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Background: There is an increased risk of second primary malignancies including second hematological malignancies (SHM) in multiple myeloma (MM) patients undergoing autologous stem cell transplant (auto-SCT) followed by lenalidomide maintenance. We analyzed the characteristics and outcomes of patients who developed SHM after an auto- SCT for MM. Methods: A retrospective study of all MM patients who underwent auto- SCT at Mayo Clinic, Rochester between January 1, 1990, and 31 August 2023 and later developed SHM. Demographic, clinical and pathologic data were collected retrospectively. Overall survival (OS) was calculated from the date of auto-SCT to the date of last follow up. Statistical analyses were performed using GraphPad prism 9.0. Chi-square test was used to calculate the difference between categorical variables. Kaplan Meier method and log rank test were used to estimate OS. Results: Among 3513 patients who underwent at least 1 auto-SCT, 104 (2.9%) developed a SHM at a median follow up of 59 (range, 0.2-265) months. Patients who developed SHM, more frequently received pretransplant alkylating agents (37.5 vs 24.2 %, odds ratio [OR], 1.87; P=0.003) and topoisomerase II inhibitors (anthracyclines/etoposide) (17.3% vs 10.4%, OR [1.79]; P=0.03) compared to a control group of MM patients without SHM. Further, exposure to lenalidomide (77.8% vs 57.6%, OR[2.59]; P <0.0001) and radiation therapy (32.6% vs 23.1%, [1.54]; P=0.04) were more often seen in the SHM cohort compared to control group. Among the 381 patients who underwent > 1 auto- SCT, 3.1% developed SHM. Therapy related myeloid neoplasms (t-MN) accounted for 90.3% of cases [n=94; t-myelodysplastic syndrome (t-MDS=64), t-acute myeloid leukemia (t-AML=12), t-MDS transformed to AML(n=16), chronic myeloid leukemia (n=1), MDS/myeloproliferative neoplasm overlap syndrome (n=1)]. Eight patients (7.6%) developed therapy related B- cell acute lymphoblastic leukemia (t-ALL); Philadelphia (Ph) negative ALL (n=7) and Ph- like ALL (n=1). One patient each developed mixed phenotype acute leukemia and acute leukemia, not otherwise specified. Sixty patients (57.6%) were males and the median age at diagnosis of SHM was 70 (range, 43-84) years. The median time from auto-SCT to diagnosis of SHM was 58.5 (range, 7-236) months. In a multivariate analysis, receiving an alkylating agent (hazard ratio [95% confidence interval]: 2.51 [1.54 to 4.01]; P = 0.0002) and/or topoisomerase II inhibitor as induction for MM (3.12 [1.59 to 5.88]; P = 0.0006), exposure to lenalidomide (7.08 [3.92 to 13.50]; P = <0.0001) and radiation therapy (1.60 [1.02 to 2.44]; P = 0.03) were independent predictors of developing SHM. At diagnosis, 57% (n=37) of t-MDS and 71% (n=20) with t-AML had high risk disease per R-IPSS and 2022 European Leukemia Net respectively. Clonal abnormality in chromosome 5 and/or 7 was present in 45% (n=42) of patients. Complex and monosomal karyotype was seen in 32% (n=30) with t-MN. The most frequently mutated genes based on next generation sequencing data included TP53 (n=33), DNMT3A (n=9), RUNX1 (n=5), TET2 (n=4) and CEBPA (n=4). In the t-MDS/AML cohort, 3 patients (3.1%) underwent second auto-SCT and 9 (9.5%) received allogenic SCT (allo-SCT) for SHM. After a median follow-up of 27.2 months, the median OS from t-MDS/AML diagnosis was 8.04 months (95%CI, 6.1-11.0 months) and there was no difference in median OS for allo-SCT recipients versus nonrecipients (9.1 vs 6.8 months, P =0.19). In the t-ALL (n=8) cohort, all of them received lenalidomide based induction and five received lenalidomide maintenance. Most of the t-ALL patients had adverse risk cytogenetics [IKZF1 deletion (n=2), complex karyotype (n=2), TP53 mutation (n=1) and P2RY8-CRLF2 fusion (n=1)]. Three patients with t-ALL underwent allo-SCT and the median OS for allo-SCT recipients versus non recipients were 8.3 vs 7.9 months respectively, P=0.50. Among patients with SHM, 92.3% (n = 96) have died with SHM (72%) being the most common cause of death. MM patients who developed SHM had an inferior OS when compared to those without SHM (median OS, 75 vs 90 months, P =0.006). Conclusion: SHM following auto-SCT tends to have aggressive disease biology with poor outcomes. Short term follow up underestimates the risk of SHM and the higher incidence noted in our study may be due to longer follow up. As the OS in MM patients continues to improve, SHM remains an important challenge in improving long term outcomes.

