Roy, Vivek

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.

Introduction: NGS is increasingly being utilized to identify pathogenic somatic and targetable variants in patients with newly diagnosed AML and MDS. Patients with high-risk disease are typically recommended to undergo allo-HCT as consolidation, upon achieving morphological complete remission (CR). But, despite achieving hematologic CR, patients often have detectable somatic variants pre allo-HCT that predict for increased risk of disease relapse. Longitudinal monitoring of somatic variants via NGS at diagnosis, pre-allo-HCT and post allo-HCT can assist in prognostication and identify patients that remain at high risk of relapse despite allo-HCT. Methods: Patients with AML or MDS who underwent a first allo-HCT and completed NGS testing at day +100 between years 2016 to 2021 were identified from the transplant registry of Mayo Clinic in Florida. The primary aim of the study was to evaluate the prognostic impact of detectable variants via NGS at day +100 days post allo-HCT on the following outcomes: 1) overall survival (OS), 2) relapse, 3) progression-free survival (PFS), and 4) non-relapse mortality (NRM). Disease risk was assessed based on European Leukemia Network (ELN) 2022 risk classification for AML and Revised International Prognostic Scoring System (R-IPPS) for MDS. Baseline variables were compared between patients with and without mutation at day +100 days post allo-HCT using Wilcoxon rank sum test for continuous variables and Fisher's exact test for categorical variables. Kaplan-Meier (KM) method was used to estimate freedom from events at different time points and draw corresponding survival curves. Results: 105 patients who underwent allo-HCT for AML and MDS and completed NGS testing at day +100 were included in the study population. Median age of the study population was 63 years (22-74) and 58% were of the male gender. Median HCT comorbidity score (HCT-CI) and KPS Karnofsky performance score (KPS) were 3 (0-8) and 90 (60-100), respectively. Matched unrelated donor (50%) and peripheral blood stem cells (98%) were the most common donor and graft source, respectively. Median number of lines of therapy pre allo-HCT was 1(0-6) and 52 (50%) patients had detectable variants after completion of chemotherapy and prior to allo-HCT. Seventeen (16%) had detectable variants via NGS on day +100. Eleven (65%) of these 17 had variants pre-allo-HCT and amongst the 88 patients with no variants post allo-HCT, 41 (47%) had detectable variants pre allo-HCT. There was no significant difference in baseline characteristics between patients with detectable variants at day+100 versus those who did not except for a higher KPS in patients with no variants at Day +100 of 90 (60-100) vs. 80 (60-100) (p=0.003). At a median follow up of 1.4 years (0.1-5.5), presence of a variant at day +100 was associated with inferior 4-year OS (32% vs. 69%, p<0.001) and higher relapse risk (64% vs. 23%, p<0.001). In univariate models, a lower KPS and presence of variants post allo-HCT were significantly associated with inferior OS, high relapse risk and worse PFS. Presence of variants pre allo-HCT was associated with an inferior PFS but did not impact OS or relapse risk. In multivariate models, KPS remained significant for OS, PFS and NRM; presence of variants at day +100 post allo-HCT approached significance for OS (p=0.06) and PFS (p=0.08) and was significant for relapse risk (p=0.002) (Table1) (Figure 1). Data regarding longitudinal evolution of variants and impact of individual variants on long term outcomes will be included at the time of presentation. Conclusion: These results indicate that presence of detectable somatic variants at day +100 is associated with poor long-term outcomes and predicts for high risk of disease relapse. Longitudinal monitoring of somatic variants via NGS should be consistently incorporated in the management of patients with high-risk AML and MDS undergoing allo-HCT. Patients with detectable somatic variants post allo-HCT should be considered for additional intervention to mitigate relapse risk.

