bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy profile of a very low dose of MC-1-50 for treatment of r/r NHL.
Authors: Li Shiqi , Yang Zhi , Liu Lin , Yuan Zhongtao , Zhang Yingzi , Luo Le , Zhang Lihua , Chen Yingnian , Zhang Qianzhen , Shen Junjie , Li Yunyan , Wang Linling , Wang Meiling , Zhu Wei , Huang Yufeng , Wang Youcheng , Dong Yancheng , Wang Sanbin , Qian Cheng
Published: June 2023

7553

Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-NHL. However, many patients fail to respond, or quickly relapse after the initial response. To improve efficacy, we established a novel PrimeCAR platform (PRIMCAR) that shortens the manufacture time to about 2 days and enriches more stem cell-like memory T (Tscm) cells in the product. The MC-1-50 CAR-T cells produced by the PRIMCAR platform have exhibited a promising efficacy for B-ALL (Shiqi Li, et al. J Clin Oncol 2022; 40 [suppl 16]. Abstract 7008). Here, we report the preliminary safety and efficacy data of MC-1-50 for r/r B-NHL. Methods: In this Phase I /II study (NCT04271410), MC-1-50 CAR T cells were manufactured by the PRIMCAR platform. T cells were infected with a lentiviral vector encoding a humanized CD19 specific scFv following 4-1BB and CD3ζ cytoplasmic domain. Patients (pts) received single-dose of MC-1-50 at dose ranged 0.5-5×105 CAR+/kg (Level 1, 0.5×105 CAR+/kg; Level 2, 3×105 CAR+/kg; Level 3, 5×105 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m2) and cyclophosphamide (200-300 mg/m2) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Primary endpoints are the dose-limiting toxicities (DLTs) rate in the first 28 d and safety to determine a recommended Phase II dose (RP2D). Results: As of May 2022, thirteen pts with r/r B-NHL were infused with MC-1-50. Disease characteristics and outcomes are shown in the table. No DLTs were reported. 3 pts (23.08%) experienced CRS, including 2 (15.38%) at grade 1, and 1 (7.69%) at grade 2, no ≥ 3 CRS were observed, and no ICANS occurred. A preliminary dose-dependent response was observed. At dose Level 1 (DL1), none of the 3 patients showed a good response. At DL2, two patients showed PR response, and 3 of the 5 patients achieved CR response. At DL3, 5 of 5 patients achieved CR response. These patients with CR response did not experience a relapse during the followed-up (ranging from 5-18 months). CAR-T expansion was observed in all dose levels, although long-term persistence cannot be evaluated yet, 4 of 5 patients in DL2 and 3 of 5 patients in DL3 had detectable CAR expression by qPCR (≥50 copy/ ug DNA) in the 6-month follow-up. Conclusions: The PRIMCAR platform could produce CAR T cells quickly with a high percentage of Tscm. Treatment of r/r B-NHL at very low dose resulted in excellent safety profiles while exhibiting a high and durable efficacy. Clinical trial information: NCT04271410 . [Table: see text]
Evaluation of outcomes between rituximab-abbs and reference product rituximab in adult patients with newly diagnosed diffuse large B-cell lymphoma in a non-inferiority study.
Authors: Nguyen Vivian , Wong Helen , Mok Timothy , Cushing Merta , Lam Michael , Ho Stephanie Lai-Ting , Law Lisa Y. , Aziz Ashraf R. , Niu Fang , Hui Rita L.
Published: June 2023

7556

Background: Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard of care for diffuse large b-cell lymphoma (DLBCL). However, adding rituximab has increased treatment costs. Thus, development of biosimilars help provide more affordable care. Though rituximab-abbs was studied primarily in the follicular lymphoma population, in 2018 the FDA approved this drug as the first biosimilar for all indications of the reference product based on extrapolation. However, there are no clinical trials studying the effectiveness and safety of rituximab-abbs in DLBCL in the U.S. Methods: This is a data-only, non-inferiority study to compare two-year overall survival (OS) and the incidence of serious adverse events (AEs) between rituximab-abbs and its reference product (RP) as R-CHOP among adult patients with newly diagnosed DLBCL, with an index date from December 1, 2018-December 31, 2020. Non-inferiority will have a margin set to the upper limit of 5% for serious AEs, and a lower limit of 5% for OS. To assess for safety, we are following up on AEs until end of patient’s Kaiser Permanente (KP) membership, death, six months after last rituximab dose, or December 2022 for all AEs except infusion reactions. For infusion reactions only, the follow up is 1 day. To assess for efficacy, we are following up on OS until end of patient’s KP membership, death, December 2022, or two years. Results: 535 patients were enrolled; 240 patients received RP rituximab and 295 patients received rituximab-abbs. The median time of follow up was 730 days, or 2 years (range in days, 2.0-730). Complete response was similar in the RP rituximab group and the rituximab-abbs group (70.4% vs. 77.3% respectively, p = 0.07). Additionally, partial response was also similar among the two products (19.2% vs. 16.9%, p = 0.51). The Kaplan-Meier two-year survival curve was also similar between the two products (p = 0.52), demonstrating no difference. Further statistical analysis confirmed the non-inferiority of the biosimilar products for survival. Infusion reaction adverse events (13.8% vs. 11.2%, p = 0.37) and non-infusion adverse events (68.3% vs. 71.2%, p = 0.47) were also similar in the two groups, with a survival curve demonstrating no difference between the two products and data analysis meeting the non-inferiority criteria. Conclusions: Rituximab and rituximab-abbs are non-inferior to each other in both efficacy and safety. Long term follow up would be needed to confirm these results.
Impact of neighborhood deprivation on disability free survival in patients with aggressive B cell non-Hodgkin lymphoma.
Authors: Burkart Madelyn , Demetriou Nicholas , Sunderraj Ashwin , Ma Shou , Winter Jane N. , Gordon Leo I. , Moreira Jonathan , Karmali Reem , Roy Ishan
Published: June 2023

