Bang, Soo‐Mee

Background: Despite recent major advances, multiple myeloma (MM) remains incurable using therapies that are currently available to patients. There are no available/approved targeted therapies for MM that allow for individualized therapeutic approaches to the disease. Fifteen to 20% of newly diagnosed MM patients have a translocation of chromosomes 4 and 14 [t(4;14)]. This translocation puts transcription of the gene encoding Multiple Myeloma SET domain-containing protein (MMSET or NSD2), a histone 3 lysine 36 methyltransferase, under the control of the IgH super enhancer. The super enhancer drives the overexpression of MMSET resulting in an abnormal histone code that promotes myelomagenesis. Presence of t(4;14) is associated with poor clinical prognosis (Caro Am Soc Clin Oncol Educ Book 2021). KTX-1001 is a first-in-class, selective and potent small molecule inhibitor of MMSET, and is the first investigational drug that targets the t(4;14) MM patient population. Methods: This Phase 1, first-in-human open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001 in relapsed/refractory MM (RRMM) and has two parts: dose escalation (Part A) and dose expansion (Part B). In Part B, only t(4;14)+ MM patients will be evaluated in single agent and combination expansion cohorts. Patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody are eligible for the dose escalation part. The primary objective of the study is to determine a recommended phase 2 dose (RP2D) and schedule of KTX-1001. Secondary and exploratory objectives include pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of KTX-1001, and assessment of preliminary efficacy. KTX-1001 is administered orally until disease progression, unacceptable toxicity, or patient withdrawal from the study. A Safety Review Committee (SRC) reviews all data prior to each dose escalation decision and on a regular basis. Results: As of June 14, 2024, 17 patients (pts) have been treated with KTX-1001 in Part A across 6 dose levels (SRC reviewed). Dose Level 7 has been reached with no dose limiting toxicities (DLTs). Ten of these patients are t(4;14) positive. Patients have received a median of 5 prior lines of therapy (range: 3-17), including 7 pts with prior BCMA CAR-T, 6 pts with prior BCMA bispecific and/or ADC, 5 pts with prior non-BCMA bispecific, and 12 pts with prior transplant. Patient demographics include a median age of 68 years (range: 50-83), 10 male/ 7 female, 13 white, 2 black or African American, 2 as other identified race, and 3 Hispanic or Latino pts. Six pts remain on treatment. KTX-1001 shows excellent tolerability to date, with treatment emergent AEs (TEAEs) (CTCAEv5.0) predominantly of grade 1 and 2 severity. Most frequently observed TEAEs suspected to be related to KTX-1001 include fatigue (35%), diarrhea (24%), and constipation (24%), for which no grade 3 or 4 events have been observed. Frequency and/or severity of TEAEs have not increased with escalating doses nor treatment duration, and no patients have discontinued due to an AE. Two heavily pre-treated patients [one known to be t(4;14)+] have demonstrated long-lasting stable disease and clinical benefit at 10 and 7 months respectively. Both patients have been intra-patient dose escalated. For PK and PD data collected to date, drug exposure and steady-state concentration of KTX-1001 (at C1D15, when steady state concentration has been reached) appear to be dose-proportional. PD data indicate a dose-dependent decrease in the H3K36me2 mark on treatment versus baseline across dose levels 1 through 6, suggesting that the RP2D may be reached by year end. Updated results will be presented at the congress. Conclusions: Dose escalation of KTX-1001 is ongoing with an excellent tolerability profile to date and demonstration of on-target pharmacodynamics that will inform the determination of the RP2D(s). These PD data support the targeted mechanism of action of KTX-1001 to selectively inhibit MMSET and break the t(4;14) histone code. Given KTX-1001's promising safety profile, single-agent and combination expansion cohorts with standard-of-care MM agents/classes will begin in 2025 to further optimize doses and provide proof of concept in Part B of the Phase 1 study.

