Xu, Tao

Abstract Background: Real world data (RWD) is one of the key components to our understanding of the treatment trajectory of patients with multiple myeloma (MM) in clinical practice. However, treatment responses recorded in patients' medical records are not often standardized. We have developed an algorithm to derive real-world response (dR) for MM patients based on the International Myeloma Working Group (IMWG) criteria to overcome issues with missing values (Xu et al. Pharmacoepidemiol Drug Saf 2021). In this study, we evaluate its association with overall survival (OS) in a RWD cohort. Methods: This study included patients diagnosed with MM between Jan 1, 2011 and Jan 31, 2021 from the US-based Flatiron Health electronic health record (EHR)-derived de-identified database. We derived overall response (partial response [PR] or better, e.g. > 50% reduction of serum M-protein from baseline) to 1L treatment in newly diagnosed MM patients based on the IMWG response criteria, taking into account missing data. Associations between dR and OS were evaluated at individual- and treatment-level. At individual-level, associations were assessed using landmark analyses at approximating 3/4/5 cycles of treatment and at 6 months. Patients who died before the landmark were excluded from the analysis. At treatment-level, we stratified the cohort by year of treatment initiation (every two years from 2011-2021). Within each stratum, treatment groups were compared to estimate the hazard ratios (HRs) of OS and odds ratios (ORs) of dR, both adjusted for potential confounding factors (age, ECOG status, cytogenetic risk groups [high vs standard], time between diagnosis and first-line [1L] start date). The association between HRs and ORs was assessed by coefficient of determination (R 2) from a stratum-size weighted linear regression model, where values close to 1 imply a strong correlation and 0 indicates no association. Only significant HRs and ORs (P < 0.05) in the multivariable analysis were used in the analysis. Results: Of 6806 patients in the Flatiron Health MM database, 70% (n=4830) had serum myeloma (M) protein measured by protein electrophoresis within 30 days before the start of 1L treatment, 27% (n=1838) had urine M protein and 57.8% (n=3935) had serum free light chains (FLCs). Patients with at least one serum M protein or FLC measurement were eligible for study entry (n=5609). During 1L treatment, 4727 patients (46% female, mean ± standard deviation age 67.8 ± 10.4 years) had valid laboratory test results for dR assessment (for each patient we required a baseline measurement plus at least one additional measurement after treatment start of the same lab type), of which 71.7% (n=3387) had PR or better. The majority of the patients (n=2188, 46.3%) received a proteasome inhibitor (PI)+steroid+immunomodulatory drug (IMiD) treatment regimen, followed by PI+chemo+steroid (n=639, 13.5%), PI+steroid (n=621, 13.1%), and steroid+IMiD (n=607, 12.8%). Other treatment groups had fewer than 100 patients and were not considered in the treatment-level analysis (Table 1). At the individual-level analysis, dR was significantly associated with OS at all landmarks (HRs 0.80 to 0.81, P < 0.001, Table 2). At treatment-level, the association between dR and OS was R 2=0.67 (P < 0.001, Figure 1). Subgroup analyses were conducted for each pair of treatment groups; however, only PI+IMiD+steroid vs PI+steroid had sufficient sample sizes, which showed R 2 of 0.82 (P = 0.02). Conclusions: In the absence of recorded response data in a patient's EHR, laboratory assessments can successfully be applied using our algorithm to determine, based on part of the IMWG response criteria, the response status for patients with MM. In the RWD cohort, patients who had PR or better to 1L treatment demonstrated longer survival than non-responders. A moderate association was observed at the treatment-level between dR at 1L and OS. However, these associations might be specific to certain treatment groups and the underlying mode of action of the drugs. Further analysis will be needed to validate these results. Figure 1 Figure 1. Disclosures Xu: F. Hoffmann-La Roche AG: Current Employment. Tyanova: F. Hoffmann-La Roche: Current Employment. Williamson: Amgen: Current equity holder in publicly-traded company; Genentech: Current Employment, Current equity holder in publicly-traded company. Rocci: Novartis: Other: Wife is and employee of Novartis and holds Novartis stocks; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Received travel sponsorship ; AbbVie: Other: Received travel sponsorship ; F. Hoffmann-La Roche Ltd.: Current Employment; NHS: Ended employment in the past 24 months; Sanofi: Consultancy; Takeda: Consultancy, Honoraria, Other: Received travel sponsorship , Speakers Bureau; Roche: Current equity holder in publicly-traded company; Owner of 100% stocks of Harlock Healthcare Consulting Ltd (UK privately-held company currently not active).: Current holder of individual stocks in a privately-held company; Celgene: Honoraria, Other: Received travel sponsorship ; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag Ltd: Honoraria, Speakers Bureau. Yousefi: Roche: Current Employment, Current equity holder in publicly-traded company. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Introduction: MM is an incurable disease with risk categorizations by cytogenetic abnormalities. Prognostic implications of chromosome translocation t(11;14)+ are important to inform development of biomarker-targeted therapies such as the B-cell lymphoma-2 (BCL-2) pathway inhibitors. This study aims to evaluate MM treatment (Tx) patterns and outcomes of t(11;14)+ compared with other cytogenetic cohorts in US routine clinical practice. Methods: A retrospective observational cohort study of the Flatiron Health database, which comprises de-identified electronic health record-derived patient (pt)-level data from over 280 community and academic cancer clinics in the US. Pts aged ≥18 years who received a first-line (1L) induction Tx within ≤60 days of MM diagnosis from 1/1/2011 to 1/31/2020, and were not enrolled in a clinical trial were identified at the start of each Tx line (index date) and followed up (f/u) until 1/31/2020. Only cytogenetic results by fluorescence in situ hybridization (FISH) were used to stratify the cohort into: t(11;14)+; standard risk, excluding t(11;14)+ (SR); and high risk, (HR; del 17p, t(4;14), t(14;16), t(14;20), chromosome 1 abnormalities as a proxy for 1q gain; and t(11;14) where it co-occurs). Descriptive analyses of pt characteristics and Tx were conducted. Kaplan-Meier analyses were used to evaluate median time to next treatment (TTNT) and overall survival (OS) with log-rank test for significance. The cohort was stratified by age ≤70/>70 years (yrs) as a proxy for transplant eligibility. Results: Of 10,703 pts with MM in the database, 5982, 3059 and 1595 pts were eligible for 1L, second-line (2L), and third-line (3L) analysis, of which 76%, 84%, and 86%, respectively, had FISH test results before Tx initiation. 14% of pts with FISH test results were t(11;14)+, ~55% SR and ~35% HR. Included pts were predominately male (55%), ~90% treated in the community setting and ~16% African-American. Pts in the 3L cohort were younger at diagnosis with a median age (interquartile range) of 67 (59 ̶ 74) yrs compared with 69 (61 ̶ 76) yrs in both 1L and 2L. The 1L Tx pattern was consistent across cytogenetic cohorts with bortezomib (V), lenalidomide (R), dexamethasone (d) as the most common Tx (>42%). Together, VRd, Rd, Vd, and cyclophosphamide (Cy) in combination with Vd represented ≥90% of 1L Tx (Figure 1). Across 2L cytogenetic cohorts, the most common Tx regimens (≥25%) were VRd and Rd. The use of regimens containing carfilzomib (K) and daratumumab (D) was emerging in 2L: KRd in 8% of t(11;14)+ and HR and 5% in SR; Kd 5% in all groups; DRd in 4% of t(11;14)+ and 3% in SR and HR (Figure 1). 3L Tx pattern was fragmented with different Tx regimens. Rd was the most common 3L Tx option: 9% in t(11;14)+, 10% in SR and 7% in HR (Figure 1). Across all lines of Tx, t(11;14)+ had similar Tx outcomes to SR, and HR had poorest outcomes (Table 1). Pts TTNT shortened as they advanced to later lines of Tx (Table 1). Although TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts, especially in 1L where transplant in those ≤70 yrs vs >70 yrs at diagnosis was 44% vs 11% for t(11;14)+, 47% vs 10% for SR and 49% vs 9% for HR. Conclusions: This study identified cytogenetic subgroups across 1L to 3L in a predominately community setting in the US. MM t(11;14)+ pts had similar 1L and 2L Tx patterns to SR and HR. Across all lines of Tx, the outcomes of t(11;14)+ and SR pts were comparable and better than HR pts. TTNT was reduced as pts advanced to later lines of Tx. Pts continuing to 3L Tx were younger at diagnosis, but there was not a clear-cut standard of care. While TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts. This study sets the benchmark for novel treatment options, such as BCL-2 pathway inhibitors, primarily wherever available biomarker-driven therapy is considered appropriate. Disclosures Atrash: Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; BMS, Jansen oncology, Sanofi: Speakers Bureau; Amgen, GSK, Karyopharm.: Research Funding. Flahavan:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Roche Products Ltd.: Current Employment. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Karve:AbbVie: Current Employment, Current equity holder in publicly-traded company. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jirau-Lucca:Genentech, Inc.: Current Employment; AbbVie: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Nixon:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ailawadhi:Takeda: Honoraria; Pharmacyclics: Research Funding; Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Phosplatin: Research Funding; Amgen: Research Funding; Celgene: Honoraria; Janssen: Research Funding.