7564

Background: Advancements in treatment over the last decade have greatly improved survival in B cell non-Hodgkin’s lymphoma (NHL), yet not all patients (pts) benefit the same. Non-Hispanic Black (NHB), uninsured and lower socioeconomic status pts continue to suffer worse survival. However, the impact of neighborhood deprivation on disability has not been explored. We aimed to assess the association between neighborhood deprivation and disability free survival (DFS) in NHL pts. Methods: 258 aggressive NHL pts treated between 2005-2020 were included. Pts without documented follow up were excluded. Race/ethnicity was categorized as non-Hispanic white (NHW), Hispanic, NHB and other. Primary outcomes included progression free survival (PFS), overall survival (OS) and DFS. DFS was defined as time to needing any rehabilitative, home-health or skilled nursing services immediately following induction therapy, indicating disability and lack of functional independence. Neighborhood deprivation was assigned using the national Area Deprivation Index (ADI), a validated measure classifying neighborhood adversity. Pts were categorized into high (67-99), intermediate (34-66) or low (1-33) ADI scores, with least disadvantaged designated by lower scores. Kaplan-Meier analyses were used to compare PFS, OS and DFS. Results: Demographic data is shown in the table; 45% were female, 65% were NHW, 10% were NHB, 8% were Hispanic and 10% were other. Median age at diagnosis was 57 years. There was no difference in PFS or OS between racial/ethnic groups (p=0.91 and p=0.23 respectively). Payor source influenced both PFS and OS (p<0.001 and p<0.001 respectively), with self-pay associated with worse PFS and OS. Neighborhood deprivation based on ADI did not influence PFS (p=0.33) or OS (p=0.76). High ADI score was associated with worse DFS compared to lower ADI scores (p=0.03). ADI score differed significantly based on race/ethnicity (p<0.0001), with more NHB pts residing in areas of high ADI scores (40% vs 5% NHW vs 10% Hispanic). There was no association between ADI score and a pt’s ECOG performance status, IPI score or albumin at diagnosis (p=0.87, p=0.78 and p=0.59 respectively). Conclusions: NHL pts with higher neighborhood adversity experience more disability after treatment despite similar survival. Further work is needed to better understand how neighborhood factors are contributing to disability before community-level strategies for improvement can be developed. [Table: see text]
Final analysis of the phase IB part of the LOC-R01 trial, a non-comparative randomized phase IB/II study of escalating doses of lenalidomide and ibrutinib in association with R-MPV for patients with a newly diagnosed primary central nervous system lymphoma (PCNSL).
Authors: Alcantara Marion , Chevrier Marion , Jardin Fabrice , Schmitt Anna , Houillier Caroline , Oberic Lucie , Chinot Olivier L. , Morschhauser Franck , Peyrade Frederic , Houot Roch , Foulon Christine , Chauvin Estelle , Ghesquieres Herve , Soussain Carole
Published: June 2023

7566

Background: Results of conventional induction chemotherapies in PCNSL need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results in the relapse setting, supporting to further assess their combination with standard high-dose methotrexate-based chemotherapy. Methods: Patients (pts) with newly diagnosed PCNSL, aged 18 to 60, were randomized to receive four 28-day cycles of either ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3+3 design for ibrutinib 420/560/280 mg (D3 to D14 and D17 to D28) and lenalidomide 20 mg D1 to 14/20 mg D1 to 21/15 mg D1 to 21. Responder pts then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. We present the results of the phase IB, including the toxicities that occurred throughout induction therapy. Results: 26 pts (median age 52) were randomized, 13 in each treatment group. Four DLTs (/21 evaluable pts) have been observed: grade 5 aspergillosis and pneumocystosis (N=1, ibrutinib 560 mg and concurrent high-dose corticosteroids without prophylaxis), grade 4 catheter-related infection > 7 days (N=1, lenalidomide 20 mg D1-14) and grade 3 increased alanine aminotransferase > 7 days (N=1, lenalidomide 20 mg D1-14 and N=1, lenalidomide 15 mg D1-21). RP2D of ibrutinib and lenalidomide were 560 mg (D3-14 and D17-28) and 15 mg (D1-21) respectively, in combination with R-MPV. One Lyell’s syndrome was reported as a serious adverse event (AE) at cycle 2 in the lenalidomide arm. Grade ≥3 treatment-related AEs occurring in ≥2 pts at any time during induction treatment are detailed in the table. After 4 induction cycles, 3/11 evaluable pts had CR/CRu and 7/11 had partial response (PR) in the ibrutinib group. In the lenalidomide arm, 6/10 evaluable pts had CR/CRu and 4/10 had PR. Survivals will be presented. Conclusions: Targeted induction immunochemotherapy with ibrutinib or lenalidomide and R-MPV is feasible for newly diagnosed PCNSL and shows promising response rates. Adverse events should be monitored carefully. The phase II part of the study is ongoing and opened to patients up to 65 years old. Clinical trial information: NCT04446962 . [Table: see text]
Unveiling the prognostic significance of BCL6+/CD10+ mantle cell lymphoma: A systematic analysis.
Authors: Castillo Dan Ran , Park Daniel , Jeon Won Jin , Chong Esther G , Joung Bowon Floyd , Moon Jin Hyun Floyd , Pham Bryan , Lee Jae , Siddiqui Zeeshan , Nguyen Anthony Loc , Zhang Ke Kurt , Cao Huynh Le
Published: June 2023