Background: CLL is one of the most common types of leukemia in the United States, with an estimated 20,700 new cases in 2024. Although cBTKis have become the standard of care for CLL/SLL in treatment-naïve and relapsed/refractory patients, cardiovascular (CV) toxicity is a known side effect. Further, clinical outcomes often worsen as patients progress beyond 1st-line therapy (1L), and the frequency of CV adverse events (CVAEs) may increase with age and as patients progress to 2nd-line or later therapies (2L+). This research evaluated the real-world incidence of CVAEs and clinical outcomes in patients who initiated cBTKi between 2020 and 2023. Methods: Adult patients diagnosed with CLL/SLL who initiated cBTKi treatment (index date) between 2020-2023 in the United States were identified using claims data from Optum's de-identified Clinformatics® Data Mart Database and followed up to 36 months post-index. Cohorts were assessed as those initiating 1L or 2L+, reflecting treatment-naïve and relapsed/refractory patients. Results were presented for patients with an incident CVAE (not present pre-index) and those without. Demographics, incident CVAEs, overall survival (OS) and proportion of patients who discontinued index cBTKi therapy, initiated next treatment or experienced death (NT+D) were assessed. Time to CV event (TTCE) for ibrutinib and acalabrutinib were determined using a Kaplan-Meier (KM) model and Log rank test. Results: Overall, 2,163 eligible patients were identified with a mean ± SD age of 73.8 ± 9.2 years, and 40.6% were female. Of these, 1,958 (90.5%) were included in the 1L cohort and 205 (9.5%) in the 2L+ cohort; 619 (31.6%) and 63 (30.7%) patients had CVAEs, respectively. The mean ± SD [median] observation period was 1.6 ± 0.9 [2.0] years in 1L and 1.5 ± 1.0 [1.0] years in 2L+. The most common cBTKi (in 1L and 2L+) at index were ibrutinib (55.5% and 55.6%), followed by acalabrutinib (40.3% and 38.5%), and zanubrutinib (4.1% and 5.9%). At 12-months post-index, the proportion of 1L patients with and without CVAEs who discontinued treatment was 44.9% and 41.6%, rising to 65.6% and 59.0% by 36-months post-index, respectively. For those in 2L+, 50.8% and 40.8% of those with and without CVAEs discontinued treatment by 12-months; 68.3% and 55.6% discontinued by 36-months. Among those with and without CVAEs, NT+D in 1L patients was 35.9% and 22.5% within 12-months post-index and 56.9% and 32.8% by 36-months. In the 2L+ cohort, 46.0% and 31.7% experienced NT+D by 12-months, rising to 63.5% and 41.5% by 36-months. OS in 1L patients was 84.7% and 93.1% in those with and without CVAEs at 12-months and 69.1% and 88.0% at 36-months. For 2L+ patients, OS was 71.4% and 88.0% at 12-months and decreased to 54.0% and 80.3% at 36-months, among those with and without CVAEs, respectively. The most common incident CVAEs following cBTKi initiation in the 1L and 2L+ cohorts were hypertension (31.2% and 21.7%), heart failure (14.6% and 17.7%), atrial fibrillation (13.9% and 18.4%), atrial flutter (13.3% and 16.9%), and ventricular arrythmias (13.0% and 14.5%). The occurrence of incident CVAEs between 1L patients who received acalabrutinib and ibrutinib was 3.4% and 13.2% for atrial fibrillation, 2.7% and 12.7% for atrial flutter, 9.3% and 31.0% for hypertension, and 6.8% and 11.7% for ventricular arrythmias. For 2L+, the proportion experiencing CVAEs with index acalabrutinib or ibrutinib were 8.6% and 14.8% for atrial fibrillation, 7.6% and 14.8% for atrial flutter, 10.5% and 25.0% for hypertension, and 10.1% and 8.8% for ventricular arrythmias. Among acalabrutinib and ibrutinib patients, KM estimates (medians not reached) in 1L showed that 84% and 72% of patients would not experience a CVAE by 12 months, with 57% and 52% not experiencing a CVAE at 36-months (p<0.001); 2L+ KM estimate rates were 77% and 73% at 12-months and 64% and 60% at 36-months (p=0.28). Mean TTCE for acalabrutinib and ibrutinib in 1L was 2.2 and 1.9 years with 1.6 and 1.2 years in 2L+. Summary/Conclusion: Utilizing real-world evidence from patients with CLL/SLL receiving cBTKIs, this study highlights the CV disease burden among patients who incur new CV events in 1L or later lines of therapy. This research underscores the need for innovative therapies with improved efficacy and CV safety profiles that delay progression to later lines of therapy, as well as careful CV monitoring to allow for early management and improved outcomes.

