BACKGROUND:Lenalidomide, bortezomib, and dexamethasone (RVD) remains a standard of care regimen for newly diagnosed multiple myeloma in centers without access to upfront anti-CD38 therapy within the Asia-Pacific. However, regimens proven efficacious in clinical trials utilize twice-weekly bortezomib, which is now thought to confer unacceptable toxicity, particularly in transplant-ineligible patients. There is a paucity of prospective data on RVD treatment schedules utilizing weekly bortezomib, which has implications for health care systems implementing standardized treatment based on clinical trial evidence. METHODS:Eighty-three patients with newly diagnosed transplant-ineligible multiple myeloma from six hospitals in Australia, received one of two RVD regimens utilizing weekly subcutaneous bortezomib (Modified SWOG and Modified RVD Lite) pragmatically adapted from their corresponding clinical trials. Baseline characteristics, response rates, toxicities, and survival were assessed. RESULTS:At a median follow-up of 27.4 months, Modified SWOG achieved an ORR 91.4%, ≥ VGPR 71.4%, and 24-month progression-free survival (PFS) of 63.1% (95% CI: 47.6-83.5). Modified RVD Lite achieved an ORR 93.9%, ≥ VGPR 64.7%, and 24-month PFS of 53.6% (95% CI: 39.1-73.4). Despite dose attenuation, significant toxicity was still seen overall with hospitalizations in 48.2% and premature cessation due to toxicity in 31.3%. Peripheral sensory neuropathy was lower than in published clinical trials, reported in 32 (38.6%) patients, with Grade 3 events in only 2 patients. CONCLUSION:This study demonstrates that real-world outcomes of weekly RVD regimens have comparable efficacy to published twice-weekly regimens; however, toxicity remains a significant challenge in this patient population.

CD19-directed chimeric antigen receptor T cell (CAR-T) therapy is now standard of care for relapsed/refractory large B cell non-Hodgkin lymphoma. Despite good overall response rates, many patients still experience disease progression and therefore it is important to predict those at risk of relapse following CAR-T therapy. We performed a prospective study using a flow cytometry assay at a single treatment center to assess early CAR T cell expansion in vivo 6 to 9 days after CAR T cell infusion. Early CAR T cell expansion was used in conjunction with additional clinical risk factors to identify those at greater risk of relapse or treatment failure. Forty-four patients treated with commercial CD19-directed CAR-T therapy were included in the study, with a median follow-up of 306 days. CART cell expansion of >30 cells/mu L was associated with a lower risk of disease progression or death (hazard ratio, 0.34; P = .048), but did not correlate with the risk of death alone. Patients who had poor early CART cell expansion (<30 cells/L) in addition to high lactate dehydrogenase (LDH) had significantly lower median progression- free survival and overall survival. High LDH level alone was not a statistically significant risk factor for death or disease progression, and thus the interaction between CAR T cell expansion and this clinical risk factor may be important in predicting response. The mean CAR T cell count was higher in patients with grade 2 to 4 cytokine release syndrome (CRS) compared to those with grade 0 to 1 CRS (54.9 cells/mu L versus 25.5 cells/mu L; P = .01). The methodology of this assay is easily reproducible outside of a clinical trial, allowing for real-life implementation in clinical settings. This study suggests that early assessment of CAR T cell expansion can assist in identifying patients with poor overall survival who may benefit from early intervention or more intensive monitoring. (c) 2025 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

CD19 directed chimeric antigen receptor (CAR) T-cell therapy is now standard of care for relapsed/refractory large B-cell non-Hodgkin lymphoma. Despite good overall response rates, many patients still experience disease progression and therefore it is important to predict those at risk of relapse following CAR T-cell therapy. We performed a prospective study using a flow cytometric assay at a single treatment centre to assess early CAR T-cell expansion in vivo 6 – 9 days after CAR-T cell infusion. Early CAR T-cell expansion was used in conjunction with additional clinical risk factors to identify those at higher risk of relapse or treatment failure. Forty-four patients treated with commercial CD19 directed CAR T-cell therapy were included in the study, with a median follow up of 306 days. CAR T-cell expansion of >30 cells/μl was associated with a lower risk of disease progression or death (HR 0.34, p=0.048), but did not correlate with the risk of death alone. Patients who had poor early CAR T-cell expansion (<30 cells/μl) in addition to high lactate dehydrogenase (LDH) had significantly lower median progression-free and overall survival. High LDH alone was not a statistically significant risk factor for death or disease progression and therefore the interaction between CAR T-cell expansion and this clinical risk factor may be important in predicting response. Mean CAR T-cell count was higher in patients with grade 2-4 cytokine release syndrome (54.9 cells/μl) compared to grades 0-1 (25.5 cells/μl, p = 0.01). The methodology of this assay is easily reproducible outside of a clinical trial, allowing for real-life implementation within clinical settings. This study suggests that early assessment of CAR T-cell expansion can assist in identifying patients with poor overall survival who may benefit from early intervention or more intensive monitoring.