Introduction: Treatment options for multiple myeloma (MM) are evolving rapidly with recent introduction of BCMA-targeting CAR-T (Ide-cel, Cilta-cel) and bispecific antibody (Bi-Ab; Teclistamab) alternatives. These are complex, logistically demanding therapies, and patient awareness/knowledge can affect treatment decisions. There are traditionally underserved patients in MM, and awareness among them must be investigated to uncover disparities which may impact their access to and choice of novel therapies, contributing to disparate outcome. Methods: The study involved an anonymous 25-question online English language survey covering basic demographics, understanding of available T-cell directed MM treatments (CAR-T, Bi-Ab), and preferences for these agents. MM patients within the Mayo Clinic database and members of International Myeloma Foundation's MM support groups were sent a link to the voluntary survey. The survey was active from March 30 until July 12, 2023. Descriptive statistics were calculated with R language (Bluesky Statistics, V7.40), and categorical variables among outcome demographic groups were compared using Pearson Chi-square test (p-value ≤0.05 considered statistically significant). Multiple model logistic regression was used for multivariate analysis amongst statistically significant outcomes. Results: The survey had 2370 respondents with median age 68 years (range: 30-95) and median age at MM diagnosis 62 years (range: 18-88). Time since diagnosis was <5 years in 59.5%. Majority of the respondents (89.4%) were non-Hispanic Whites (NHW). Maximum education categories were high school (10.9%), some college but no degree (18.1%), associate/bachelor (39.7%), and master's/professional (32.3%). Geography and type of residence were reported as: West (24%), Midwest (46.2%), Northeast (3.3%), South (24.8%), outside U.S. (1.7%), and rural (26.7%), urban (21.4%), suburban (51.9%). The goals of MM treatment in order of reported importance were complete remission (66.1%), longer survival (55.3%) and low symptom burden (43.3%). Only 6.5% and 2.6% of respondents had received CAR-T and Bi-Ab, respectively, while 27.9% and 70.5% had never heard of CAR-T and Bi-Ab, respectively. A high proportion of respondents did not understand the risks/benefits of CAR-T (65.5%) or Bi-Ab (90.7%). Given a preference among CAR-T products, 5.4% would prefer Cilta-cel, 1.9% Ide-cel and 92.7% were not sure/no preference. Amongst only those who reported understanding the risks/benefits of CAR-T, the majority (73%) said they would prefer Cilta-cel. The majority (87.5%) were not sure of any differences between the two CAR-T products while some reported different targets (6.3%), response rate (5.9%), response duration (6.2%), side effects (4.9%), and manufacturing time (2.7%). The biggest concern for both CAR-T and Bi-Ab was side effects. Majority (89.4%) were not sure that Teclistamab Bi-Ab targeted BCMA, and nearly 70% felt that CAR-T was superior to Bi-Ab for treating MM. Reported sources of knowledge about MM treatment were healthcare team (82.6%), online resources (43.6%) and other patients/support groups (37.9%). Several demographic characteristics that significantly affected patient's responses to different questions in the survey. Selected questions and respondent categories with statistically significant results in multivariate analysis are shown in Table 1. Generally, higher education, living in northeast U.S., urban or suburban residency, and >5 years since MM diagnosis were associated with better awareness/understanding of CAR-T and Bi-Ab. Respondents with >70-year age were less likely to be aware of these agents or understand their risks/benefits. Race-ethnicity had no statistically significant associations in this cohort of predominantly NHW. Conclusions: This large cross-sectional study identifies lack of adequate awareness regarding CAR-T and Bi-Ab and provides a glimpse of current understanding of these complex therapies. There are disparate groups including rural, less educated, elderly and those with recent diagnosis of MM who have significantly lesser awareness. Some better-informed respondents had preferences among these treatments. Targeted awareness campaigns should be developed so that knowledge gaps can be bridged and patients across all sociodemographic groups are better equipped to take informed decisions about MM treatment.

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

While immunotherapies, such as CAR T therapy and bi-specific antibodies, have revolutionized the treatment of multiple myeloma (MM), patients with AL amyloidosis have been excluded from trials with these agents due to concerns of underlying autonomic, cardiac, and renal dysfunction, leading to potentially fatal toxicities from these therapies. In this communication, we described the outcomes of two patients with AL amyloidosis and concurrent MM with underlying cardiac and/or renal dysfunction who underwent anti-BCMA CAR T cell therapy with ide-cel or cilta-cel, received cytokine release syndrome prophylaxis, and tolerated therapy well with manageable toxicities and achieved a MRD-negative state. We described the preliminary efficacy and safety of CAR T in patients with AL amyloidosis and highlighted the importance of patient selection and medical optimization of cardiac and renal function prior to CAR T.