Introduction: Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by tissue deposition of misfolded immunoglobulin light chains in the form of amyloid, leading to organ dysfunction. Halting the production of the amyloidogenic free light chains by achieving a deep hematologic response (HemR) is key to improving organ function, however, variation in organ responses exists. In this work, we investigated variables associated with liver response (LivR) in a large cohort of patients with AL amyloidosis. Methods: Retrospective study of newly diagnosed AL amyloidosis patients with liver involvement seen at Mayo Clinic within 90 days of diagnosis between January 2000 and December 2021. Patients were eligible if they (1) had liver involvement, defined as a baseline alkaline phosphatase (ALP) ≥ 1.5 x upper limit of normal (ULN) and (2) had LivR measurements at least twice annually in the first year from treatment and annually afterward. LivR was defined as a >50% reduction in alkaline phosphatase (ALP) from baseline value or normalization of ALP. LivR was recorded at 6, 12, and 24 months from treatment initiation and at the best LivR achieved. Patients who died prior to landmark assessment were considered non-responders at subsequent milestone assessments. Covariates associated with LivR were identified by univariate and multivariable logistic regression analyses and a proportional subdistribution hazard (Fine-Gray) model for competing risk (treating death as a competing event). Multivariable logistic regression models for LivR were created using best subset selection, with calculation of odds ratio (OR) and 95% confidence interval (CI). Results: A total of 130 patients were included, with a median age of 60 years (IQR 53-66), male predominance (69%), and a median follow-up of 8.8 years. Sixty percent of patients had lambda isotype, the median ALP was 368 IU/mL (IQR 279-589), with 48% of patients having ALP ≥3 fold the upper limit of normal (ULN). Median bilirubin was 0.7 mg/dL (IQR 0.5-1.1). Forty-three percent of patients received front-line autologous stem cell transplant (ASCT) with or without prior induction therapy, and 5% received daratumumab-based therapy as their front-line treatment. Liver response rate increased with time, with 36 patients (28%) achieving a LivR at 6 months, 47 (36%) at 12 months, 63 (48%) at 24 months, and 94 (72%) at best response. The median time to liver response was 14 months (7.22-32.67). At the 24-month landmark, age <60 years, ALP ≥3 fold ULN, and front-line ASCT were significantly associated with achieving a LivR on univariate logistic regression. On univariate logistic regression at best liver response, age <60 years, ALP ≥3 fold the ULN, kappa isotype, ≥HemVGPR within 6 months, and front-line ASCT were significantly associated with obtaining a LivR. On multivariable logistic regression, at 24 months, ALP ≥3 folds of ULN (OR=2.9, 95% CI 1.4-6.3, P=0.004) was significantly associated with an increased likelihood of LivR. Achieving ≥HemVGPR and front-line ASCT were also associated with increased LivR likelihood, although not statistically significant (p=0.094, p=0.078, respectively). At best liver response, achieving ≥HemVGPR within 6 months (OR=5.2, 95% CI 1.9-14.8), kappa isotype (OR=3.2, 95% CI 1.1-10.0), ALP ≥3 folds of ULN (OR=3.3, 95% CI 1.3-9.9), and front-line ASCT (OR=5.3, 95% CI 1.9-16.7) were factors significantly associated with LivR. The Fine-Gray model demonstrated kappa isotype (HR=1.7), baseline ALP ≥3 folds of ULN (HR=2.1), ≥HemVGPR within 6 months (HR=1.9), and age <60 years at diagnosis (HR=1.9) to be positively associated with achieving LivR (P<0.05). Conclusions: In this large cohort of liver AL amyloidosis, LivR was achieved in 72% of patients, and amongst responders, the median time to response was 14 months from therapy initiation. Predictors of LivR included kappa isotype, deep hematological response in the first 6 months of initial therapy, ASCT usage, and higher baseline ALP levels. These findings better inform clinicians on the likelihood of achievement of liver response and may enable ways to improve its achievement.

