Dingli, David

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset >= 3 days from infusion, CRP<100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

Background: Cytopenias are a common complication of and prolonged (beyond month 3 post CAR-T infusion), severe (grade 3 or higher) cytopenias can be difficult to manage. Stem cell boosts have been reported to restore hematopoiesis; however, stem cells would need to be available prior to CAR-T therapy for potential use post CAR-T. Most lymphoma patients and limited number of myeloma patients may have pre-collected stem cells in storage. Identifying patients at high risk for prolonged and severe cytopenia post CAR-T at the time of CAR-T evaluation (baseline), before leukapheresis, can help identify the patients for coordination of stem cell collection during CAR-T manufacturing and increase the likelihood that the collected stem cells would be used. In this study, we aim to identify clinical variables at the time of CAR-T evaluation, prior to leukapheresis, that are associated with severe cytopenias at month 3 post CAR-T infusion and identify patients who could be considered for pre-emptive stem cell collection prior to CAR-T therapy. Methods: We conducted a retrospective analysis of patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) who received CAR-T products at Mayo Clinic from 01/2016 to 06/2022. Patients with progressive disease in the first year post CAR-T were excluded from the analysis. Baseline (at CAR-T evaluation, prior to leukapheresis) variables were compared between those with and without severe cytopenia at month 3 post CAR-T. Severe cytopenias were defined as hemoglobin (Hg) < 8 g/dL, absolute neutrophil count (ANC) < 0.5 x 10 9/L, and/or platelet count (PLT) < 50 x 10 9/L. Statistically significant variables (p<0.05) by analysis were examined for statistical significance in multivariate analysis (MVA). Results: Among the 166 patients who received CAR-T (88 NHL, 78 MM) during the study period, 31 (18.67%) had a severe cytopenia at month . Twenty baseline variables were examined; HGB, PLT, ANC, and c-reactive protein (CRP) We devised a cytopenia risk score using 1 point each for Hg<10 or PLT<100k at baseline, with a range of 0 to 2. Demographics and clinical outcome by cytopenia risk score is shown in Table 1B. A higher percentage of patients with a score of 1 or 2 had a severe cytopenia at month 3 (Figure 1). In particular, there was a . In addition Conclusion: Baseline cytopenias before leukapheresis may identify patients with increased risk for severe cytopenias at month 3 post CAR-T. These patients can have continued slow hematopoietic recovery in the first year. Stem cell collection, if feasible, could be considered before CAR-T to alleviate post-CAR-T severe prolonged cytopenias.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening, stem cell disorder that renders red blood cells vulnerable to complement-mediated hemolysis. This study describes the health-related quality of life (HRQoL) and symptom-specific functional impairment of patients with PNH in a real-world setting. Methods: US-based adults with PNH treated with a parenterally administered complement inhibitor (PACI) for ≥6 months completed an online, cross-sectional, observational survey; a subset of patients also participated in individual semi-structured qualitative interviews after completing the survey. The survey included the PROMIS® 29+2 Profile v2.1 (PROMIS 29+2) to measure HRQoL. The FACIT Fatigue, Neuro-QOL Item Bank v2.0 Cognitive Function Short Form, and PROMIS Item Bank v1.0 Dyspnea Functional Limitations 10a Short Form measured functional impairment associated with specific symptoms of PNH. For each patient with PNH who completed the online survey, up to 3 age- (+/- 3 years) and sex-matched adults without PNH also completed the survey. The HRQoL and functional impairment of the PNH sample was compared to that of general population (GP) sample using independent samples t-tests or Mann-Whitney tests. To further explore the experiences of patients with PNH, the association between HRQoL/functional impairment and fatigue severity was investigated. Patients with PNH were grouped according to their self-reported fatigue severity over the past 7 days (very mild or mild vs moderate, severe, or very severe [no patients reported no fatigue]). Differences in scores across these 2 groups were tested. Data from the qualitative interviews were coded using thematic analysis to explore key concepts related to HRQoL and impairment due to PNH symptoms. Data collection began in March 2023; results are based on interim data. Results: Demographic characteristics of the study samples (PNH survey sample: N=31, GP survey sample: N=62, PNH interview sample: N=10) are shown in Table 1. Patients were treated for PNH with eculizumab, pegcetacoplan, or ravulizumab, with an average duration of current PACI treatment of 3.4 years. Compared to the age and sex-matched GP sample, patients with PNH had significantly higher median scores on the PROMIS 29+2 fatigue domain (GP: 48.70 vs PNH: 57.10, p=0.041) and PROMIS Dyspnea Functional Limitations short form (GP: 40.70 vs PNH: 48.60, p=0.036), indicating that patients with PNH experience more fatigue and dyspnea limitations than the GP sample. Patients with PNH also had significantly lower median scores on the PROMIS 29+2 ability to participate in social roles/activities domain (GP: 53.50 vs PNH: 44.20, p=0.013), indicating greater role/activity limitations among patients with PNH. Compared to the GP sample, patients with PNH had numerically lower (i.e., worse) median PROMIS 29+2 cognitive functioning domain scores (GP: 50.00 vs PNH: 46.30, p=0.058) and FACIT Fatigue scores (GP: 39.50 vs PNH: 30.00, p=0.057). Within the PNH sample, statistically significant associations (p<0.05) were observed between fatigue severity and HRQoL/functional impairment for all outcomes except for the PROMIS 29+2 sleep disturbance and cognitive functioning domains (Table 2). Patients with more severe fatigue had worse HRQoL and more functional impairment than patients with less severe fatigue. Interview participants described fatigue-related functional impairments in their physical, social, and cognitive functioning. Fatigue made daily activities (e.g., cooking, cleaning, going for a walk) difficult and sometimes impossible. Planning social activities in advance was also challenging as patients could not predict how they would feel on any given day, and often found they had to miss, postpone, or cancel social engagements. Finally, patients described experiencing “brain fog” including difficulty concentrating, forgetfulness, and delayed cognitive processing. Conclusions: Despite receiving treatment for PNH, patients experienced deficits in areas of HRQoL related to fatigue, participation in social roles, cognitive function, and functional limitations due to dyspnea, relative to a sample of GP adults. During follow-up interviews, patients emphasized the deep and broad impacts that fatigue and cognitive functioning had, making daily activities and their social lives very difficult.