7572

Background: Mantle cell lymphoma (MCL) is heterogenetic B-cell neoplasm that characterized by the presence of the IgH/CCND1 translocation. The significance of CD10 expression in MCL is not fully understood. The co-expression of CD10 and BCL6 in MCL is rare requiring further investigation to determine its clinical significance. This meta-analysis aims to examine the relationship between MCL variants and their cellular behaviors and clinical outcomes. Methods: A search of the GDC and dbGaP database was conducted using the PICOS model and PRISMA guidelines to retrieve survival data. Overall survival (OS) data was pooled from multiple studies and analyzed using the R programming package survival and a log-rank test was performed to compare OS. Mean differences between BCL6+ vs. BCL6- for individual studies were calculated and combined to minimize batch effects. Summary statistics across studies were obtained by averaging mean differences and pooling individual standard deviations. The correlation between CD10 and BCL6 was tested using Fisher's exact test, with a significance level of 0.05. Results: The analysis included a total of 537 patients (425 males and 112 females), with a median age at diagnosis of 69 years in CD10+ MCL and 61.5 years in CD10- MCL. Out of the 537 patients, 70 were CD10+ positive, and BCL6 positivity had an odds ratio of 5.11 [95% CI [2.49, 10.46]; p = 0.0000286) for CD10 positivity compared to CD10 negativity. The subgroup analysis revealed a higher frequency of blastoid/pleomorphic/small variants in BCL6+/CD10+ MCL. BCL6 positivity was associated with worse OS, independent of CD10 expression (median OS of 14 months in BCL6+ MCL vs. 43 months in BCL6- MCL; p = 0.01). The co-expression of BCL6 and CD10 was associated with a shorter median OS (22 months in BCL6+CD10+ vs. 55 months in BCL6-CD10+, p = 0.01) and significantly higher mitotic index (Ki67%) compared to BCL6-/CD10+ MCL (mean Ki67% of 63.13 ± 19.45% vs. 45 ± 21.69%, p < 0.01). The forest plot analysis showed that BCL6 expression was correlated with a significantly higher Ki67% (difference of 24.29; p = 0.0094). Conclusions: Our meta-analysis found that BCL6 expression correlates with CD10 positivity in MCL variants and has a negative impact on prognosis, independent of CD10 expression. Higher Ki67% levels in BCL6+ MCL compared to BCL6- MCL support the prognostic value of the BCL6+ immunophenotype in MCL variants. Prognostic scoring systems adjusted for BCL6 expression should be incorporated into MCL management. Targeted therapies against BCL6 may offer potential treatment options for MCL subtypes. [Table: see text]
Investigating the impact of demographic disparities on clinical outcomes in cutaneous T-cell lymphoma (CTCL): A multicenter retrospective cohort analysis.
Authors: Niyogusaba Tim , Switchenko Jeffrey M. , Rozati Sima , Iyer Swaminathan Padmanabhan , Talluru Sai , Huen Auris , Greenwell Irl Brian , Scribner Jane , Rangarajan Sunil , Mehta Amitkumar , Beaven Anne , Bhatti Safiyah , Krishanasamy Shalini , Porcu Pierluigi , Sethi Tarsheen , Foss Francine M. , Paulino Darina , Case Katherine , Lechowicz Mary Jo , Allen Pamela Blair
Published: June 2023

7573

Background: Black patients have been shown to have a higher incidence of cutaneous T-cell lymphomas (CTCL) and display unique clinicopathologic features at diagnosis, however, drivers of these disparities and the role of social determinants of health (SDoH) remain poorly understood. Methods: To further characterize the prognostic relevance of racial and demographic disparities in CTCL, we performed a retrospective review of 1,198 patients seen at 8 different academic treatment centers in the United States between 2000-2020. Clinical variables included demographics, disease characteristics, and survival. Race and ethnicity were stratified into 2 groups for this analysis: non-Hispanic Black (B) and Non-Black (NB). Distance to center was stratified into short, intermediate, or long commute ( < 10, 10-50, > 50 miles, respectively) based on home zip code. The primary endpoint was overall survival (OS). Univariate association and multivariable analyses were assessed using Cox proportional hazards models. Results: Among 1,198 total patients, 42.4% identified as B and 58.6% as NB. B patients presented younger, had a shorter commute, lower income, but no difference in insurance compared to NB patients. There was no difference in survival by race (Median OS 74 months (95% CI 65-84) compared to 65 (95% CI 58-75) for NB patients). Distance to center was strongly associated with survival and remained significant on multivariate analyses after controlling for age, race, and other SDoH. Longer commute was associated with worse OS compared to short commute for both B and NB counterparts (median 55 months [95% CI 49-66] vs. 79 [95% CI 69-90] and 75 [95% CI 63-86], respectively, p = 0.006). Conclusions: We characterized the impact of race and SDoH on overall survival (OS) in a diverse, multicenter cohort of patients with CTCL. We found that distance to cancer center was the most important factor contributing to disparities in OS in this study. This highlights the importance of improving access to care, particularly in rare and clinically heterogeneous diseases such as CTCL.
CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma.
Authors: Lin Yi , Martin Thomas G. , Usmani Saad Zafar , Berdeja Jesus G. , Jakubowiak Andrzej J. , Agha Mounzer E. , Cohen Adam D. , Deol Abhinav , Htut Myo , Lesokhin Alexander M. , Munshi Nikhil C. , O'Donnell Elizabeth , Jackson Carolyn Chang , Yeh Tzu-min , Banerjee Arnob , Zudaire Enrique , Madduri Deepu , delCorral Christopher , Bubuteishvili-Pacaud Lida , Jagannath Sundar
Published: June 2023

8009

Background: Heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with standard of care therapy have median overall survival (OS) of ~12 months (mo). In the single-arm, phase 1b/2 CARTITUDE-1 study (NCT03548207), pts received a single infusion of ciltacabtagene autoleucel (cilta-cel), a CAR-T cell therapy targeting BCMA. At the final protocol-specified analysis (27.7-mo median follow-up [MFU]), overall response rate (ORR) was 98%, with 83% stringent complete response (CR); 27-mo rates of progression-free survival (PFS) and OS were 55% and 70%, respectively. Here, we report study closeout results. Methods: Eligible pts received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD); and had received prior PI, IMiD, and anti-CD38 antibody therapy. Primary endpoint was ORR and safety; secondary endpoints included PFS, OS, and minimal residual disease (MRD) negativity at 10-5. Results: 97 pts received cilta-cel (median age 61 years [y]; median 6 prior LOT; 42% penta-drug refractory; 88% triple-class refractory; 99% refractory to last LOT). As of October 14, 2022, MFU was 33.4 mo (range, 1.5-45.2). Median (m) duration of response was 33.9 mo (95% CI, 25.5–not estimable [NE]). mPFS was 34.9 mo (95% CI, 25.2–NE), with an estimated 47.5% progression free and alive at 36 mo. mOS was not reached (NR), with an estimated 62.9% survival at 36 mo. Of 49 MRD-evaluable pts, 26 had MRD negativity sustained for ≥12 mo, of which 20 had sustained MRD-negative ≥CR. mPFS was NR in these subgroups (Table). 18 pts were MRD negative with ≥CR at 24 mo post infusion. No new safety signals and no new neurotoxicity events were reported since the 27.7-mo MFU. 6 new cases of second primary malignancy were reported, including 2 cases of basal cell carcinoma and 1 case each of myelodysplastic syndrome, B-cell lymphoma, melanoma, and prostate cancer. 5 additional deaths occurred (progressive disease [PD], n=3; pneumonia and sepsis, n=1 each [both unrelated to cilta-cel]), for a total of 35 (PD, n=17; unrelated to cilta-cel, n=12; related, n=6). Conclusions: Longer mPFS was observed after a single infusion of cilta-cel than any previously reported therapy in heavily pretreated pts with RRMM. Achieving CR and/or sustained MRD negativity was associated with prolonged PFS. Pts continue to be followed for safety and survival in the 15-y CARTINUE long-term study (NCT05201781; MMY4002). Clinical trial information: NCT03548207 . [Table: see text]
Safety and efficacy of standard of care (SOC) ciltacabtagene autoleucel (Cilta-cel) for relapsed/refractory multiple myeloma (RRMM).
Authors: Hansen Doris K. , Patel Krina K. , Peres Lauren C. , Kocoglu Mehmet H. , Shune Leyla , Simmons Gary , Ferreri Christopher J. , Atrash Shebli , Parrondo Ricardo Daniel , Chhabra Saurabh , Costello Patrick , Midha Shonali , Alsina Melissa , Voorhees Peter M. , Htut Myo , Sborov Douglas W. , Khouri Jack , Janakiram Murali , Lin Yi , Sidana Surbhi
Published: June 2023

8012

Background: Cilta-cel was FDA approved in 2022 for the treatment of RRMM. We evaluated the outcomes of patients treated with intended SOC cilta-cel. Methods: 12 US academic medical centers contributed data to this retrospective study. As of 12/31/2022, 177 patients were leukapheresed and 139 received cilta-cel. Results: The table describes the study population compared to the CARTITUDE-1 trial. More patients in our study had extramedullary disease (EMD, 35%) and high-risk cytogenetics (41%). 55% of the patients would not have met eligibility criteria for CARTITUDE-1. Common reasons for ineligibility were cytopenias (19%), prior BCMA therapy (14%), organ dysfunction (12%), oligosecretory disease (13%), and plasma cell leukemia (8%). 83% of the patients received bridging chemotherapy (overall response rate, ORR: 28%). Lymphodepletion included fludarabine (Flu) + cyclophosphamide (Cy): 81%, bendamustine: 11%, Cy: 4%, and cladribine + Cy: 4%. Median CAR-T cells infused were 0.6 million/kg (range: 0.1-0.9), and 19% of patients were treated on an expanded access protocol (EAP). Median follow-up was 2.3 months (range: 0-8). Cytokine release syndrome (CRS) was seen in 81% (≥ grade 3: 7%) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 22% (≥ grade 3: 8%) of patients. Tocilizumab, steroids, and anakinra were used in 61%, 44%, and 10% of patients, respectively. Delayed neurotoxicity (NT) was seen in 9% (cranial nerve palsy: 8, Parkinsonism: 2, others: 3). Grade ≥ 3 cytopenias at day ≥ 30 were seen in 75% of patients. Infections were seen in 32% of patients. Day 30 (N=115) and best response rates (N=118) were: ≥ partial response (PR), 75/80%; ≥ very good PR, 44/62%; and ≥ complete response (CR), 26/40%, respectively. In the non-EAP FluCy population (N=88), best ORR/≥CR were 89/49%. 17 patients died by data cut-off, 4 due to disease progression and 13 (9%) due to non-relapse mortality (NRM) (grade 5 CRS: 3, infection: 6, CRS/infection: 1, grade 5 ICANS: 1, delayed NT: 2). Conclusions: Patients treated with intended SOC cilta-cel had a favorable ORR (80%) despite a larger proportion of patients having high-risk features relative to trial patients and limited follow-up. Response rates were higher in patients receiving conforming products with FluCy conditioning (89%). Delayed NT and NRM were seen in 9% of patients. Results will be updated with continued follow-up. D.K.H., K.K.P, M.J., Y.L. & S.S. contributed equally. [Table: see text]
Plasma cell leukemia: A multicenter retrospective study of 150 patients.
Authors: Chineke Iloabueke Gabriel , Wertheim Betsy C. , Roe Denise , Larsen Ashley , Sborov Douglas W. , Vardell Victoria , Green Damian Jonathan , Degraff Dominique , Liedtke Michaela , Okoniewski Maire , Wazir Mohammed , Nadeem Omar , Paquin Shubert Ashley , Silbermann Rebecca Wang , Schachter Levanto Gershon , Coffey David , Schmidt Timothy Martin , Brunner Matthew , Wong Sandy Wai Kuan , Gowin Krisstina L.
Published: June 2023

8014

Background: Despite the use of novel induction regimens, stem cell transplantation (SCT), and maintenance therapy, plasma cell leukemia (PCL) remains a challenging disease with a dismal prognosis. Currently, there is no agreed standard of care management for PCL. We conducted a multicenter retrospective analysis of the clinical presentation, treatment, and outcomes of 150 patients with PCL. Methods: Data of patients diagnosed with pPCL or sPCL between 01/2010 and 01/2021 were entered into a study-specific REDCap database from 7 different U.S. academic sites. PCL was defined as ≥ 5% circulating plasma cells. Clinical data included baseline patient characteristics, clinical presentation, treatment, therapeutic response, and survival outcomes. Overall survival (OS) curves were plotted using the Kaplan-Meier method. Cox proportional hazards regression tested associations between patient characteristics and OS, generating hazard ratios (HR) and 95% confidence intervals (CI), adjusted for PCL type (primary or secondary) and SCT. Results: The analytical cohort included 93 pPCL and 57 sPCL patients. Median age at diagnosis was 60 years. High-risk cytogenetics were found in 56.7% of the patients where it was documented. Of the 79 patients with a documented induction regimen, 58.2% received a proteasome inhibitor triplet, 22.8% received a VTD-Pace like conventional chemotherapy, and 3% received a daratumumab quadruplet regimen. SCT (autologous or allogeneic) was done in 56.1% of the patients. The median OS for all patients, those with pPCL, and those with sPCL was 20.3, 36.6, and 3.2 months, respectively. Secondary PCL was associated with worse survival outcomes compared with pPCL (HR, 2.46; 95% CI, 1.51-3.98; p<0.001) (Table). Median OS was better in patients treated with a proteasome inhibitor triplet regimen vs VTD PACE-like combination (28.2 versus 12.6 months). OS was prolonged among patients who underwent any type of SCT compared with those who did not undergo SCT (44.0 versus 5.7 months, p<0.001). Conclusions: This multicenter retrospective study is one of the largest PCL analyses performed to date and reveals the clinical practice patterns of treatment and survival of PCL patients across the U.S. in the novel treatment era. The survival analysis reinforces the poor prognosis in sPCL patients and the continued need for novel treatment approaches in this patient population. While limited by retrospective design, this analysis suggests prolonged survival with transplantation in both pPCL and sPCL. [Table: see text]
Disparities in multiple myeloma: A global perspective on drug toxicity trends.
Authors: Jaberi-Douraki Majid , Xu Xuan , Faiman Beth , Wyckoff Gerald , Riviere Jim , Khouri Jack , Mazzoni Sandra Ann , Ramachandran Remya Ampadi , Gadara Nuwan Millagaha , Golmohammadi Mobina , Williams Louis , Samaras Christy Joy , Valent Jason Neil , Anwer Faiz , Raza Shahzad
Published: June 2023

8015

Background: The FDA Adverse Event Reporting System (FAERS) is one of the largest pharmacovigilance databases containing information on adverse events (AEs) received from manufacturers, consumers and healthcare professionals. The purpose of this study is to evaluate the global disparities in multiple myeloma (MM) through data mining of FAERS. Methods: We examined AEs associated with FDA-approved MM drugs from 2003-2022 from FAERS and the Medical Dictionary for Regulatory Activities. Patient data were then stratified based on age, sex (F/M) and 6 geographical regions. We evaluated the reporting odds ratio (ROR) combined with a 95% confidence interval for the elevated incidence of AEs. Results: The data curation provided 381,378 patients with information from North America (NA), Europe (EU), Asia (AS), Africa (AF), Oceania (OC) and Latin America & the Caribbean (LA), merged from 129 countries and 27 phenotypic systems and organs categories when the number of AEs happened more than 0.1% of the total. Cardiotoxicities (n=23160) and vascular toxicities (n=26716) were seen more in NA (M) (ROR=1.16±0.02 and EU (M) (ROR=1.11± 0.03) compared to the rest of the World. Nephrotoxicity (n=17486) was reported more in AF (M) (ROR=2.92±0.41) compared to AS (M) (ROR≥1.17± 0.12), EU (M) (ROR≥1.34± 0.13) and NA (M) (ROR=1.09± 0.03). Peripheral neuropathies (n=14786) were frequent among EU (F) (ROR=1.09±0.07) and OC (M) (ROR=1.08± 0.04). Mortality was higher among AS and EU (ROR≥2.15± 0.93) compared to NA and OC. There were 18,222 secondary neoplasms in FAERS. Skin neoplasms (n=4650) more frequently occurred in OC and EU (ROR≥1.70 ±0.16). Breast neoplasms (n=694) were the highest in EU (F) (ROR=4.01+0.63) and lowest in OC (F) (ROR<1). Gastrointestinal neoplasms (n=1564) were more common among AS, EU and OC (M) with (ROR≥2.23±0.47). Lymphomas (n=542) were predominant in AS(M) (ROR=2.21±0.98) and OC (M) (ROR=3.35±2.23). Leukemias (n=3896) cases were significantly higher in EU (M) (ROR=4.08 ± 0.40) and EU (F) (3.11 ± 0.26). Respiratory tract and mediastinal neoplasms (n=796) were more common in AS, EU and OC(M) where ROR≥1.36±0.33. More phenotypic characterization are tabulated below. Conclusions: FAERS can be used to assess cancer disparity from a global perspective. Our results indicates that certain AEs are influenced by gender and geographical location. These disparities in MM AEs may be the result of factors such as genetics, dosing/regimen, comorbidities, age and sex. These variables must be investigated for improved patient care, strategies for AE reduction, mortality reduction and optimal allocation of healthcare resources. [Table: see text]
Analysis of infections and parameters of humoral immunity in patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with talquetamab (tal) monotherapy in MonumenTAL-1.
Authors: Rodríguez-Otero Paula , Schinke Carolina D. , Chari Ajai , Lipe Brea , Lavi Noa , Rasche Leo , Vishwamitra Deeksha , Skerget Sheri , Verona Raluca , Ma Xuewen , Khedkar Sheetal , Hilder Brandi , Masterson Tara J. , Campagna Michela , Renaud Thomas , Tolbert Jaszianne A. , Heuck Christoph , Smit Marie-Anne Damiette , van de Donk Niels W.C.J.
Published: June 2023

8020

Background: Infection, a key complication of MM, may be due to patient, disease, or treatment-related factors. Immunotherapies that impact normal immune cells may increase risk of infection. Tal, a bispecific antibody with clinical benefit in pts with RRMM, targets G protein–coupled receptor family C group 5 member D (GPRC5D), a protein of unknown function with significantly higher expression on malignant versus normal plasma cells. We report the infection profile and immune function with tal in the phase (ph) 1/2 MonumenTAL-1 study (NCT03399799/NCT04634552). Methods: Pts had RRMM, were intolerant to/progressed on established therapies (ph 1), or had ≥3 prior lines of therapy (ph 2; ≥1 proteasome inhibitor/immunomodulatory drug/anti-CD38 antibody). Subcutaneous tal was given at 0.4 mg/kg QW or 0.8 mg/kg Q2W. Infections (graded by CTCAE v4.03) were treated per local guidelines. B-cell subpopulations and IgG levels were assessed from whole blood and serum samples, respectively. Results: We evaluated 339 pts on tal QW or Q2W, of whom 51 had prior T-cell redirection therapy (pTCRT); infection rates are shown in the table (median follow-up, 15.9, 10.1, and 13.1 mo, respectively). New-onset infections were most prevalent during cycles 1–2. Grade (gr) 3/4 infections observed in >2 pts were pneumonia (3.5%) and UTI (2.1%) on tal QW; pneumonia (2.1%) and COVID-19 (2.1%) on tal Q2W; and pneumonia (5.9%) with pTCRT. Opportunistic infections were observed in 3.5%, 4.1%, and 5.9% of pts, respectively. Less than 1.5% of pts died from infections: COVID-19 pneumonia (n=2) and one each due to septic shock, fungal sepsis, and unknown etiology. Hypogammaglobulinemia rates by IgG values were 64.3% (tal QW), 65.5% (tal Q2W), and 70.6% (pTCRT); IVIg use was 14.7%, 12.4%, and 15.7%, respectively. CD19+ B-cell levels were stable, and there was a trend toward increased non-clonal IgG over time. Conclusions: Roughly 20% of pts had gr 3/4 infections on tal (most frequently cycles 1–2), with low rates of opportunistic infections, discontinuation, and death. Infection rates, particularly rates of fatal infections, appear lower with tal than with BCMA-targeted T-cell–based therapies. A trend toward increased non-clonal IgG suggests potential recovery of humoral immunity accompanies rapid, deep, and durable responses to tal. These results distinguish tal as an important emerging therapy for RRMM. Clinical trial information: NCT03399799 , NCT04634552 . [Table: see text]
Prognostic value of month 1 bone marrow and PET MRD status in CAR-T therapy for myeloma.
Authors: Bansal Radhika , Babcock Jeffrey , Brunaldi Larissa , Chhabra Saurabh , Parrondo Ricardo Daniel , Gertz Morie A. , Hathcock Matthew , Dingli David , Kapoor Prashant , Kourelis Taxiarchis , Cook Joselle , Hayman Suzanne R. , Warsame Rahma M. , Binder Moritz , Fonseca Rafael , Bergsagel Peter Leif , Ailawadhi Sikander , Kumar Shaji , Broski Stephen M , Lin Yi
Published: June 2023

8024

Background: Minimal residual disease (MRD) is prognostic for survival in multiple myeloma (MM). MRD is usually assessed in the bone marrow (BM) by flow cytometry or NGS. MRD by FDG PET/CT provides a global representation of the tumor burden, including response assessment of extramedullary disease. We examined MRD status in MM pts using both BM and PET/CT at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CAR-T between 4/2018 and 12/2022. All PET/CT scans were assessed by radiologists. BM MRD was assessed by flow cytometry with a sensitivity of 10-5. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Results: Among the 157 CAR-T pts, including 89 pts who received FDA-approved CAR-T, median age was 63 years, 59% (92/157) were males, 42% (66/157) had high risk cytogenetics with median of 5 prior lines of therapy, 36% (57/157) had plasmacytoma. Incidence of CRS was 83%, 5% grade ≥ 3 CRS. Incidence of ICANS was 19%, 4% grade ≥ 3 ICANS. CR/sCR rate was 37%. One hundred and thirty-seven pts (87%) had evaluable BM at month (mo) 1, 85% (117/137) were BM MRDneg at mo 1. Baseline demographics were comparable between the two groups except age, % BM plasma cells and use of bridging therapy. Among the MRDneg pts, CR/sCR rate was 44% (51/117) and 95% (111/117) had sFLC below normal. At median follow-up of 13.8 months, median PFS among pts with BM MRDneg at 1 mo was 12 mo (95% CI: 11, 30) vs 3 mo (95%CI: 2, 7) for BM MRDpos (p<0.001). Median OS among pts with BM MRDneg at 1 mo was 34 mo (95% CI: 24, NR) vs 22 mo (95%CI: 7, NA) for BM MRDpos (p<0.01). At month 1, 112 pts had both BM and PET/CT assessments available, 64/112(57%) were both BM MRDneg/PET MRDneg, 38/112 (34%) were MRDneg for either BM or PET and 10/112 (9%) were positive for both BM and PET (MRDpos/PET MRDpos). Baseline demographics except age were comparable between the 2 groups (Table). Rate of conversion from MRDpos to MRDneg was low. Rate of sustained BM and PET MRDneg at mo 12 was 44% (8/18). The median PFS and OS for BM MRDneg/PET MRDneg was significantly longer as compared to others (Table). Conclusions: Achieving FLC below normal, BM MRDneg and PET MRDneg at 1 month, regardless of IMWG response at that time, is prognostic for both PFS and OS in MM pts receiving CAR-T. Failure to achieve any of these confers poor prognosis. [Table: see text]
Population pharmacokinetic-pharmacodynamic model of nirogacestat effects on B-cell maturation antigen in healthy subjects.
Authors: Shearer Todd , Williams Rex L. , Johnson Mark , Cendrowicz Ewa , Leonowens Cathrine , Smith Margaret , Baughman Todd , Breitbach Caroline J. , Smith L. Mary , Cheng Shinta
Published: June 2023

8027

Background: B-cell maturation antigen (BCMA) is expressed on the membrane of normal plasma cells (PCs) and multiple myeloma (MM) cells and is the target of several investigational agents and approved products for MM treatment. Mechanistically, BCMA is cleaved from the cell surface by the enzyme gamma secretase, resulting in reduced levels of membrane-bound BCMA (mbBCMA) and release of soluble BCMA. Gamma secretase inhibitors (GSIs) have been shown to increase BCMA receptor density and potentiate the activity of several BCMA-targeted therapies in both clinical trials and in vitro studies. Although the effect of GSIs on BCMA receptor density has been well characterized in vitro, their effect on BCMA dynamics is incompletely understood in humans. This study sought to evaluate the pharmacodynamics (PD) of the GSI nirogacestat on mbBCMA in healthy subjects. Methods: A total of 23 healthy subjects were administered single doses of 50, 150, or 300 mg nirogacestat or multiple doses of 100 mg every 12 hours. Density of mbBCMA on PCs isolated from whole blood and bone marrow was measured by flow cytometry at baseline and 1, 2, 4, 8, 24, and 48 hours after single doses and 24 and 48 hours after the first dose in subjects receiving multiple doses. Nirogacestat serum concentrations were also measured at multiple time points to fully characterize the pharmacokinetics (PK). A population PK-PD model of the effect of nirogacestat on BCMA dynamics in humans was developed and used to simulate various administration dose levels and schedules to find an optimal nirogacestat regimen that continually increases mbBCMA over the dosing interval. Results: A 2-compartment model with linear absorption and elimination described serum nirogacestat in healthy subjects. A sequential PK-PD model that included an effect compartment and drug effect on mbBCMA cleavage rate described mbBCMA values. Simulations indicated that a 100-mg dose administered twice daily sufficiently maintained elevated and clinically relevant mbBCMA levels. Exposure and efficacy benchmarks from in vitro experiments and published clinical studies were used to contextualize simulations and hypothesize various dose and schedule scenarios to minimize dose of the BCMA-targeting therapy while maximizing BCMA potentiation. Conclusions: These results suggest that nirogacestat dose and schedule may have direct implications on the potentiation of BCMA-targeting therapies. Simulations suggest that the 100-mg, twice-daily nirogacestat dose results in elevated mbBCMA levels that could even allow for use of lower doses of BCMA-targeted agents while maintaining or improving efficacy. Study results along with this PK-PD model will be used to support nirogacestat dose and schedule in ongoing and planned studies in patients with MM.
Health related quality of life (HRQoL) in patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE RRMM) treated with idecabtagene vicleucel (ide-cel) versus standard regimens: Patient-reported outcomes (PROs) from KarMMa-3 phase 3 randomized controlled trial (RCT).
Authors: Delforge Michel , Patel Krina K. , Eliason Laurie , Dhanda Devender , Shi Ling , Guo Shien , Marshall Thomas , Arnulf Bertrand , Cavo Michele , Nooka Ajay K. , Manier Salomon , Callander Natalie Scott , Giralt Sergio , Einsele Hermann , Ailawadhi Sikander , Popa McKiver Mihaela , Cook Mark , Rodríguez-Otero Paula
Published: June 2023

8032

Background: Patients (pts) with TCE RRMM have few treatment (Tx) options and poor HRQoL. Ide-cel, the first in class CAR T cell Tx for pts with TCE RRMM, improved PFS versus standard (std) regimens in the KarMMa-3 trial. We report the PRO results comparing the Tx arms. PROs provide further understanding of Tx benefit of ide-cel from the pts’ perspective. Methods: KarMMa-3 (NCT03651128) is an open-label phase 3 RCT comparing the efficacy and safety of ide-cel with std regimens in pts with TCE RRMM, who had received 2–4 prior regimens. In addition to clinical endpoints, we evaluated the impact of ide-cel compared with std regimens on the changes in HRQoL, measured by the EORTC QLQ-C30, EORTC QLQ-MY20, and the EQ-5D-5L questionnaires. PROs were collected at baseline (screening), day of infusion and monthly from 2–24 months (mo) and thereafter every 3 mo. This interim analysis reports PROs through 20 mo. Comparisons were performed on least squares mean (LSM) changes from baseline over time between arms using constrained longitudinal data analysis (cLDA). Results: In total, 386 pts were randomized (ide-cel, 254; std regimens, 132). PRO compliance was high over time ( > 80%). At baseline, PROs were similar between arms. LSM changes from baseline to 20 mo showed significant differences ( P < 0.05), with effect sizes of 0.3–0.7, in favor of ide-cel for most domains, including global health status/QoL, cognitive functioning, fatigue, and pain (EORTC QLQ-C30); side effects of Tx (EORTC QLQ-MY20); and the EQ-5D-5L VAS. The difference in overall LSM change reached or exceeded the pre-specified between-groups minimal importance difference (MID) for improvement in most domains in favor of ide-cel (Table). Conclusions: Ide-cel showed statistically significant and clinically meaningful improvements in HRQoL, including key MM symptoms and functioning, for pts with TCE RRMM compared with std regimens. The PRO data for ide-cel expands upon the clinical outcomes observed in the KarMMa-3 trial. Clinical trial information: NCT03651128 . [Table: see text]
Evaluation of prophylactic tocilizumab (toci) for the reduction of cytokine release syndrome (CRS) to inform the management of patients (pts) treated with teclistamab in MajesTEC-1.
Authors: van de Donk Niels W.C.J. , Garfall Alfred L. , Benboubker Lotfi , Uttervall Katarina , Groen Kaz , Rosiñol Laura , Hodin Caroline , Stephenson Tara , Trancucci Danielle , Perales-Puchalt Alfredo , Kobos Rachel , Banerjee Arnob , Mateos Maria-Victoria
Published: June 2023