Background: Although Covalent BTKis have revolutionized treatment of CLL/SLL, cardiotoxicity is a known side effect, which can increase the total costs to the healthcare system. This study evaluated the real-world healthcare resource utilization (HCRU) and costs in patients who did and did not experience incident cardiovascular adverse events (CVAEs) during cBTKi treatment. Methods: Adult patients diagnosed with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020-2023 in the United States were identified using claims data from Optum's de-identified Clinformatics® Data Mart Database and followed up to 36 months post-index. Patients were stratified into two cohorts based on the presence of an incident CVAE during treatment with index cBTKi, defined as the occurrence of a CVAE not present in a patient's medical history. HCRU and costs were evaluated on a per 1,000 patient-months basis. Z tests and univariate gamma general linear models were used to compare HCRU and cost rates. HCRU between those who received ibrutinib or acalabrutinib were also assessed. Results: Overall, 2,069 eligible patients were identified with a mean ± SD age of 73.7 ± 9.1 years, and 40.4% were female. The mean ± SD [median] treatment-specific observation period was 11.4 ± 9.5 [8.5] months. Of the total cohort, 442 (21.4%) experienced at least one incident CVAE, while 1,627 patients (78.6%) experienced no CVAEs. Among those without a pre-index history of the specific CV AE of interest, the proportion of patients with incident events were 21.4% for hypertension, 9.8% for atrial fibrillation, 9.2% for atrial flutter, and 9.6% for ventricular arrhythmias. Patients who experienced an incident CVAE had 4,334 total days with medical service compared to 3,138 days in those who did not (p<0.001). The drivers of differences in total medical service days between those with and without CVAEs were inpatient days (690 vs 230), followed by outpatient days (2,798 vs 2,425), other visits (e.g., hospice; 662 vs 375), and emergency room (ER) visits (184 vs 109). Total days with medical service were 3,458 in those who received ibrutinib and 3,410 with acalabrutinib. Total healthcare cost rates in those who experienced an incident CVAE were $20,250,560 compared to $17,413,460 in those without CVAEs (p<0.001). Inpatient costs drove differences in total costs between those with CVAEs and those without ($3,417,948 vs $915,839, p<0.001), followed by outpatient ($2,415,060 vs $1,769,628, p<0.01) and ER costs ($186,820 vs $87,585, p<0.001). Pharmacy costs were the largest contributor to total cost rates for both cohorts ($14,016,900 for those with a CVAE vs $14,473,270 without any CVAEs, p<0.001). Regarding specific incident CVAEs, the cost difference in total costs between those with and without the event were $3,789,820 for atrial fibrillation (higher in those with the event), $3,867,160 for atrial flutter, $3,674,860 for ventricular arrhythmias, and $721,840 for hypertension. Inpatient costs were the largest driver in total cost differences between those with and without the specific CVAE of interest; inpatient cost differences were $3,255,699 higher in those with atrial fibrillation, $3,436,913 with atrial flutter, and $3,299,371 with ventricular arrhythmia. For hypertension, pharmacy costs drove differences in total costs and were $346,570 higher in those with the CVAE. Summary/Conclusion: Overall, the economic burden remains high in patients treated for CLL/SLL, especially in cBTKi patients experiencing an incident CVAE. These findings highlight the importance of careful treatment selection, safety monitoring, and early management of CVAEs in order to improve patient outcomes and reduce the downstream impacts on healthcare resources and costs.

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: Chimeric antigen receptor T-cell (CAR-T) therapy has shown substantial promise in treatment of hematological malignancies, including non-Hodgkin Lymphoma (NHL). A subset of patients develop prolonged cytopenia, comprising quality of life, increasing healthcare utilization, and imparting considerable morbidity and mortality. Therapy-related myeloid neoplasms (t-MN), typically seen in patients who receive DNA-damaging agents such as radiotherapy and alkylators, have also been observed in CAR-T recipients. CAR-Hematotox score predicts the development of hematotoxicity in CAR-T recipients using laboratory parameters obtained at lymphodepleting (LD) chemotherapy, a timepoint when the patient has already gone through leukapheresis thus committed to the CAR-T process. Therefore, it is critical to identify patients at the highest risk of prolonged cytopenia and/or t-MN prior to apheresis, making it possible for a better triage of those who will proceed with CAR-T and those who might benefit from other strategies. Methods: A retrospective analysis was conducted in NHL patients who received commercial CAR-T products between January 2018 and March 2024 at Mayo Clinic Rochester, Arizona and Florida. Clinical and laboratory data including age, hemoglobin (Hb), absolute neutrophil count (ANC), platelet (PLT), ferritin, and LDH, obtained at the initial CAR-T evaluation, typically within 1 week of leukapheresis, were used for analysis. Prior lines of therapies including autologous stem cell transplant (ASCT) were collected. Prolonged cytopenias were defined as Hb < 8 g/dL, ANC < 0.5 x 109/L, and/or PLT < 50 x 109/L at 3 months