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Abstract BACKGROUND Participation in mentorship programs for early career physicians is crucial to developing key skills and professional networks, but availability and opportunities for mentorship may be hampered by racial, ethnic and gender leadership disparities in medicine. A 6-month virtually facilitated peer mentorship program for women and diverse early career faculty was developed and piloted through the Society for Neuro-Oncology (SNO) Women & Diversity Committee. METHODS We designed and conducted a 6-month pilot open to SNO’s multidisciplinary early career members, leveraging peer-mentoring sessions with mid-to late-career physician mentors. A curriculum with online resources was provided and group assignments were based on time-zones and interests. Pre- and post-participation surveys assessed mentee experience and descriptive statistics assessed participant demographics and survey results. Results/ CONCLUSION Twenty mentee applicants participated in 5 groups. Mentees were 90% women, 60% from diverse racial and ethnic backgrounds. Most were aged 31-40 (75%) and junior faculty (50%) in neuro-oncology (65%). Five mentors (2 female) practiced either neuro-oncology (3), neurosurgery (1) or radiation oncology (1). The proportion of mentees with a signature talk increased from 15% to 71% during the pilot. A large majority (64%) reported a positive impact of the program on their profile, career and networking, and reported participation was worthwhile (86%), and worth recommending to others (93%). Feedback themes included personal growth, peer support, networking, job opportunities, desire for late career female mentors, and scheduling constraints. The virtual environment during a global pandemic allowed participants to connect, creating a venue to discuss topics such as work-life balance, burnout, and self-advocacy. We did not have 100% post pilot follow up despite multiple attempts, limiting complete understanding of the pilot. This virtual mentorship pilot program proved feasible and of value in development of early career women and diverse individuals. A resource toolkit has been designed to scale and diffuse.

11039 Background: Participation in mentorship programs for early career physicians may be crucial to developing key skills and professional networks to navigate racial, ethnic and gender leadership disparities in medicine. A 6-month virtual facilitated peer mentorship program was developed and piloted through the Society for Neuro-Oncology (SNO) Women & Diversity Committee. The evaluation of the program’s feasibility to positively impact early career physicians, investigators and trainees is presented here. Methods: We designed and conducted a virtual mentoring program pilot open to SNO’s multidisciplinary members in residency, fellowship, or early career phase, leveraging peer-mentoring sessions with mid-to late-career physician mentors. A curriculum with online resources was provided recommending groups meet for 6 sessions: 3 involving the mentor and 3 dedicated to peer-mentoring. Group assignments were based on time-zones and interests. Pre- and post-participation surveys assessed mentee experience. Descriptive statistics were used to assess participant demographics and survey results. Results: Our call for participation was broad; all 20 mentee applicants participated in 5 groups. Mentees were 90% women and 60% were from diverse racial and ethnic backgrounds. Most were aged 31-40 (75%) and junior faculty (50%) in neuro-oncology (65%). The 5 senior mentors (3 men and 3 of diverse race and ethnic backgrounds) practiced either neuro-oncology (3), neurosurgery (1) or radiation oncology (1). The proportion who reporting having a signature lecture increased from 15% to 62% during the pilot. A large majority reported their participation was worthwhile (85%), that they would participate again (92%) and would recommend it to others (92%). Feedback themes included positive personal growth, peer support, networking and job opportunities, access to CV reviews, lack of and desire for late career female mentors, and virtual scheduling constraints. While the pilot was limited by several variables, it was timely to connect participants in Q3 of 2020 early in the COVID-19 global pandemic. The virtual meeting environment created a venue to share and discuss topics such as work-life balance, burnout, leading through change and social connection. Despite not achieving 100% professional concordance, participants found the experience worthwhile. The tools and curriculum of topics provided was implemented differently across groups, leading to varied experiences. Finally, we did not have 100% post pilot follow up despite multiple attempts limiting our complete understanding of the pilot. Conclusions: This virtual mentorship pilot program proved feasible and of value in development of early career women and diverse individuals. A resource toolkit has been designed to scale and diffuse.