The survival of newly diagnosed patients with multiple myeloma has improved significantly over the past 20 years with significant therapeutic advances. Despite this, high-dose chemotherapy followed by autologous stem cell transplantation remains the standard of care in newly diagnosed patients who are considered transplant eligible. Here, we summarise the recommendations of the Medical and Scientific Advisory Group of Myeloma Australia for patients considered suitable for high-dose chemotherapy and autologous stem cell transplantation as part of the initial therapy.

The utility of serum free light chain measurements (SFLC) to predict renal outcome, to optimize prognosis and avoid dialysis, was investigated in myeloma patients with renal impairment treated with carfilzomibdexamethasone. We found a significant correlation between the change in involved SFLC at Cycle 2 with renal function, from which a threshold to change therapy is proposed to avoid suboptimal outcome. Disease response and survival were favorable but there was significant toxicity including cardiac impairment and infections. Background and Purpose: Renal impairment (RI) confers adverse prognosis in myeloma; its reversal and avoidance of dialysis are crucial. We investigated whether serum free light chain (SFLC) measurements can predict renal outcome, to enable change in therapy to optimize prognosis and avoid dialysis. Patients and Methods: We investigated 36 myeloma patients (17 newly diagnosed [ND]; 19 relapsed refractory [RR]; with median of 5 prior lines) with eGFR 15-40 ml/min treated with carfilzomib (Cfz)-dexamethasone to determine whether SFLC kinetics can predict renal outcomes, and assess efficacy and tolerability. Results: The change in involved SFLC at Cycle 2 Day 1 was significantly correlated with renal function; for every one log10 reduction in involved SFLC, eGFR increased by 9.0-15.0 mL/min at cycles 2-4, with SFLC reduction of 54%-78%. At a median follow-up of 30.6 months, renal outcomes were favorable-CRrenal 25%, MRrenal 36%. Disease responses (ND 100%, RR 75%), progression-free survival (ND 32.2 months, RR 11.1 months) and overall survival (ND not reached, RR 42.0 months) were comparable to patients without RI. There was significant toxicity, including Cfz-related cardiac impairment of 20% within a cohort with high co-morbidity, and a high incidence of infections. Conclusion: We propose that one log10 reduction in involved SFLC at Cycle 2 Day 1 is an appropriate target for reducing the risk of dialysis in myeloma patients with RI; below this threshold patients may benefit from a change in therapy. While Cfz-dexamethasone achieved favorable renal and disease outcomes, toxicity can be significant in this vulnerable cohort.

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.

Multiple myeloma (MM) is an incurable disease of the bone marrow (BM) characterized by the uncontrolled proliferation of neoplastic plasma cells. While CD8+ T cells have an established role in disease control, few studies have focused on these cells within the MM tumor microenvironment (TME). We analyzed CD8+ T cells in the BM and peripheral blood (PB) of untreated patients with MM and non-myeloma controls using flow cytometry, mass cytometry and single-cell RNA sequencing, using several novel bioinformatics workflows. Inter-tissue differences were most evident in the differential expression of Granzymes B and K, which were strongly associated with two distinct subsets of CD8+ T cells delineated by the expression of CD69, accounting for roughly 50% of BM-CD8+ T cells of all assessed cohorts. While few differences were observable between health and disease in the BM-restricted CD8CD69+ T-cell subset, the CD8+CD69- T-cell subset in the BM of untreated MM patients demonstrated increased representation of highly differentiated effector cells and evident compositional parallels between the PB, absent in age-matched controls, where a marked reduction of effector cells was observed. We demonstrate the transcriptional signature of BM-CD8+ T cells from patients with MM more closely resembles TCR-activated CD8+ T cells from age-matched controls than their resting counterparts.

thrombopoietic growth factors and platelet transfusion.Conclusions: We analyzed the factors affecting thrombocytopenia in RRMM patients after anti BCMA CAR -T treatment and developed for the first time a predictive model for prolonged thrombocytopenia recovery.Prolonged thrombocytopenia may occur in patients with low bone marrow reserve and high tumor burden.

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Commercial autologous CD19 directed chimeric antigen receptor (CAR) T-cell therapy is an established therapy for relapsed/refractory large B-cell lymphomas. CAR T-cell expansion and persistence in vivo correlates with clinical response in some clinical trials. To date, measuring CAR T-cell expansion lacks consistency between labs and has been challenging to routinely perform outside of clinical trials. The value of measuring expansion with a readily available rapid assay at the centre of delivery is unclear. Aims: To evaluate and quantify by flow cytometry the in vivo CAR T-cell expansion (including CD4+ CAR T-cells and CD8+ CAR T-cells) and expression of PD1, TIGIT and CD69 on CAR T-cells in patients treated with tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) and correlate this with clinical outcomes. Methods: Patients with relapsed/refractory large B-cell lymphoma treated with axi-cel or tisa-cel from August 2021 to December 2022 at our institution had peripheral blood collected between D7 to D14 post CAR-T cell infusion. Samples were analysed with an eight colour flow cytometry panel containing antibodies to FMC63, CD3, CD4, CD8, CD45, CD69, PD1 and TIGIT. The anti-FMC63 antibody specifically recognises the antigen-recognition domain of FMC63 found on commercial CD19 directed CARs and allows CAR T-cells to be separated from normal T-cell populations. Data was collected via BD FACS Canto II cytometer and analysed using FlowJo (BD Life Sciences). Statistical analysis was via GraphPad PRISM. Results: 20 patients were identified as suitable for analysis. The mean absolute CAR T-cell count was 36 x106/µL of which 21.3 x106/µL were CD4+ and 16 x106/µL were CD8+ suggesting a predominance of CD4+ CAR T-cells over CD8+. CAR T-cells represented on average 4.5% of total cells, with CD4+ being 2.4% and CD8+ being 2.1%. The median CAR T count for axi-cel was 49x106/µL with tisa-cel 37.9 x106/µL suggesting this assay is suitable for both products. CAR T-cell expansion of ≥2% of total leukocytes was associated with a trend to higher progression free survival (PFS) with a sustained complete remission rate of 80%. TIGIT or CD69 expression levels on either CD4+ or CD8+ CAR T-cells were not associated with a significant difference in response rates. Higher expression of PD1 on CD8+ CAR T-cells trended towards improved PFS.Summary/Conclusion: Quantification and immunophenotypic characterisation of CAR T-cells is accessible and feasible in a treatment centre outside of a clinical trial setting. Early data suggests an improved overall response rate with increased CAR T-cell absolute number and percentage of leukocytes. There is a trend to improved PFS with higher expression of PD1 on CD8+ CAR T-cells. These findings should be explored further in a larger cohort of patients. Keywords: Immunotherapy, Diffuse large cell lymphoma, CAR-T

Background: Autologous CAR T-cell therapies have altered the treatment landscape for many patients (pts) with advanced B-cell malignancies, however custom manufacturing precludes prompt treatment and can result in manufacturing failure. T-cell mediated toxicities are common and can be severe, thereby limiting the population of eligible pts. These challenges limit CAR T-cell therapy administration to certified treatment centers, further restricting patient access. NKX019 is a cryopreserved, allogeneic CD19-targeting CAR NK-cell therapy, derived from healthy donor NK cells, with CD3 zeta and OX40 costimulatory domains and a separate membrane bound IL-15 for activation. NKX019 has shown encouraging in vitro and in vivo cytotoxicity. Development of an on demand allogeneic NK-cell therapy may address challenges associated with CAR-T therapy. Methods: This is an open label, phase 1 trial (NCT05020678) for adults with r/r B-cell malignancies with ≥2 prior lines of therapy excluding prior auto CD19 CAR T-cell therapy. Following 3 days of lymphodepletion (LD) with fludarabine and cyclophosphamide, pts received NKX019 at 3 dose levels (3 × 108, 1 × 109, or 1.5 × 109 CAR+ NK cells/dose on days 0, 7, and 14 of a 28-day cycle). Additional cycles were allowed to deepen response. Tolerability, anti-tumor activity, cellular kinetics, and immune responses were evaluated. Results: As of November 2022, 19 pts in the US and Australia with r/r B-cell malignancies (14 with non-Hodgkin lymphoma (NHL) (LBCL, FL, MZL, or MCL) and 5 with leukemia (ALL or CLL)) received NKX019. Median age was 59 years (range 21–82), with median 4 prior lines of therapy. RP2D of 1.5 × 109 cells was determined. Grade 3/4 hematologic toxicity was 84%, consistent with expected myelosuppression related to LD. There was one grade 3 infection. There were no treatment related AEs leading to discontinuation of NKX019. No dose limiting toxicities, neurotoxicity, or GvHD were reported. Five of 19 pts (26%) developed transient fever within 8 hours of NKX019 dosing, but no pts developed signs of cytokine release syndrome beyond 24 hours after cell infusion. Responses for pts with NHL were as follows: 2 out of 4 (3 × 108 dose level), 5 out of 6 (1 × 109 dose level) and 3 out of 4 (1.5 × 109 dose level). Of the 8 patients who achieved CR, 3 with indolent lymphoma subsequently relapsed, each after more than 6 months of remission. One pt with CLL had stable disease. Pharmacokinetic data showed a correlation between higher cell doses and higher peak concentration (Cmax), with a trend toward higher Cmax in pts achieving CR. No association was observed between clinical response and elevation of serum cytokines. Encore Abstract - previously submitted to EHA 2023 Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Ongoing Trials Conflicts of interests pertinent to the abstract. M. Dickinson Consultant or advisory role: AbbVie, BMS, Gilead, Novartis, Roche; Janssen; Genmab Honoraria: Roche; Amgen; Janssen; BMS; Novartis; Gilead; Abbvie Research funding: Celgene; Gilead, Novartis, Roche; Takeda; Lilly; MSD Educational grants: Roche N. Hamad Consultant or advisory role: Novartis C. E. Bryant Consultant or advisory role: Janssen, BMS/Celgene, Skyline Diagnostics, Antengene Honoraria: Amgen N. Kothari Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics P. Ojeras Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics A. Vohra Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics M. Lin Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics M. Tohme Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics J. Trager Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics D. Shook Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics B. T. Hill Consultant or advisory role: Novartis; Epizyme; AstraZeneca; Beigene; Kite; Pfizer; Karyopharm; Incyte; Genentech; Celgene; AbbVie Honoraria: Novartis; Epizyme; AstraZeneca; Beigene; Kite; Pfizer; Karyopharm; Incyte; Genentech; Celgene; AbbVie Research funding: Novartis; Beigene; Kite; Karyopharm; Incyte; Genentech; Celgene; AbbVie Educational grants: Kite

disease, cfDNA was more sensitive compared to CRC, with DM detectable in cfDNA in 3 patients in a CR.cfDNA assessment also outperformed MRD testing, with 40% of MRD negative timepoints demonstrating cfDNA positivity.Importantly, changes in VAF were prognostic.Patients achieving cfDNA negativity had the longest remissions (median 23.5 months) whereas those who did not demonstrated short time to progression (median 6 months).In 2 patients who experienced EMD relapse from cfDNA negativity, cfDNA became positive prior to overt relapse by PET/CT, CRC, or BM MRD.Finally, DM were detectable in cfDNA prior to the initial development of EMD, in one case two years before EMD diagnosis.Liquid biopsies from an additional 24 patients are being analysed.Conclusions: In EMD patients MAPK activating DM are detectable in cfDNA.cfDNA is complementary to PET/ CT scanning, more sensitive than BM MRD and CRC, and is a predictor of EMD relapse.DM exist in cfDNA prior to EMD, and their detection may allow tailored monitoring strategies and early intervention.

Internal Medicine JournalVolume 52, Issue 4 p. 693-694 Letter to the Editor Hyperammonaemic encephalopathy John D. Chetwood, John D. Chetwood johnchetwood@doctors.org.uk orcid.org/0000-0002-8947-9817 A W Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorDavid Koorey, David Koorey A W Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorChristian Bryant, Christian Bryant Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia The Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this author John D. Chetwood, John D. Chetwood johnchetwood@doctors.org.uk orcid.org/0000-0002-8947-9817 A W Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorDavid Koorey, David Koorey A W Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia Sydney Medical School, University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorChristian Bryant, Christian Bryant Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia The Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, AustraliaSearch for more papers by this author First published: 13 April 2022 https://doi.org/10.1111/imj.15738Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume52, Issue4April 2022Pages 693-694 RelatedInformation

We describe a case of truncal sensory polyneuropathy in a patient with light-chain amyloidosis. We highlight the clinical signs and differential diagnoses related to the presentation.

The current landscape of multiple myeloma treatment has greatly improved outcomes for the majority of patients and includes proteasome inhibitors, immunomodulatory imide drugs, and more recently, a number of monoclonal antibodies. However, there remains a proportion of patients that possess inherent resistance and fail to achieve optimal responses to these treatments. To overcome this problem, the continued research into and development of novel therapies is needed with the hope of further improving outcomes for all MM patients. This chapter will discuss novel targeted therapies currently being evaluated for the treatment of MM including antibody therapies, cellular therapies, and small-molecule inhibitors.