Citations

Here, we identified a cross talk between SET and MYND domain-containing lysine methyltransferase 2 (Smyd2) and transforming growth factor (TGF)-β-Smad3 signaling and a synergistic feedback loop between them, in which TGF-β stimulates expression of Smyd2 in a Smad3-dependent manner, and upregulation of Smyd2 regulates the transcription of TGF-β and other fibrotic marker genes through direct binding on their promoters or methylating histone H3 indirectly to regulate the transcription of those genes in fibroblasts. Thus, the Smyd2-TGF-β-Smad3-Smyd2 signaling axis plays an important role in promoting renal fibrosis, and targeting Smyd2 with its specific inhibitor should not only delay cyst growth but also ameliorate renal fibrosis in ADPKD.

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]

8028 Background: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, led to early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study (NCT03548207) in heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM). At ̃1-year (y) median follow-up (MFU), overall response rate (ORR) was 97%; 67% of pts achieved stringent complete response (sCR). 1-y progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively (Berdeja 2021). Updated results 2-y post last patient in (LPI) will be presented (̃30-month total MFU). Here, we report CARTITUDE-1 results at 21.7-month MFU. Methods: Eligible pts with RRMM received ≥3 prior lines of therapy (LOT) or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Bridging therapy was permitted after apheresis. Pts received a single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) 5–7 days after lymphodepletion. Primary objectives were to evaluate cilta-cel safety and efficacy. Response was assessed per International Myeloma Working Group criteria by independent review committee and minimal residual disease (MRD) negativity at 10-5 by next-generation sequencing. Results: As of July 22, 2021, 97 pts (59% male; median age 61 y) received cilta-cel. Pts had a median of 6 (range 3–18) prior LOT; 84% were penta-drug exposed, 88% were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to last LOT. ORR was 97.9% (95% CI 92.7–99.7), 94.9% achieved very good partial response, and 82.5% achieved sCR. Median times to first response, best response, and ≥CR were 1.0, 2.6, and 2.9 months (m), respectively; median duration of response was not reached (NR). Of 61 pts evaluable for MRD, 92% were MRD negative (10-5), sustained for ≥6 m in 44% (27/61) and ≥12 m in 18% (11/61). 2-y PFS was 60.5% (95% CI 48.5–70.4). Median PFS and OS were NR. 2-y PFS rates in pts with sustained MRD negativity for ≥6 m and ≥12 m were 91% and 100%, respectively. There were no new safety signals or new events of CAR-T cell neurotoxicity, movement and neurocognitive treatment-emergent adverse events, or treatment-related deaths since 1-y MFU. 15 second primary malignancies were reported in 11 pts over ̃2-y MFU. Conclusions: At ̃2-y MFU, a single cilta-cel infusion led to deepening and durable responses in heavily pretreated pts with RRMM with a manageable safety profile. Follow-up is ongoing, and landmark 2-y post LPI data (̃8 m additional follow-up; ̃30 m total MFU) will be presented. Further investigations of cilta-cel are ongoing in earlier LOT and outpatient settings across the CARTITUDE program (NCT04133636, NCT04181827, NCT04923893). Clinical trial information: NCT03548207.

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

7010 Background: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the US to treat adult R/R B-ALL based on the ZUMA-3 study. The overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) was 71% (95% CI, 57-82) after 16.4 mo median follow-up (N = 55; Shah et al. Lancet 2021). Here, we report updated outcomes with longer follow-up in these pts and in a larger pooled analysis of Phase (Ph) 1 and 2 pts who received the pivotal dose of KTE-X19. Methods: Eligible adults (≥18 years) had R/R B-ALL and received a single infusion of KTE-X19 at the pivotal dose (1×106 CAR T cells/kg) following leukapheresis and conditioning chemotherapy. The primary endpoint was CR/CRi rate by central review. Results: As of 23 July 2021, median follow-up was 26.8 mo (range, 20.7-32.6) for treated Ph 2 pts (N = 55). The CR/CRi rate per central review was 71% (95% CI, 57-82; 56% CR; 15% CRi). Eleven pts (20%; 8 CR and 2 CRi) proceeded to subsequent allogeneic stem cell transplant (alloSCT). Median duration of remission (DOR) censored at subsequent alloSCT was 14.6 mo (9.4-not estimable [NE]); not censored: 18.6 mo (9.6-NE); 6/39 responders (15%) had ongoing responses at data cutoff. Median (95% CI) relapse-free survival (RFS) was 11.6 mo (2.7-20.5) censored at subsequent alloSCT and 11.7 mo (2.8-20.5) not censored at subsequent alloSCT; 18-mo RFS rates (95% CI) were 35% (20.5-50.6) and 42% (28.0-55.0), respectively. Median (95% CI) overall survival (OS) was 25.4 mo (16.2-NE) among all KTE-X19-treated pts and not reached (25.4-NE) in pts with CR (n = 31). For Ph 1/2 pts (N = 78) who received the pivotal KTE-X19 dose (median follow-up: 29.7 mo; range 20.7-58.3), the CR/CRi rate by independent review was 73% (95% CI, 62-82). Medians (95% CI) for DOR, RFS, and OS were 18.6 mo (9.6-NE), 11.7 mo (6.1-20.5), and 25.4 mo (16.2-NE), respectively. A subgroup analysis revealed that in pts aged 18-39 (n = 36), 40-59 (n = 27), and ≥60 (n = 15) years, the CR/CRi rates (95% CI) were 69% (52-84), 70% (50-86), and 87% (60-98); 24-mo OS rates (95% CI) were 48% (30-64), 54% (33-71), and 57% (28-78), respectively. In pts with pre-KTE-X19 infusion marrow blast percentages > 25 to ≤50 (n = 12), > 50 to ≤75 (n = 14), and > 75 to 100 (n = 30), CR/CRi rates (95% CI) were 83% (52-98), 86% (57-98), and 57% (37-75); 24-mo OS rates (95% CI) were 58% (27-80), 55% (26-77) and 37% (19-55), respectively. There were no new safety signals; the proportion of treated Ph 2 pts with Gr ≥3 treatment emergent adverse events was unchanged since prior data cutoff. One pt had an ongoing neurologic event of Gr 1 finger numbness. Conclusions: With longer follow-up and an expanded data set by independent review, outcomes remain durable in adults with R/R B-ALL, most of whom were heavily pretreated, with median OS not yet reached in pts with CR. Long-term safety was favorable. Clinical trial information: NCT02614066.