Kroog, Glenn S.

Background As therapeutic advances have increased life expectancy for patients (pts) with relapsed/refractory (RR) multiple myeloma (MM), second primary malignancies (SPMs) have become an increasingly important safety consideration. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation, and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased risk of SPM. Pts who are triple-class exposed (TCE), defined as prior exposure to an IMiD, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb), represent an increasingly large subgroup of RRMM pts. The objective of this study was to describe the incidence and characteristics of SPMs in Medicare-insured pts with TCE RRMM initiating a new line of therapy (LOT). Methods Adult pts with an incident diagnosis (Dx) of MM (≥2 outpatient Dx 30-365 days apart OR ≥1 inpatient Dx AND 6 months of continuous eligibility prior to initial Dx) during the study period (Nov 14, 2006-Dec 31, 2020) who were TCE (≥1 claim each for an IMiD, a PI, and an anti-CD38 mAb) were selected from the Center for Medicare and Medicaid Services Chronic Conditions Data Warehouse (TCE pts were assumed to have RRMM based on exposure). The first LOT after TCE was defined as the index LOT and the associated date of initiation was defined as the index date. Pts with SPMs prior to the index date were excluded. SPMs were identified based on having ≥2 outpatient Dx of SPM (of the same cancer type) 30-365 days apart OR ≥1 inpatient Dx of SPM. Dx of SPM included Dx of invasive malignancies or myelodysplastic syndromes (MDS), excluding MM, Waldenström macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a Dx of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each pt. Cumulative incidence of SPM (with death as a competing risk) was also calculated. For pts who experienced SPM, overall survival (OS) and measures of healthcare resource utilization (HRU) and costs (in 2021 USD, on a per patient per month [PPPM] basis) were calculated. Results A total of 3,088 TCE RRMM pts were identified, of whom 989 had no evidence of SPM prior to the index date (Table). These 989 pts had a mean age of 75.2 years, a mean of 2.9 prior LOTs and a mean of 3.1 years since MM Dx. Over a median follow-up of 7.1 months, 166 pts (19.3 per 100 PY) experienced an SPM, including 93 (10.8 per 100 PY) with a solid tumor and 73 (8.5 per 100 PY) with a hematologic malignancy. The latter included 27 (3.1 per 100 PY) with acute myeloid leukemia (AML) and 18 (2.1 per 100 PY) with MDS. The cumulative incidence of SPM (95% confidence interval [CI]) at 12, 24, and 36 months was 15.2% (12.8-17.9%), 19.7% (16.8-22.8%), and 23.8% (20.2-27.6%), respectively (Figure). Median (95% CI) OS from SPM Dx was 7.9 months (5.4-10.9). Kaplan-Meier estimated probability of survival (95% CI) at 12, 24, and 36 months following SPM Dx was 40.3% (31.6-48.9%), 27.6% (18.6-37.4%), and 9.5% (2.1-23.8%), respectively. Mean (95% CI) total costs after SPM were $22,514 ($19,105-$26,404) PPPM. Conclusions The incidence of SPM in Medicare-insured TCE RRMM pts is high. Many SPMs in these pts, such as AML, are life-threatening and may interfere with or prevent MM treatment. Pts with SPMs have poor survival and high HRU and costs. With increasing OS for RRMM pts due to therapeutic advancements, there is a need for effective treatments that are not associated with increased risk of SPMs.