8033

Background: Teclistamab is the first BCMA × CD3 bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM). In MajesTEC-1, CRS occurred in 72.1% of pts treated at the recommended phase 2 dose (RP2D) of weekly teclistamab 1.5 mg/kg (50.3% grade [gr] 1; 21.2% gr 2; 0.6% gr 3), and was successfully managed using toci in 36.4% of pts (± other interventions) without affecting response to teclistamab. Emerging data show that prophylactic administration of toci prior to first dose of bispecific antibodies reduces CRS incidence and severity, which may facilitate outpatient initiation of therapy. The current analysis includes the first prospective study of effects of prophylactic toci on incidence and severity of CRS with teclistamab. Methods: Eligible pts were aged ≥18 y with RRMM and had previously received a PI, IMiD, and anti-CD38 antibody. Pts received subcutaneous teclistamab (following 2 step-up doses) in a prospective exploratory cohort at the RP2D or in a fixed-dose cohort. Toci (single 8 mg/kg IV dose) was given ≤4 hours before the first teclistamab step-up dose. CRS was graded per Lee et al 2014 and managed per institutional guidelines. Results: 14 pts were included: median age 64 y (range 50–82); all pts had ECOG score ≤1 and ISS I/II; 91% had standard cytogenetic risk; 21% had extramedullary plasmacytomas; 31% had ≥30% BMPCs; median 4 prior lines of therapy (range 2–7); 64% triple-class refractory. Median follow-up was 1.2 mo (range 0.2–4.6). CRS occurred in 4 pts (29%; no gr ≥3 CRS); 1 had a subsequent CRS event (table). Median time to onset was 2 d (range 1–3); median duration was 2 d (range 2–4); all events were managed with toci and resolved without teclistamab discontinuation. 7 of 14 pts had gr 3/4 neutropenia (consistent with the overall MajesTEC-1 population). 2/14 had a gr 3/4 infection. 2/14 had a neurotoxicity AE. Of the response evaluable patients, 4/7 responded. Cytokine and PK data in additional pts with longer follow-up will be presented to further inform pt management. Conclusions: A single dose of toci before teclistamab treatment appeared to reduce the incidence of CRS relative to the overall MajesTEC-1 study population with no new safety signals and no evidence of impact on response to teclistamab considering the short follow-up. Prophylactic toci has the potential to reduce CRS risk in pts with disease profiles suitable for outpatient dosing, reducing the burden of hospitalization during teclistamab step-up dosing. Clinical trial information: NCT03145181 , NCT04557098 . [Table: see text]
Clinical characteristics, markers of adverse prognosis, and predictors of development of extramedullary multiple myeloma.
Authors: Zanwar Saurabh , Ho Matthew , Kapoor Prashant , Binder Moritz , Buadi Francis , Dispenzieri Angela , Dingli David , Fonder Amie L. , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hwa Yi Lisa , Hobbs Miriam A. , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Muchtar Eli , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji
Published: June 2023

8043

Background: Extramedullary Multiple Myeloma (EMM) has an aggressive clinical course and can present at diagnosis [primary EMM, (pEMM)] or relapse [secondary EMM, (sEMM)]. Here, we report clinical characteristics and outcomes of EMM, and predictive factors for the development of sEMM. Methods: We identified 299 patients with biopsy-proven EMM between 01/01/2000 and 12/31/2021. Patients with solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia were excluded. A 1:1 matched pair analysis (matched for year of diagnosis of MM for comparable follow-up and treatment eras) was performed to compare clinical characteristics and outcomes for patients with and without sEMM. Results: The median follow-up from the diagnosis of MM was 11.5 years (95%CI: 9.3-14.8). Of 299 patients, 204 (68%) patients had sEMM and 95 (32%) had pEMM, with largely comparable baseline characteristics (Table). The median overall survival (OS) from the diagnosis of sEMM was 0.7 (95% CI: 0.6-0.9) years compared to 3.6 (95%CI: 2.4-5.6) years for pEMM (p<0.0001). For sEMM, mutlvariable analysis (MVA) for OS identified visceral organ involvement (eg. liver, lung/pleura, brain, pancreas, etc.) to be associated with inferior OS [HR 1.6 (95% CI: 1.1-2.4), p=0.01]; high-risk cytogenetics (HR-CTG), ISS-3 stage, and age did not impact OS from sEMM. For pEMM, HR-CTG [HR 2.3 (95% CI 1.1 -4.8), p=0.03] and ISS-3 stage [HR 3.1 (95% CI 1.5-6.7), p=0.003] were associated with inferior OS on MVA whereas visceral EMM or age did not impact OS from pEMM. On univariate analysis, patients with sEMM were younger (median age 58.7 vs 61 years, p=0.006), had a higher proportion of 1q duplication (32% vs 17%, p=0.001), t(4;14) [16% vs 9%, p=0.047] and elevated LDH (30% vs 19%, p=0.04), compared to the matched cohort of patients without sEMM. On MVA, younger age at diagnosis, t(4;14) and 1q duplication at diagnosis of MM were independent predictors of development of sEMM. The median OS from diagnosis of MM was 5.4 years (95%CI: 4.1-6.2) for patients with sEMM versus 7.5 years (95% CI: 6.4-10.1; p <0.001) for the matched cohort. Secondary EMM was an independent poor prognostic marker for OS from the diagnosis of MM [HR 1.6 (95%CI: 1.2-2.1); p=0.004] in addition to age, ISS3 disease and HR-CTG. Conclusions: Outcomes of patients with EMM, especially sEMM, remain dismal. Patients with sEMM have higher rates of 1q duplication and t(4;14) at diagnosis of MM and carried an independent adverse prognosis in a matched cohort. [Table: see text]