after CAR-T. t-MN was diagnosed per WHO 2016. For prolonged cytopenia, the optimal cutoff points for continuous variables were determined by maximizing the sum of sensitivity and specificity. Logistic regression was then used to determine the factors associated with cytopenia at 3 months post-CAR-T. For t-MN, maximally selected log-rank statistics was used to determine the optimal cutoffs. We used competing risk analysis to determine the factors associated with development of t-MN. Death without t-MN was considered a competing risk. For both analyses, the factors with P < 0.1 in univariate analysis (UVA) were included in multivariate analysis (MVA). Results: Among the 387 NHL patients, with a median follow-up of 11 months (95% CI 8.7 - 12.2 months), 56 (14.4%) developed (41, 10.5% with 1 cytopenia; 14, 3.6% with 2 and 1, 0.2% with cytopenia in all 3 lineages), 20 (5.2%) developed and 315 (81.2%) did not have either. Factors associated with prolonged cytopenia: were age >, PLT ≤ 150, ferritin ≥ 600, and LDH ≥ 250. Univariate analysis identified baseline Hb, ANC, PLT and ferritin to be significantly associated with prolonged cytopenia. MVA identified Hb ≤ 11 (HR = 1.98; 95% CI 1.03-3.85, P = 0.042) and PLT ≤ (HR = 2.56; 95% CI 1.39-4.78; P = 0.003) to be associated with the development of prolonged cytopenia. Factors associated with t-MN:were age > 65 years, Hb ≤ 9 g/dl, ANC < 3.8, PLT ≤ 80, Univariate analysis identified age, Hb, ANC, PLT, ferritin, and ≥ 3 prior lines of treatment to be significantly associated with t-MN. On MVA, age ≥ 65 (HR = 3.91; 95% CI 1.52-10.03; P = 0.004), Hb ≤ 9 (HR = 3.49; 95% CI 1.38-8.85; P = 0.008), ferritin ≥ 300 (HR = 3.06 ; 95% CI 1.08-8.67; P = 0.035) and ≥ 3 prior lines of therapy (HR = 3.25; 95% CI 1.33-7.94 ; P = 0.010) were associated with t-MN development. Association of prolonged cytopenia with t-MN development: Prolonged cytopenia was noted in 45% of patients who developed t-MN and 15% of those who did not (P = 0.002). Cumulative incidence of t-MN at 1 year was 3.3% and the presence of prolonged cytopenia was associated with a higher 1of t-MN (HR 8.93, 95% CI 2.15 - 37.1, P = 0.003). Conclusions: Readily accessible clinical and lab data such as blood count and inflammatory markers at the time of CAR-T evaluation were associated with the development of prolonged cytopenias. Similarly, advanced age, anemia, high ferritin levels and history of ≥3 lines of therapy were associated with the development of t-MN. These findings, when validated in larger dataset, can be used for patient counseling and therapy selection by identifying patients at high-risk of developing hematotoxicity and/or t-MN development.

Background: AL amyloidosis is a potentially fatal plasma cell dyscrasia. In a randomized phase 3 study (Kastritis E et al, NEJM 2021;385:46-58), the addition of daratumumab to cyclophosphamide, bortezomib and dexamethasone (Dara-CyBorD) significantly improved hematological and organ responses, and prolonged event-free survival (EFS). There was no overall survival (OS) difference at a median follow-up of 11.4 months. Methods: A retrospective study of AL amyloidosis patients seen at our institution between January 2018 and December 2022 who received upfront Dara-CyBorD or CyBorD. We excluded patients who received other forms of upfront therapy (including modifications of the above regimens, such as bortezomib-dexamethasone or daratumumab-dexamethasone). We compared the hematologic and organ responses, EFS and OS between the two treatment groups. Hematologic response was assessed at 2 and 6 months from therapy initiation, while cardiac and renal responses at 6- and 12-month landmarks. In all response evaluations, we included responses up to autologous stem cell transplantation (ASCT) if used or second-line therapy for any reason. For EFS analysis, an event was defined as death of any cause, hematological progression, end-stage cardiac or renal failure, or need for subsequent anti-plasma cell therapy in the absence of hematological progression. OS was calculated from the time of treatment initiation to death or last follow-up. Results: Among 641 newly diagnosed patients seen at our center between 2018 and 2022, 361 patients (56%) were included on intention-to-treat analysis [Dara-CyBorD =147 (41% of the cohort); CyBorD=214 (59%)]. There was no difference in the baseline characteristics between the treatment groups, including age, sex, difference between involved and uninvolved light chains, bone marrow plasma cells percentage, NT-proBNP and 24-hour proteinuria. The 2-month hematologic complete response (hemCR; 15.3% vs 4.4%, P<0.001) and very good partial response or better (≥hemVGPR; 62.2% vs 32.5%, respectively; P<0.001) were higher with Dara-CyBorD compared to CyBorD. At 6 months, the hemCR and ≥hemVGPR were again in favor of the Dara-CyBorD group compared to CyBorD (32.0% vs 13.7%, and 72.8% vs 46.7%, respectively; P≤0.002). The 6- and 12-month cardiac response rate in the Dara-CyBorD and CyBorD groups were 40.2% vs 22.6% (P=0.01) and 44.1% vs 23.2%, respectively (P=0.006). Cardiac ≥VGPR at the 6- and 12-month landmarks were statistically higher with Dara-CyBorD compared to CyBorD and increased in both arms between 6 and 12 months [20.5 % vs 9.3% (P=0.03) and 34.3 % vs 20.0% (P=0.04), respectively]. The 6-month and 12-month renal response to first-line therapy were numerically higher with Dara-CyBorD compared to CyBorD but were not statistically significant (48% vs 31.3%, P=0.10; 54.1% vs 30.1%, P=0.05). The 6 month and 12 months, renal ≥VGPR were numerically higher with Dara-CyBorD compared to CyBorD, again without statistical significance (26% vs 19.6%, P=0.63; 35.7% vs 17.2%, P=0.11, respectively). Treatment with Dara-CyBorD was significantly associated with lower 6-month mortality rate compared to CyBorD (8.8% vs 16.3%, P=0.04). With a median follow-up of 43.3 months (30 vs 59.4 months for Dara-CyBorD vs CyBorD, respectively; P<0.001), the two-year EFS was superior in the Dara-CyBorD group compared to CyBorD (69.1% vs 30.3%, hazard ratio (HR) 0.36, 95% confidence interval (CI), 0.26 to 0.48, P<0.001). The 2-year OS was also statistically higher in the Dara-CyBorD group compared to CyBorD (82.0% vs 69.6%, HR 0.53, 95% CI, 0.36 to 0.79, P=0.003). 148 patients (40.9%) proceeded to second-line therapy with a median of 5.1 months from first line therapy. To adjust for difference in follow-up time between the two treatment groups, we analyzed the second line therapy utilization at the 12-month mark which was statistically higher with CyBorD compared to Dara-CyBorD (42.9% vs 14.9%, P<0.001). Also, at 12 months, a higher proportion of patients treated with CyBorD received ASCT compared to Dara-CyBorD (24.3% vs 13.6%, P= 0.01). Conclusions: In this cohort of newly diagnosed AL amyloidosis patients in a large referral center, we confirmed higher hematological and organ response rates with Dara-CyBorD compared to CyBorD. We have also demonstrated that these higher response rates translate into a survival advantage of Dara-CyBorD over CyBorD.

Background and significance: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare condition caused by a somatic mutation in the PIG-A gene, leading to complement-mediated hemolysis and severe complications such as anemia and thrombosis. Patients often experience fatigue, dyspnea, and abdominal pain, impacting their daily lives and emotional well-being. This study aims to comprehensively explore the impact of PNH on health-related quality of life (HRQoL), alongside real-world treatment utilization and symptom burden patterns, especially as new treatments become available to this patient population. These results are based on interim baseline data from currently enrolled study participants, providing an initial assessment of their PNH disease experience. This analysis does not include any data collected prospectively during the data collection period. Study design and methods: This ongoing, prospective, observational study (NCT06411626) aims to enroll at least 128 US-based participants aged 18 or older with PNH, regardless of treatment usage. Participants are recruited through clinician-based referrals, patient advocacy organizations, and community-based online channels. All activities can be completed remotely using the Folia Health app, the single site for this study. This app-based study aims to comprehensively assess patient-reported symptom burden, treatment use patterns, and impacts of PNH on health and FACIT-Fatigue through self-reported home-reported outcomes (HROs). Participants will track symptoms and treatment use, including recently approved treatments (e.g., iptacopan, danicopan, crovalimab). HROs consist of participants' self-identified symptoms and personalized treatment plan that are tracked longitudinally against self-reported baselines. Semi-structured interviews and collaborative feedback sessions with PNH patients and clinicians yielded a comprehensive outcomes inventory for tracking key health outcomes specific to PNH. This inventory includes the ability to track infusion treatments and denote flare-ups in fatigue. Participants can customize their data collection to track symptoms in additional domains beyond those initially suggested (e.g., respiratory or immune). At enrollment, participants report baseline health status and select their relevant symptoms and treatments to routinely track for 6 months. Monthly in-app surveys will collect data on overall health and the FACIT- Fatigue. The Folia app allows participants to visualize symptoms trends, set treatment reminders, and generate reports for their care team. Results: Enrollment began on June 11, 2024. As of July 22, 2024, an interim data analysis was conducted on 20 participants; 65% (n=13) enrolled through online community-based channels and 35% (n=7) enrolled through clinic referrals. Participants selected 37 distinct symptoms and measurements and 26 distinct treatments to track over the 6-month period. The most common symptoms selected at baseline include fatigue (n=19), brain fog (n=17), and dark colored urine (n=15). PNH treatments selected for tracking include iptacopan (n=9), ravulizumab (n=5), eculizumab (n=4), and pegcetacoplan (n=3). The mean baseline FACIT- Fatigue score (n=18) was 35.7 and the median was 40 (IQR= 16). Further descriptive analyses stratified by primary treatment use will be conducted assessing characteristics of symptom burden, satisfaction with treatments-in-use, and self-reported impact on HRQoL. Conclusions: Initial interim baseline data of recently enrolled participants with PNH show a variable disease experience. This app-based, observational study aims to establish a new real-world data source to understand patient priorities related to symptom variability, treatment patterns and preference, and impacts of condition management on HRQoL.

