defined as the date when the study investigator determines to end diagnostic evaluation triggered by a “signal detected” test result. Health resource utilization, the number and types of tests and time required to reach this point, is the primary endpoint. Secondary objectives include evaluation of test performance (specificity, positive predictive value, and TOO accuracy), and assessment of participants' perceptions about the test and changes in anxiety and health-related quality of life. Exploratory aims include assessment of the number and types of invasive cancer diagnoses among participants with “signal not detected” test results and changes in attitude toward adherence to guideline-recommended screening. Citation Format: Lincoln Nadauld, Charles H. McDonnell III, Minetta C. Liu, Eric Klein, Tomasz M. Beer, Deborah Schrag, Andrew G. Hudnut, Richard Whittington, Bruce Taylor, Joanna Tierney, Catherine Marinac, Jafi Lipson, Margarita Lopatin, Karen C. Chung, Eric Fung, Anne-Renee Hartman, Geoffrey R. Oxnard. The PATHFINDER Study: Assessment of the implementation of an investigational multi-cancer early detection test into clinical practice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT291.

BACKGROUND Waldenström macroglobulinemia (WM) is preceded by asymptomatic WM (AWM), for which the risk of progression to overt disease is not well defined. METHODS We studied 439 patients with AWM, who were diagnosed and observed at Dana-Farber Cancer Institute between 1992 and 2014. RESULTS During the 23-year study period, with a median follow-up of 7.8 years, 317 patients progressed to symptomatic WM (72%). Immunoglobulin M 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration 70% or greater, β2-microglobulin 4.0 mg/dL or greater, and albumin 3.5 g/dL or less were all identified as independent predictors of disease progression. To assess progression risk in patients with AWM, we trained and cross-validated a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as continuous measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. We validated this model in two external cohorts, demonstrating robustness and generalizability. For clinical applicability, we made the model available as a Web page application ( www.awmrisk.com ). By combining two cohorts, we were powered to identify wild type MYD88 as an independent predictor of progression (hazard ratio, 2.7). CONCLUSION This classification system is positioned to inform patient monitoring and care and, for the first time to our knowledge, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention.