Search

Encouraging results have been reported with sirolimus, tacrolimus and low-dose methotrexate after non-myeloablative allogeneic hematopoietic cell transplant. We conducted a retrospective analysis of 71 patients with lymphoid malignancies treated with this prophylaxis regimen after non-myeloablative or reduced intensity allogeneic hematopoietic cell transplant. Grafts were human leukocyte antigen (HLA)-matched related in 29 (41%), matched unrelated in 36 (51%) and 9/10 HLA-matched unrelated in six (8%) patients. The regimen was well tolerated and over 90% of patients completed the planned treatment. The cumulative incidences of 1-year grade B-D and C-D acute graft-versus-host disease (GVHD) were 0.28 (95% confidence interval [CI], 0.18-0.39) and 0.07 (95% CI, 0.03-0.15), respectively, and of 1- and 2-year chronic GVHD (National Institutes of Health criteria) in 70 evaluable patients were 0.15 (95% CI, 0.08-0.24) and 0.33 (95% CI, 0.22-0.44), respectively. The median day of onset of acute GVHD was 123 days (range, 17-268 days). Peri-transplant rituximab or anti-thymocyte globulin did not affect GVHD. The cumulative incidence of 1-year non-relapse mortality and relapse were 4% and 20%, respectively. With a median follow-up of 3.5 (range: 0.18-5.1) years, overall survival and progression-free survival at 2 years were 82% and 66%, respectively. This GVHD regimen results in a low incidence and severity of acute and chronic GVHD after reduced intensity and non-myeloablative allogeneic hematopoietic cell transplant for lymphoid malignancies. The study also highlights the incidence of late onset acute GVHD in non-myeloablative/reduced intensity conditioning, and the contribution of the new GVHD staging system that more accurately reflects clinical outcomes. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC‐1 study. Cytokines, especially interleukin (IL)‐6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL‐6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL‐6 kinetics profiles were assessed, the mean IL‐6 profile with a maximum concentration (Cmax) of IL‐6 (21 pg/mL) and the IL‐6 profile of the patient presenting the highest IL‐6 Cmax (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC‐1. For the mean IL‐6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87–1.20). For the maximum IL‐6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90–2.23), and minimal for caffeine and s‐warfarin (mean AUC ratios 0.82–1.25). Maximum change in exposure for these substrates occurred 3–4 days after step‐up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL‐6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step‐up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS. [ABSTRACT FROM AUTHOR]

The article presents the discussion on supporting the use of soluble BCMA as a biomarker for tumor burden and treatment response.

Background: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody., Objective: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study., Methods: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection., Results: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from C max in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after T max and a 97% reduction from C max in teclistamab concentration at a median time of 69 days (32-163 days) after T max . Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles., Conclusion: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM., Clinical Trial Registration: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020)., (© 2023. The Author(s).)

