"Fast but not so furious": A condensed step-up dosing schedule of teclistamab for relapsed/refractory multiple myeloma.

Teclistamab is a B-cell maturation antigen (BCMA)-directed bispecific T-cell engager approved for relapsed-refractory multiple myeloma (RRMM). Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) are well-documented treatment -related adverse events of teclistamab. The prescribing information recommends step-up dosing on days 1, 4, and 7 with 48-72 h of inpatient observation after each dose to monitor for CRS. This leads to a more than weeklong hospital stay, adding to the cost of therapy, resource utilization, and patient inconvenience. Here, we present a single center retrospective analysis addressing the safety and utility of a condensed step-up dosing schedule for teclistamab. All patients who were treated with teclistamab from November 2022 to August 2023 at the Medical University of South Carolina were included in the analysis. Patients received subcutaneous (SC) teclistamab with step-up doses (0.06 and 0.3 mg/kg) separated by either 2 or 3 (48-72 h) before the administration of the first full (1.5 mg/kg) dose (days 1, 3, and 5 'condensed' schedule or days 1, 4, and 7 'standard' schedule, respectively). All patients were hospitalized for the two step-up doses and first full dose of teclistamab and received pre-medications prior to each dose. Patients could be discharged after a minimum of 24 h following the full dose, if they did not have any CRS or ICANS. Relevant data regarding incidence, severity, and onset of CRS was collected. Statistical analysis was completed to assess the probability of fever with the first full dose of teclistamab based on incidence of fever with previous doses. A total of 25 patients were included in the analysis. Twenty-eight percent (7/25) of patients underwent the standard step up while the remaining 72% (18/25) underwent a condensed step up of teclistamab. More than half (53%, 13/25) of the patients experienced CRS during step up dosing. Grades 1 and 2 CRS occurred in 48% (12/25) and 4% (1/25) patients, respectively. Of the 13 patients that experienced CRS, 30% (4/13) fevered with the first dose, 84% (11/13) fevered with the second dose, and one patient developed fever after the third dose. The negative predictive value of being 'fever free' after doses 1 and 2 and remaining 'fever free' throughout hospitalization was 0.92. The median length of hospital stay among the 1, 3, and 5 step up group was 6 days (6-25) and 70% (14/20) of patients were discharged from the hospital within 7 days of treatment initiation. This report demonstrates the utility of a condensed step-up schedule for teclistamab initiation. The schedule was found to be safe and reduced hospital length of stay. These results should prompt consideration of shorter hospital stays for patients who do not experience CRS and raise the possibility of outpatient administration with close observation.

Early de-escalation of antibiotic therapy in hospitalized cellular therapy adult patients with febrile neutropenia.

Febrile neutropenia (FN) is an oncologic emergency frequently encountered in hematopoietic cell transplant (HCT) and chimeric antigen receptor (CAR) T-cell therapy patients, which requires immediate initiation of broad-spectrum antibiotics. Data regarding antibiotic de-escalation (DE) in neutropenic patients are limited, and guideline recommendations vary. A clinical protocol for antibiotic DE of broad-spectrum agents was implemented if patients were afebrile after 72 hours and had no clinical evidence of infection. The primary endpoint was the difference in the number of antibiotic therapy days between the pre-and post-DE protocol implementation group. Secondary endpoints included rates of subsequent bacteremia during index hospitalization, 30-day mortality, and hospital length of stay. Retrospective chart reviews were conducted to assess outcomes for patients who received allogeneic HCT, autologous HCT, or CAR T-cell therapy under the antibiotic de-escalation protocol (post-DE) compared to those who did not (pre-DE). The pre-DE group underwent HCT/CAR T-cell from February 2018 through September 2018 (n=64), and the post-DE group from February 2019 through September 2019 (n=67). The median duration of antibiotics was significantly lower in the post-DE group (6 days; range 3-60 days) compared to the pre-DE group (8 days; range 3-31 days) (p=0.034). There were no differences in any secondary endpoints. We conclude that antibiotic DE in neutropenic HCT or CAR T-cell therapy patients treated with broad-spectrum antibiotics for at least three days who are afebrile and without documented infection appears to be a safe and effective practice. Adopting it significantly reduces the number of days of antibiotics without compromising patient outcomes.