Abstract The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n=71), 51 progressed by last follow-up; the MDEs included: bone lesions(37%), anemia(35%), hypercalcemia(8%), and renal failure(6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression(14%), bone pain(20%), and hospitalization/ED presentations due to MM complications/symptoms(4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

European Society for Blood and Marrow Transplantation (EBMT) hematologic response categories comprehensively assess complement inhibitor responses in patients with paroxysmal nocturnal hemoglobinuria (PNH). Using data from the 16-week randomized controlled period of the phase 3 PEGASUS trial (N = 80), we estimated the treatment cost per responder by the EBMT response category for pegcetacoplan and eculizumab in adults with PNH and a suboptimal response to eculizumab. Average drug costs per responder, number needed to treat, and incremental drug costs per responder were estimated using dosages administered during the trial (base case). A US payer perspective (2020 US dollars) was used. Scenario analyses were conducted for various costs, dosages, treatment durations, patient populations, and settings. In total, 30 of 41 (73%) who switched to pegcetacoplan and 2 of 39 (5%) patients who continued eculizumab had a good, major, or complete response (good-to-complete responders) at Week 16. Average weekly drug costs per good-to-complete responder were USD 15,923 with pegcetacoplan and USD 216,100 with eculizumab; average weekly drug costs per patient were USD 11,651 and USD 11,082, respectively. Average drug costs per good-to-complete responder with pegcetacoplan were similar across complement inhibitor-naïve populations and were consistently lower than with eculizumab. Switching from eculizumab to pegcetacoplan allowed more patients with a suboptimal response to attain a good-to-complete response at lower costs. These results apply to patients with a suboptimal response to prior eculizumab treatment only.

Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis, and is associated with high healthcare burden. We evaluated the cost–effectiveness of pegcetacoplan, a proximal complement-3 inhibitor (C3i), compared with the C5i, eculizumab and ravulizumab, in complement treatment-naive adults with PNH, from the US healthcare payer perspective. Materials & methods: A de novo cost–effectiveness model based on a Markov cohort structure evaluated lifetime (55-year) PNH costs and outcomes. The 6-month cycles of the model reflected the follow-up period of PRINCE (NCT04085601), an open-label trial of pegcetacoplan compared with eculizumab in C5i-naive patients. Data from PRINCE informed the clinical, safety and health-related quality of life outcomes in the model. Results: Pegcetacoplan was associated with lifetime cost savings of USD1,176,808 and USD213,062 relative to eculizumab and ravulizumab, respectively (largely attributed to reduced drug costs and blood transfusions), and additional quality-adjusted life years (QALYs) of 0.25 and 0.24. Conclusion: In patients with PNH who are treatment-naive, the base-case cost–effectiveness analysis, scenario analysis and sensitivity analysis showed both lifetime cost savings and increased QALYs associated with pegcetacoplan compared with eculizumab or ravulizumab in the USA.

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 < .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.

Abstract Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6–0.9) years for secondary EMM and 3.6 (95%CI: 2.4–5.6) years for de novo EMM. The median progression‐free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4–3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7–18 months) for de novo EMM. Patients with secondary EMM treated with CAR‐T therapy ( n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months‐not reached; NR). Patients with EMM treated with bispecific antibodies ( n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months‐NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t (4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6–5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1–2], p = .001).