Abstract Abstract 5247 Background: Vena cava filters (VCF) has been used as a method to prevent pulmonary embolism (PE). The indication for VCF in patients with venous thromboembolism (VTE) according to the American College of Chest Physicians (ACCP) guidelines has been changed to recommend that VCF is only indicated in case of contraindication to anticoagulation. Also, there is very limited data describing the long-term effectiveness and safety of these devices if they are not removed. There is no data for VCF in Korea. The aim of this study is to evaluate and compare the change of practice patterns of VCF according to the change of the ACCP guidelines and the outcomes of VCF. Patients and Method: The data from patients who had the placement of VCF from Jan 2001 to Mar 2010 was collected from 6 academic institutes in Korea, retrospectively. We analyzed the patients grouped into 3 groups according to ACCP guidelines published year. These are -2004 group, 2005–2008 group, and 2009- group. Results: All 460 cases were collected and analyzed. Permanent and retrievable filter was 109 (24%) and 351 (76%), respectively. 49% of retrievable filters was attempted to remove and 88% removal success rate was showed. The patient's number is 79 in -2004 group (17%), 254 in 2005–2008 group (55%), and 127 in 2009- group (28%), respectively. The number of patients in indications of VCF was contraindication to anticoagulation 177 (38%), extensive thrombosis for preventing PE 207 (45%), recurrent VTE during anticoagulation 39 (8%), and others 37 (9%), respectively. The practice pattern in indication for VCF was changed in recurrent VTE during anticoagulation (P=0.012). Any complications after VCF insertion were developed in 107/460 (23%) dung follow-up. Inferior vena cava thrombosis, new DVT after placement of VCF, and new DVT with PE after placement of VCF were developed in 45/460 (10%), 91/460 (20%), and 14/460 (3%), respectively. Median follow-up durations were 49.6 months (range, 0–124.4), 12.3 months (0–67.5) and 6.0 months (0–26.9) for -2004, 2005–2008, and 2009- group, respectively. Vena cava thrombosis was significantly decreased in 2009- group (P=0.022). 75% thrombosis-free time was 3.7 months, 13.0 months, and not estimable in -2004, 2005–2008, and 2009- group, respectively (P=0.10). Conclusion: This is first report on VCF in Korea. The practice for indication of VCF insertion in patients with VTE was still out of boundaries from the ACCP guidelines in Korea. Complications after VCF insertion was decreased as time went by. The more follow-up durations was needed to evaluate the development of complication or thrombosis after VCF insertion in 2005–2008 group and 2009- group. Prospective randomized study is needed in Korea to confirm that VCF insertion plus anticoagulation will truly decrease the development of PE than standard anticoagulation. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3980 Background: Nearly half of patients with multiple myeloma (MM) are over 70 years at the time of diagnosis. While the survival of patients with myeloma has improved in the last decade, several studies have suggested no significant change for the elderly patients. These patients often have other comorbidities and are less likely to tolerate standard treatment approaches. We retrospectively studied the treatment patterns, outcomes, and prognostic factors in patients over 75 years of age. PATIENTS AND METHODS: We identified 212 patients who were older than 75 years from among 1545 patients seen at the Mayo Clinic within 90 days of diagnosis during 1999 to 2008. We only included 139 patients in whom complete treatment details were available. RESULTS: The median age was 80 years (range: 76–94) with 20 (14%) patients older than 85 years; 79 (57%) were male. Thirty-five patients (25%) had a history or coexistence of one or more malignancies. Chromosome analysis and FISH were performed in 65% and 22% respectively. Abnormal cytogenetics were seen in 30 (33%) of the 90 tested patients. The median survival of the 139 elderly patients was 27 months (95% CI: 20∼35) compared to 62 months (56∼68) for 1,290 patients ≤ 75 years of age seen during the same period. Sixty-nine (50%) patients received one or more novel agents (thalidomide, lenalidomide, pomalidomide, bortezomib) and showed longer median survival (40 months vs 13 months) compared with those not receiving these agents (p=0.0008). Age over 85, initial poor performance score > 1, thrombocytopenia, elevated serum LDH or beta2-microglobulin, response more than stable disease to first therapy resulted in inferior survival. Among them, only performance status had the persistent significance in multivariate analysis. CONCLUSION: Older patients receiving newer therapies appear to have a better outcome, which is still lagging behind the younger patients. A poor performance score at diagnosis predicts for eventual poor outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

AbstractImmunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.