Impact of age, obesity, and renal impairment on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

INTRODUCTION: There remains a need to determine whether certain subgroups of newly diagnosed multiple myeloma (NDMM) derive the same benefit from high-dose chemotherapy-autologous stem cell transplant (HDT-ASCT). We describe our institutional experience highlighting the impact of age, obesity, and renal impairment on outcomes after HDT-ASCT for patients with NDMM in a real-world setting. METHODS: A total of 449 consecutive patients were included in this retrospective analysis. RESULTS: No difference in median progression free survival or overall survival was seen for patients with age > 65, body mass index (BMI) > 30 kg/m2, or estimated glomerular filtration rate < 60 mL/min/1.73 m2 when compared to those without these characteristics. From a safety standpoint, there were no differences in the incidence of transplant-related mortality or secondary malignancy among subgroups. CONCLUSION: For patients with NDMM undergoing HDT-ASCT, there is no difference in outcomes based on age, BMI, or renal function, and the presence of one or more of these factors should not preclude patients from HDT-ASCT.

Impact of race and ethnicity on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

Non-Hispanic Black patients are disproportionally affected by multiple myeloma (MM) and whether efficacy outcomes after autologous stem cell transplant (ASCT) differ by race and ethnicity remains an area of active investigation. This study included 449 patients enriched with a large proportion of non-Hispanic Black patients and sought to highlight the impact of race and ethnicity on outcomes after HDT-ASCT for patients with newly diagnosed MM. We found induction chemotherapy followed by high-dose therapy-ASCT and maintenance chemotherapy is associated with long-term PFS and OS, regardless of race or ethnicity.

Early versus standard management of chimeric antigen receptor therapy toxicities and management's impact on safety and efficacy.

BACKGROUND: Cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS) are well-documented toxicities of CAR T-cell therapy. To mitigate excessive toxicity, our center has formulated treatment protocols (early vs. standard) for timely management of CRS and ICANS with tocilizumab and/or corticosteroids. METHODS: This retrospective, single-center analysis included patients treated with CAR T-cell therapy. The goal was to describe the association of two management protocols with toxicity and efficacy outcomes. RESULTS: Fifty-five percent of the 40 patients assigned to early management, out of which 5% and 9% developed grade 3+ CRS and ICANS, respectively. Seventy-seven percent and 41% of these patients received tocilizumab and corticosteroids, respectively. Forty-five percent of patients were stratified as standard management, out of which 0% and 11% developed grade 3+ CRS and ICANS, respectively. Seventeen percent and 28% of these patients received tocilizumab and corticosteroids, respectively. The day +90 overall response rate (ORR) for all patients was 63%, with an ORR of 89% for those managed per early management versus 50% for those managed per standard protocol. CONCLUSION: Early use of tocilizumab and corticosteroids is effective in preventing excessive CAR-T-related toxicities with no negative impact on efficacy.

Solution phase high repetition rate laser pump x-ray probe picosecond hard x-ray spectroscopy at the Stanford Synchrotron Radiation Lightsource.

We present a dedicated end-station for solution phase high repetition rate (MHz) picosecond hard x-ray spectroscopy at beamline 15-2 of the Stanford Synchrotron Radiation Lightsource. A high-power ultrafast ytterbium-doped fiber laser is used to photoexcite the samples at a repetition rate of 640 kHz, while the data acquisition operates at the 1.28 MHz repetition rate of the storage ring recording data in an alternating on-off mode. The time-resolved x-ray measurements are enabled via gating the x-ray detectors with the 20 mA/70 ps camshaft bunch of SPEAR3, a mode available during the routine operations of the Stanford Synchrotron Radiation Lightsource. As a benchmark study, aiming to demonstrate the advantageous capabilities of this end-station, we have conducted picosecond Fe K-edge x-ray absorption spectroscopy on aqueous [FeII(phen)3]2+, a prototypical spin crossover complex that undergoes light-induced excited spin state trapping forming an electronic excited state with a 0.6-0.7 ns lifetime. In addition, we report transient Fe Kß main line and valence-to-core x-ray emission spectra, showing a unique detection sensitivity and an excellent agreement with model spectra and density functional theory calculations, respectively. Notably, the achieved signal-to-noise ratio, the overall performance, and the routine availability of the developed end-station have enabled a systematic time-resolved science program using the monochromatic beam at the Stanford Synchrotron Radiation Lightsource.