Abstract Background: MM remains incurable and new tx options are needed, especially in heavily pre-treated R/R pts. REGN5459, a BCMAxCD3 bispecific Ab, binds to BCMA on MM cells and with low affinity to CD3 on T cells, triggering T-cell activation and plasma cell depletion with low cytokine release preclinically. This first-in-human study aimed to assess the safety, tolerability, and preliminary anti-tumor activity of REGN5459 monotherapy in pts with R/R MM. Methods: Eligible pts had received ≥3 prior lines of tx including an anti-CD38 Ab, proteasome inhibitor, and immunomodulatory drug, and had exhausted all available tx options. Pts could receive REGN5459 until progression/intolerable toxicity. Primary objectives were to assess safety, tolerability, dose limiting toxicities (DLTs), and determine the recommended Ph 2 dose (RP2D) of REGN5459 (Ph 1) and assess efficacy of REGN5459 (Ph 2) per ORR. Results: As of June 9, 2022, 43 pts were enrolled (Ph 1, 33; Ph 2, 10): median age 67 yrs (range, 26-85), 51% female, 16% high cytogenetic risk, 14% extramedullary plasmacytoma, 37% R-ISS Stage III disease, 61% triple-class refractory, and median of 5 (range, 2-9) prior lines of tx. In Ph 1, one DLT was reported in a pt receiving the highest dose (900 mg; Gr 3 hypoxia, pt later found to have primary lung cancer). RP2D was identified as 480 mg. All pts enrolled had ≥1 TEAE, 74% had Gr ≥3 TEAEs. TEAEs all-Gr in ≥30% of pts were CRS (54%), fatigue (44%), neutropenia (37%), anemia (35%), cough (30%), and diarrhea (30%). Gr ≥3 TEAEs in ≥15% of pts were neutropenia (37%), anemia (26%), lymphopenia (23%), thrombocytopenia (19%), and hypertension (16%). CRS Gr 1, 2, and 3 were reported in 47%, 2%, and 5%, respectively; there was no Gr 4 or 5 CRS. No Gr 3 CRS with RP2D. Tocilizumab was used in 19% and steroids in 9% of pts. One pt developed ICANS (2%, Gr 2). Incidence of serious TEAEs and TEAEs leading to tx discontinuation was 63% and 16%. Infections occurred in 61% (37% Gr ≥3). After data-cutoff, two deaths due to COVID pneumonia and COVID infection have been reported. ORR was 67% (58% ≥VGPR) for the entire cohort and 100% (85% ≥VGPR; 15% sCR; 39% CR) among pts receiving the RP2D (n=13). Median follow-up was 7 mos (range, 1-26) with longest response ongoing for 22+ mos. Median time to response was 0.8 mos. Median DOR was NR (95% CI, 12-NE); 12-mo DOR for RP2D was 66.7% (95% CI, 5.4-94.5). Of pts in ≥CR with available MRD results (n=8), 50% were MRD negative at the 10−5 threshold. Conclusion: These initial data show that REGN5459 has acceptable safety/tolerability in R/R MM with most CRS of low grade and low incidence of ICANS. Modulation of CD3 affinity on bispecific Abs to maximize tumor killing, and mitigate CRS and T-cell exhaustion, warrants further research. Efficacy in this heavily pre-treated cohort was encouraging, with 100% ORR with the RP2D. Updated data will be presented at the meeting. Citation Format: Attaya Suvannasankha, Prashant Kapoor, Matthew J. Pianko, Joshua Richter, Anita D'Souza, Larry D. Anderson, Andrew Magyar, Oluwaseun Aina, Anita Boyapati, Damien Cronier, Nikhil Singh, Karen Rodriguez-Lorenc, Glenn S. Kroog, Hans C. Lee. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT013.

8038 Background: Multiple myeloma (MM) predominantly affects older patients (pts) (median age at diagnosis 69 yrs) in whom comorbidities must be considered to manage the disease appropriately. Some anti-MM therapies can be associated with ocular toxicities and require careful attention when used among pts with pre-existing ocular comorbidities (OC). In 2018, 41% of Medicare enrollees had OC. Despite the potential implication on treatment decisions, information on pre-existing OC (e.g., disorders of lens, glaucoma) in MM pts is limited. This study aims to describe the prevalence of OCs among real-world pts with MM in 2011-2020 in the US. Methods: Adults with newly diagnosed MM (NDMM) with or without treatment, with 1L systemic therapy, and with relapsed/refractory MM (RRMM) who received up to 4 lines of systemic therapies (LOT) for MM were identified in the IQVIA PharMetrics Plus data. The index date was the date of initial MM diagnosis or a LOT initiation date. The prevalence of OC in each group was defined as the presence of any OC ICD 9/10 diagnosis codes in the 12 months prior to the index date. OCs (e.g., disorders of conjunctiva, lens, choroid, retina, glaucoma) were considered a potentially MM-related disease manifestation or MM treatment-related toxicity based on published literature and clinical expert opinion. Results: The median age at initial MM diagnosis was 64 yrs overall (N=49,814), and 63 yrs among treated pts (N=22,963). The median age was 63 yrs at 1L initiation and 64 yrs at 2L, 3L, and 4L initiation. The prevalence of OC at initial MM diagnosis was 39.0% overall and 35.2% among treated pts (Table). The OC prevalence was 35.8% prior to 1L initiation and higher in RRMM pts (42.1%, 44.9%, and 45.7% prior to 2L, 3L, and 4L initiation, respectively). This trend was observed across all OC categories, among MM-related OCs, and across all age groups. The prevalence of OC by MM stage was stable over the years. Conclusions: Approximately 40% of NDMM pts have a pre-existing OC, and the prevalence increases with the number of LOT in RRMM. While some OC may be due to aging, the impact of OC on treatment decisions for MM should be explored. [Table: see text]