Introduction: Ven is a BCL2 inhibitor that has shown clinical efficacy in RRMM patients (pts) particularly those that harbor t(11;14). Ven has been evaluated in clinical trials as a single agent, in combination with dexamethasone (dex), immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and anti-CD38 monoclonal antibodies (MAb) yet its place in the therapeutic landscape remains in question. In this retrospective analysis, we aim to evaluate the real-world efficacy of Ven-based regimens in RRMM pts treated outside of a clinical trial across the 3-site MCCC. Methods: We retrospectively analyzed the medical records of pts with RRMM treated with Ven-based regimens between January 2015 and October 2023 at the MCCC. Refractoriness was defined by progression on or within 60 days of stopping treatment. Categorical variables were compared with Chi-square tests and continuous variables were compared with t-tests. Outcomes were estimated using the Kaplan-Meier method and curves were compared between the groups using log-rank tests. Results: 83 pts were included in the analysis. The median age was 71 (39-93), 63% were male, 93% were white, 27% had ISS III, 18% had high risk cytogenetics (HRCyto), 76% had t(11;14), the median prior lines of therapy (LOT) was 4 (1-15), 68% received ≥ 4 prior LOT, 87% received prior autologous transplant, 58% were triple-class refractory (TCR), 64%/23% were penta-drug exposed/refractory (PDE/R), 8% received prior BCMA-directed therapies (BDT), 58% received Ven+dex, 25% received Ven+PI +/-dex, 6 % received Ven+anti-CD38 MAb+/-dex and 11% received Ven+other. The median follow-up time from start of a Ven-based regimen was 29 months (mo). The median Ven dose was 800mg (20-1600) with 25% of pts receiving Ven ramp-up dosing. The overall response rate (ORR) to a Ven-based regimen was 58% and was 64% for pts with t(11;14) and 40% for pts without t(11;14); p=0.06. Ven-treated pts with HRCyto had inferior PFS (3mo) and OS (8mo) compared to patients who did not have HRCyto who had a PFS of 9mo (p=0.020) and OS of 80mo (p<0.001). The ORR for TCR and PDR pts were 52% and 42%, respectively. No significant ORR differences were noted across the different Ven-based regimens (p=0.32). The median PFS for pts with t(11;14) was 10mo compared to 2mo for pts w/o t(11;14); p=<0.001. The median OS for pts with t(11;14) was 80mo compared to 10mo for pts without t(11;14); p=0.001. Ven-treated pts who received 1-3 prior LOT has superior ORR, median PFS, and median OS; 89%, 25mo, and 99mo, respectively, compared to pts who received ≥4 prior LOT who achieved an ORR of 43% (p<0.001), median PFS of 5mo (p<0.001) and median OS of 25mo (p<0.001). Ven-treated pts that were TCR had inferior PFS (5mo) and OS (26mo) compared to pts who were not TCR who achieved a PFS of 12mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts that were PDR had inferior PFS (4mo) and OS (22mo) compared to pts who were not PDR who achieved a PFS of 9mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts who received prior BDT (n=7) achieved an ORR of 29% and had a median PFS and OS of 2mo and 6mo, respectively on a Ven-based therapy. 59 pts received additional therapy in the post Ven-progression setting. The ORR to post-Ven progression therapies was 53% (n=31/59), the median PFS was 9mo and median OS was 35mo. The most common post-Ven progression regimens used were PI-based (n=16; ORR=56%), anti-CD38 MAb-based (n=14; ORR=50%), BDT (n=12; ORR=83%), selinexor-based (n=3; ORR=0%) with BDT resulting in highest ORR (p=0.048) and PFS (p=0.005). Conclusions: Ven-based regimens are effective in heavily pre-treated pts with RRMM however they are more effective when used within 1-3 prior LOT, in pts with t(11;14), and in pts without HRCyto, TCR or PDR MM. BDT appear to be the most efficacious therapies in the post-Ven progression setting.