Newly approved and forthcoming T-cell-redirecting bispecific antibodies for the treatment of relapsed/refractory multiple myeloma.

OBJECTIVE: Summarize the background, clinical trials, and place in therapy for the newly Food and Drug Administration (FDA) approved and forthcoming bispecific antibodies for relapsed/refractory (R/R) multiple myeloma. DATA SOURCES: A search of the PubMed database was conducted using the following search terms: B-cell maturation antigen (BCMA), teclistamab, myeloma, BsAbs, GPRC5D, and bispecific. Ongoing clinical trials as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents were evaluated. Prescribing information was also reviewed. SUMMARY: For patients with R/R multiple myeloma who have failed available therapies, treatment options are limited and survival is short. The FDA recently approved teclistamab, a T-cell-redirecting bispecific antibody, in patients with R/R multiple myeloma who have failed four prior lines of therapy. Teclistamab targets both CD3 expressed on T-cells and BCMA expressed on the surface of myeloma cells, mediating T-cell activation and lysis of plasma cells that express BCMA. Accelerated approval was granted based upon the results of the MajesTEC-1 study, which showed a durable response in a high proportion of heavily pretreated patients. Teclistamab is the first bispecific antibody approved for use in patients with multiple myeloma and the fourth approved agent targeting BCMA. Additional T-cell redirecting bispecific antibodies for use in multiple myeloma are also currently being studied. CONCLUSION: Teclistamab is the newest agent granted FDA approval for use in R/R multiple myeloma and represents a promising new option for patients. Ongoing trials are investigating teclistamab and other novel bispecific antibodies in the upfront and R/R setting.

Prophylactic Trimethoprim-Sulfamethoxazole for Allogeneic Hematopoietic Stem Cell Transplant Recipients During the Pre-engraftment Period.

BACKGROUND: Our institution has used trimethoprim-sulfamethoxazole (TMP-SMX) as the antibacterial agent of choice for infection prophylaxis during the pre-engraftment period in the allogeneic transplant (allo-HCT) population. METHODS: This retrospective, single center study was developed to compare the safety of that antibacterial prophylaxis to fluoroquinolones in allo-HCT. The primary endpoint was time to neutrophil engraftment. RESULTS: A total of 366 patients were reviewed (TMP-SMX n = 332, fluoroquinolone n = 34). No difference in days to neutrophil engraftment was found (median 15 versus 16 days, p = 0.62). Hyperkalemia was more common in the TMP-SMX cohort (32.2% versus 14.7%, p = 0.035); this did not contribute to a higher rate of agent discontinuation or arrhythmia. There was no significant difference in the incidence of neutropenic fever; however, those in the TMP-SMX cohort were more likely to have microbiologically confirmed bacteremia (24.1% versus 8.8% respectively, p = 0.043). There was no significant difference in infections. No long-term implication of prophylactic antibacterial agent selection was observed in terms of graft-versus-host-disease, underlying disease relapse, or mortality. CONCLUSION: The use of TMP-SMX was associated with a higher likelihood of bacteremia and hyperkalemia; however, this did not result in increased hospital stay, escalation of care, or mortality. The use of TMP-SMX for prophylaxis during the pre-engraftment period for allo-HCT recipients is safe and effective.

Fever Characteristics and Impact on Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy.

BACKGROUND: Fever is a hallmark symptom of cytokine release syndrome (CRS) after chimeric antigen receptor (CAR) T-cell therapy. Fever characteristics and the impact of fever on safety and efficacy post CAR T are not well understood. We sought to explore the impact of fever and its characteristics on safety and efficacy post CAR T-cell therapy. PATIENTS AND METHODS: We reviewed 40 patients with various hematologic malignancies (non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma) treated with CAR T-cell therapy between March 2019 and March 2022. We evaluated all patients who developed fever after CAR T infusion and analyzed the association of fever with toxicity (CRS and neurotoxicity) and efficacy (overall response (ORR) and complete response (CR) at day +90 post CAR T infusion). Fever was defined as per Lee criteria (equal to or greater than 38°C). CRS and immune-effector cell associated neurotoxicity syndrome (ICANS) were graded using American Society for Transplantation and Cellular Therapy grading system. RESULTS: Fever occurred in 75% (30/40) of patients. Rates of all grade and grade 3+ CRS and ICANS were 75%, 2%, 33% and 10%, respectively. Fever occurred within 24 and 72 hours after CAR T infusion in 40% and 53% of patients, respectively. Fifty percent of patients received tocilizumab (toci) for CRS. After the first dose of toci, fever recurred in 38% of the patients, of which 67% had recurrence within 24 hours. Day +90 CR rates were 43% and 10% in patients with and without fever, respectively (Table 3). CONCLUSION: While fever is common after CAR T-cell therapy, early-onset and higher magnitude do not appear to affect safety or efficacy of CAR T. Absence of fever may affect response to CAR T.

Impact of Cytogenetic Abnormalities, Induction and Maintenance Regimens on Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: A Decade-Long Real-World Experience.

Background: High-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) has become a standard of care for transplant eligible newly diagnosed multiple myeloma (NDMM) patients. While cytogenetic abnormalities have been shown to affect outcomes after HDT-ASCT in clinical trials, these trials often exclude or underrepresent elderly patients with comorbidities and those belonging to ethnic minorities. We describe our institutional experience highlighting the impact of high-risk cytogenetic abnormalities (HRCAs) on outcomes after HDT-ASCT for NDMM patients. Methods: A total of 449 patients with NDMM who underwent HDT-ASCT between February 2012 and August 2022 were included in this retrospective analysis. HRCAs included the presence of one or more of: deletion 17p, t(14;16), t(4;14), and amplification 1q. Survival analyses, including progression-free survival (PFS) and overall survival (OS), were performed using Kaplan-Meier estimator. Results: With a median follow-up of 29 (1 - 128) months for the entire patient population, the best overall response rate for the patients with HRCAs was lower compared to those with standard risk cytogenetics (90% vs. 96%; P = 0.01). Patients with HRCAs had an inferior PFS compared to patients with standard-risk cytogenetics (29 vs. 58 months; P < 0.001) without a difference in OS (70 months vs. not reached; P = 0.13). Conclusions: In a multivariable analysis adjusting for factors including age, race, and comorbidities, HRCAs, non-lenalidomide-based maintenance, non-proteasome inhibitor-based maintenance, and age greater than 65 were associated with inferior PFS. Amongst these factors, only non-lenalidomide-based maintenance was associated with inferior OS.

Safety and tolerability of lenalidomide maintenance dosing in patients with multiple myeloma post-autologous stem cell transplant.

BACKGROUND: For transplant-eligible newly diagnosed multiple myeloma patients, autologous hematopoietic stem cell transplant followed by maintenance lenalidomide is a standard of care practice. Maintenance lenalidomide dosing practices vary amongst physicians and current literature lacks comparisons on intermittent versus continuous dosing. In this retrospective study, we compared the safety, tolerability, and efficacy of continuous versus intermittent lenalidomide dosing. METHODS: This single-center, retrospective review included 72 patients with multiple myeloma receiving lenalidomide maintenance between 2018 and 2021. The primary objective was to determine the incidence of dose modification, defined as any dosage reduction, delay in treatment, or discontinuation of therapy. The secondary objectives were to determine the incidence of hematological and non-hematological toxicities between the two groups. RESULTS: A total of 58 patients in the continuous group and 14 patients in the intermittent group were included. Fifty-four percent of patients in the continuous group required dose modification versus 30% in the intermittent group. Patients who received continuous dosing appeared to have a higher incidence of adverse events when compared to intermittent dosing with the most common adverse events being neutropenia, fatigue, and rash. Twenty-four patients in the continuous group switched to an intermittent schedule after an adverse event. Of these patients, only 8% required further dose modification. CONCLUSION: The higher incidence of lenalidomide dose modifications in the continuous arm suggests that a majority of patients are not able to tolerate continuous lenalidomide maintenance. A more tolerable option for maintenance may be an intermittent schedule, as reflected by the favorable safety outcomes in this group.