Abstract Purpose Loneliness may compromise health-related quality of life (HRQOL) outcomes and the immunological impacts of loneliness via neuroendocrinological mechanisms likely have consequences for patients who have undergone a hematopoietic stem cell transplantation (HSCT). Research Approach and Measures: Loneliness (pre-transplant), immunological recovery (Day 30, Day 100, 1-year post-transplant), and HRQOL (Day 100, 1 year) were measured in a sample of 205 patients completing a HSCT (127 autologous, 78 allogenic). Results Greater levels of pre-transplant loneliness predicted poorer HRQOL at Day 100 and 1-year follow-up. Loneliness also was associated with higher absolute neutrophil to absolute lymphocyte (ANC/ALC) ratios in the entire sample at Day 30, which in turn predicted Day 100 HRQOL. Conclusions Findings demonstrate that pretransplant loneliness predicts HRQOL outcomes and inflammatory immunological recovery patterns in HSCT patients. The balance of innate neutrophils to adaptive lymphocytes at Day 30 present a distinct profile in lonely individuals, with this immunity recovery profile predicting reduced HRQOL 100 days after the transplant. Addressing perceptions of loneliness before HSCT may be an important factor in improving immunological recovery and HRQOL outcomes.

AbstractIntroductionHealth information technology (HIT) has the potential to improve healthcare delivery and engagement. Studying racial‐ethnic disparities in HIT engagement will help understand and overcome challenges to healthcare utilization.MethodsWe undertook a patient‐reported survey among patients with lymphoid malignancies at two campuses of Mayo Clinic, Florida to explore HIT‐related disparities. Variables between Whites and non‐Whites, and non‐Whites from the two campuses were compared.ResultsThe survey was completed by 1004 respondents, with 71% whites, 27% non‐Whites (race‐ethnicity not reported by 2%). Non‐Whites included 30% responders at the main campus and 64% at an inner‐city campus. Whites were significantly older and had higher education, while non‐Whites had lesser access to a computer. Only 51% of non‐Whites were registered to use electronic medical records (EMR) as compared to 72% Whites (p < 0.001) and significantly lesser number of non‐Whites even knew that EMR existed (81% vs. 92%, p < 0.001). Encouragingly, a higher number of non‐Whites wanted to engage in EMR. Non‐Whites from the main campus were older, more educated and had more access to a computer as compared to those from the inner‐city campus. Similar disparate factors were noted among minorities from the two campuses, suggesting impact of socioeconomic backgrounds on EMR usage among non‐Whites. Linguistic barriers were more striking among inner‐city campus non‐Whites.ConclusionsNon‐Whites continue to struggle with suboptimal utilization of the healthcare system and barriers related to integration in HIT, including disparities representing socioeconomic differences. Efforts need to be made at several levels to help racial‐ethnic minorities overcome awareness, access, and linguistic barriers to HIT utilization.

Abstract Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P &lt; .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.

AbstractIn this phase 1/2 study, carfilzomib was added to high‐dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days −6, −5, −2, and −1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days −4 and −3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4–88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3–4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

Background: Multiple myeloma (MM) is the second most common hematologic malignancy, with 34,470 estimated new cases in 2022. High-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) remains a standard treatment for MM even in the era of novel therapies. This is usually performed in hospital-based settings, either in the inpatient or outpatient units. Advanced Care at Home (ACH) represents a virtual hybrid hospital-at-home program that combines a virtual provider-staffed command center with a vendor-mediated supply chain capable of delivering high-acuity care in the comfort of the patients’ own homes. In our program, we used the existing ACH platform to deliver post-HCT care for recipients of auto-HCT. Patients and methods: Four patients (female = 2, 50%) with MM, with a median age of 60 (range, 40–74) years, were admitted to the inpatient Blood and Marrow Transplant (BMT) unit. The conditioning regimen consisted of melphalan 200 mg/m 2 , administered on day –2. All patients received stem cell infusion (day 0) in the inpatient setting, with a median dose of 3.64 (range, 2.92–8.22) × 10 6 /kg CD34 cells. Results: Patients were discharged to their homes after completing the infusion on day 0 or day +1 at the latest. Postinfusion care was provided by the ACH team in coordination with the BMT team. The median time intervals to absolute neutrophil count and platelet engraftment were 12 (range, 11–13) and 11 (range, 9–16) days, respectively. All patients were successfully discharged from the ACH program at a median of day +14 (range, day +14 to day +15). Conclusions: Our results highlight the feasibility of delivering post-HCT care for auto-HCT recipients in the home setting and confirm the generalizability of this approach.