Introduction: Uniform assessment of response to treatment is crucial to managing myeloma and developing new therapies. Measurement of the monoclonal protein (s) secreted by the myeloma cells forms the cornerstone of disease assessment in MM and has primarily been performed by electrophoretic methods in the serum and urine, as well as assessment of free light chains in the serum. According to international myeloma working group (IMWG) guidelines, serial serum-free light chain (sFLC) is included in MM response assessment to define stringent complete response and for evaluating partial response (PR) or progressive disease (PD) in non/oligo-secretory MM. This study aims to determine the added value of serial sFLC measurements in monitoring response and progression in MM with measurable disease by comparing the kinetics of FLC with M spike measured by electrophoresis in serum or urine. Methods: This retrospective observational study included newly diagnosed MM patients evaluated at Mayo Clinic in Rochester between 2011-2021. All patients had measurable sFLC (involved FLC level ≥ 10mg/dL, with abnormal sFLC ratio) along with measurable M-protein by serum or urine protein electrophoresis at diagnosis. Serial measurements of sFLC and M-protein by electrophoresis (sPEP/uPEP) were prospectively collected from the electronic medical records at different time points. FLC-response and FLC-PD were evaluated based on IMWG criteria. Results: The study cohort included 839 patients, 52% with measurable M protein by electrophoresis in serum, 27% in both serum and urine, and 21% in urine-only. A significant association was observed between sFLC and electrophoretic response during the induction and at the time of best response (p <.001). Serum FLC showed a comparable response rate of 98% (≥ PR) at the time of best electrophoretic response (p <.001). Ninety-nine percent of early FLC responders eventually achieved an overall response by sPEP/uPEP (p <.001). In the urine-only group, 99% achieved at least a PR by uPEP, and all showed at least a PR based on sFLC. We observed comparable median percentage changes in serial dFLC and urine M-protein, with parallel trends (p <0.001). The correlation coefficients between the change of sFLC and urine M-protein showed a moderate/strong correlation with coefficients (r) of 0.791, 0.597, 0598, 0.545, after cycles 1, 2, 3, 4, respectively, (p < .001). The response for all cohorts was detected earlier by dFLC (median time 1.1 months, 95% CI: 1.06-1.17), in comparison with serum M-protein (1.5 months, 95% CI: 1.40-1.62) and urine M-protein (2.8 months, 95% CI: 2.42-3.10) with p < .001. In the urine-only group, earlier detection of response by dFLC (1.1 months, 95% CI: 1.00-1.2) was observed, compared to urine M-protein (2.4 months, 95% CI: 2.00-2.7) (p <.001). After a median follow-up of 52 (IQR 27.6, 72.3) months, 56% had PD: 62% by s-FLC, 56% by serum M-protein, and 24% by urine M-protein. Among patients with PD by uPEP, all except one patient met sFLC-PD. Within patients with PD, sFLC was the only detectable tumor marker in 12% of cases at the time of the second line of treatment. After four cycles of induction, there was no difference in PFS between VGPR response determined by sFLC, sPEP, and uPEP (p =0.538). The median second-PFS for patients with onlysFLC-PD was similar to those with urine M-protein PD with or without sFLC-PD (HR 1.28, 95% CI =0.77-2.13. p 0.334). However, the median overall survival (OS) from the first relapse was significantly better for patients with onlysFLC-PD than those with urine M-protein PD (HR 1.87, 95% CI =1.07-3.27. p 0.026). Conclusions: In this study, achieving sFLC-VGPR has a similar impact on PFS as electrophoretic-VGPR after induction, indicating that serial sFLC can potentially replace the requirement for urine M-protein response (< 100mg in 24-hours urine) as part of the electrophoretic-VGPR criteria, as required by IMWG. A similar response rate between sFLC and urine paraprotein confirms the current cutoffs (90% for urine and 50% for dFLC for VGPR) used for response categories for s-FLC. We also observed that in 12% of patients with PD, sFLC was the only marker of progression, highlighting the value of serial s-FLC in monitoring relapse. In conclusion, our study supports the integration of serial sFLC measurements for monitoring response and progression in MM, even with electrophoretic measurable disease.