Introduction: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation., Methods: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study., Results: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments., Conclusion: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: CARTITUDE-1 is a phase 1b-2 study evaluating ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma. Primary efficacy outcomes have previously been reported. Here, we report health-related quality of life (HRQOL) secondary outcomes evaluated using patient-reported outcomes., Methods: This single-arm, open-label, phwase 1b-2 study was done at 16 centres in the USA. Patients were aged 18 years or older with diagnosis of multiple myeloma and Eastern Cooperative Oncology Group performance status of 1 or less with three or more previous lines of therapy, or were double refractory to a proteasome inhibitor and immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10 6 CAR + T cells per kg) was administered 5-7 days after lymphodepletion. Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core 30-item, pre-specified items from the EORTC myeloma module, and EuroQol five-dimensional descriptive system questionnaire. Clinically meaningful changes in patient-reported outcomes were defined by anchor-based minimally important differences. This trial is registered with ClinicalTrials.gov, NCT03548207. This trial is completed but feeding into a long-term follow-up study., Findings: Between July 16, 2018, and Oct 7, 2019, 78 patients were enrolled and underwent apheresis in phase 2 of the study. 68 patients were treated (43 [63%] male, 49 [72%] White), and their patient-reported outcomes assessed (median follow-up 16·9 months, IQR 15·7-17·5). After infusion, a transient decline was observed, followed by improvements in global health status (mean change from baseline to day 464 +8·0 points, SD 20·9), physical (+4·6 points, 21·1), and emotional functional scales (+1·9 points, 23·7) over time, and declines for symptom-based scores (-14·1 pain, SD 31·5 and -15·4 fatigue; SD 29·5), indicating improved patient HRQOL following treatment with cilta-cel., Interpretation: These durable HRQOL improvements are consistent with clinical findings, in which a single cilta-cel infusion led to substantial and durable responses in heavily pre-treated patients with relapsed or refractory multiple myeloma. These results support the use of cilta-cel in patients with relapsed or refractory multiple myeloma., Funding: Janssen Research & Development and Legend Biotech USA., Competing Interests: Declaration of interest TM receives research funding from Janssen. YL is a consultant for Bluebird Bio, Celgene/BMS, Fosun Kite, Gamida Cells, Iovance, Janssen, Juno/BMS, Kite/Gilead, Legend Biotech, Novartis, Pfizer, Takeda, and Vineti; receives research funding from Bluebird Bio, Celgene/BMS, Janssen, Kite/Gilead, Merck, Takeda Pharmaceuticals, Legend Biotech, and Boston Scientific; and has participated in a data safety monitoring board or advisory board for NexImmune, Pfizer, and Sorrento. ADC reports personal fees from AstraZeneca, Bristol Myers Squibb/Celgene, Genentech/Roche, Janssen, Kite Pharma, Oncopeptides, Seattle Genetics, and Takeda and personal fees and grants from GlaxoSmithKline and Novartis. MH is a current employee of City of Hope Medical Center. AKS receives honoraria from Amgen, Aventis, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Oncopeptides, and Sanofi and serves in a leadership or fiduciary role for Genomics England and Tempus. PH receives consulting fees and honoraria from AbbVie, Bristol Myers Squibb, Celgene, Janssen, Kite, Sanofi Genzyme, Spectrum, and Takeda Pharmaceuticals and receives research funding from Amgen, Bristol Myers Squibb, Celgene, Sanofi Genzyme, and Spectrum. JGB receives research funding from AbbVie, Acetylon, Amgen, Bluebird, Bristol Myers Squibb, Celgene, Cellularity, Constellation, CRISPR Therapeutics, CURIS, Eli Lilly and Company, EMD Serono, Genentech, Glenmark, Janssen, Kesios, Novartis, Poseida, Takeda Pharmaceuticals, Teva, and Vivolux and is a consultant for Amgen, Bioclinica, Bristol Myers Squibb, Celgene, CRISPR Therapeutics, Janssen, Karyopharm, Kite Pharma, Legend, Prothena, SecuraBio, Servier, and Takeda Pharmaceuticals. SZU is a consultant for AbbVie, Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Sanofi, Seattle Genetics, SkylineDX, and Takeda Pharmaceuticals; receives honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, MundiPharma, Pharmacyclics, Sanofi, and Takeda Pharmaceuticals; and receives research funding from Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda Pharmaceuticals. T-MY, YO, JDG, JMS, WD, KSG, JMF, and JJT are employed by Janssen. DM is a consultant for GlaxoSmithKline, Sanofi, Janssen, Celgene, BMS, and Takeda; receives honoraria from GlaxoSmithKline, Sanofi, Janssen, Celgene, BMS, and Takeda; and has received research funding from Janssen. CCJ is employed by Janssen and is a consultant physician at the Memorial Sloan Kettering Cancer Center. MAk and LP are employed by Legend Biotech. AJ receives consulting fees and honoraria from AbbVie, Adaptive, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Juno, Karyopharm, and Sanofi and serves in a leadership or fiduciary role for AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, and Sanofi. SJ is a consultant for Bristol Myers Squibb, Janssen, Karyopharm Therapeutics, Legend Biotech, Merck, Sanofi, and Takeda Pharmaceuticals; participates in a data safety monitoring board or advisory board for DMC; and serves in a leadership or fiduciary role for ASH, IMS, and SOHO. MAg declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma., Methods: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better)., Results: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2)., Conclusions: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.)., (Copyright © 2022 Massachusetts Medical Society.)

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication after allogeneic stem cell transplantation (allo-HCT). However, there is no uniform consensus on the optimal strategy for SOS prevention. Ursodeoxycholic acid is the most used regimen, even though its administration is challenging in recipients unable to tolerate oral medication. Defibrotide was recently studied in a phase 3 trial, but enrollment was stopped early due to futility. Low-dose unfractionated heparin (UFH) is an alternative strategy. However, its efficacy is reputed but unproven increased risk of bleeding has not been fully established. We evaluated 514 adult allo-HCT recipients who received SOS prophylaxis with low-dose UFH. Bleeding complications occurred in 12 patients 2.3% of patients of which only 2 (0.4%) had significant grade 3 bleeding. Only 14 patients were diagnosed with hepatic SOS. Univariate analysis showed that day 100 SOS was higher in recipients of unmodified grafts when compared to CD34+ selected ex vivo T-cell depleted grafts (p ≤ 0.001), and patients with hepatitis B and/or C exposure pre-HCT (p = 0.028). Overall, UFH was well tolerated and associated with a low incidence of subsequent hepatic SOS. Low-dose UFH prophylaxis can be considered in select patients who cannot tolerate oral ursodiol., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple myeloma cells in preclinical studies., Objective: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma., Patients and Methods: To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC 50 and EC 90 values from an ex vivo cytotoxicity assay)., Results: The doses predicted to have average serum concentrations between the EC 50 and EC 90 range were validated. In addition, simulations showed that weekly intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively, resulted in mean trough levels comparable to the maximum EC 90 . The most active doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg subcutaneous doses selected as the recommended Phase II dose (RP2D). With active doses, exposure was maintained above the mean EC 90 . All patients who responded to the RP2D of teclistamab had exposure above the maximum EC 90 in both serum and bone marrow on cycle 3, Day 1 of treatment., Conclusions: Our findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody's therapeutic range., Clinical Trial Registration: NCT03145181, date of registration: May 9, 2017., (© 2022. The Author(s).)