Toxicity analysis of busulfan pharmacokinetic therapeutic dose monitoring.

Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided therapeutic drug monitoring of busulfan for myeloablative conditioning regimens. The objective was to compare toxicity of intravenous busulfan before and after therapeutic drug monitoring implementation. The primary endpoint was incidence of hepatotoxicity. Medical records were retrospectively reviewed with weight-based dose Busulfan/Cyclophosphamide (BuCy) conditioning from August 2017 through March 2018 (N = 14) and therapeutic drug monitoring from April 2018 through December 2018 (N = 22). Recipients of busulfan therapeutic drug monitoring were younger than those receiving weight-based dose (median: 45 vs. 58 years, p = 0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between therapeutic drug monitoring and weight-based dose (median 1 vs. 0 days, p = 0.40). In the therapeutic drug monitoring group, 45% of patients had increases and 41% had decreases in busulfan dose after Bu1. Repeat pharmacokinetic after Bu2 were required in 32% of patients. A pharmacokinetic dose monitoring program for myeloablative conditioning intravenous busulfan regimens may be considered a safe practice in stem cell transplant recipients. The majority of patients receiving pharmacokinetic-guided therapeutic drug monitoring required dose changes and therapeutic drug monitoring patients had no significant difference in toxicity compared to those receiving weight-based dose.

Reduction of Electron Repulsion in Highly Covalent Fe-Amido Complexes Counteracts the Impact of a Weak Ligand Field on Excited-State Ordering.

The ability to access panchromatic absorption and long-lived charge-transfer (CT) excited states is critical to the pursuit of abundant-metal molecular photosensitizers. Fe(II) complexes supported by benzannulated diarylamido ligands have been reported to broadly absorb visible light with nanosecond CT excited state lifetimes, but as amido donors exert a weak ligand field, this defies conventional photosensitizer design principles. Here, we report an aerobically stable Fe(II) complex of a phenanthridine/quinoline diarylamido ligand, Fe(ClL)2, with panchromatic absorption and a 3 ns excited-state lifetime. Using X-ray absorption spectroscopy (XAS) and resonant inelastic X-ray scattering (RIXS) at the Fe L-edge and N K-edge, we experimentally validate the strong Fe-Namido orbital mixing in Fe(ClL)2 responsible for the panchromatic absorption and demonstrate a previously unreported competition between ligand-field strength and metal-ligand (Fe-Namido) covalency that stabilizes the 3CT state over the lowest energy triplet metal-centered (3MC) state in the ground-state geometry. Single-crystal X-ray diffraction (XRD) and density functional theory (DFT) suggest that formation of this CT state depopulates an orbital with Fe-Namido antibonding character, causing metal-ligand bonds to contract and accentuating the geometric differences between CT and MC excited states. These effects diminish the driving force for electron transfer to metal-centered excited states and increase the intramolecular reorganization energy, critical properties for extending the lifetime of CT excited states. These findings highlight metal-ligand covalency as a novel design principle for elongating excited state lifetimes in abundant metal photosensitizers.

Capturing photochemical and photophysical transformations in iron complexes with ultrafast X-ray spectroscopy and scattering.

Light-driven chemical transformations provide a compelling approach to understanding chemical reactivity with the potential to use this understanding to advance solar energy and catalysis applications. Capturing the non-equilibrium trajectories of electronic excited states with precision, particularly for transition metal complexes, would provide a foundation for advancing both of these objectives. Of particular importance for 3d metal compounds is characterizing the population dynamics of charge-transfer (CT) and metal-centered (MC) electronic excited states and understanding how the inner coordination sphere structural dynamics mediate the interaction between these states. Recent advances in ultrafast X-ray laser science has enabled the electronic excited state dynamics in 3d metal complexes to be followed with unprecedented detail. This review will focus on simultaneous X-ray emission spectroscopy (XES) and X-ray solution scattering (XSS) studies of iron coordination and organometallic complexes. These simultaneous XES-XSS studies have provided detailed insight into the mechanism of light-induced spin crossover in iron coordination compounds, the interaction of CT and MC excited states in iron carbene photosensitizers, and the mechanism of Fe-S bond dissociation in cytochrome c.