The Glass Wall: Gendered Authorship Disparities in CD 19 and BCMA CAR-T Clinical Trials for Lymphoma and Myeloma.

INTRODUCTION: Existing literature suggests that women are significantly underrepresented in the field of hematology-oncology. Women make up 35.6% of hematologists and data on females as site investigators for pivotal trials and authors in publications of pivotal trials in hematologic malignancies, specifically in the novel niche of Chimeric antigen receptor T cell (CAR-T), is sparse. METHODS: We examined the proportion of women in pivotal trials, screening a total of 2180 studies from PubMed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 2180 initially searched records were filtered by date (2017-2023) and clinical trial status, yielding 149 records. Following a manual review, we included 15 studies that led to the approval of or anticipated approval of CD19 and BCMA CAR-T therapies in lymphoid and plasma cell malignancies. We examined overall number of female authors, number of lead female authors, and ratio of all authors to female authors in the 15 trials, which were all high impact, cited on average 1314 times. RESULTS: Of the 436 authors assessed, 132 were female, correlating to 29.5% female authorship. The only study with female authorship >50% was ELIANA, a 2017 pediatric study. 7 of the 15 studies had female lead authors; notably, 6 out of 7 of these studies were published in 2021 or later. CONCLUSION: In conclusion, our data suggests gender iniquities for female investigators exist in the field of immune effector cell therapy. We suggest further investigation and strategies to decrease gendered authorship disparities.

Timing of Toxicities and Non-Relapse Mortality Following CAR T Therapy in Myeloma.

BCMA-directed chimeric antigen receptor T-cell (CAR T) therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed the treatment landscape for relapsed-refractory multiple myeloma (RRMM), offering remarkable efficacy with hallmark toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA mandates a 4-week monitoring period at the treatment center as part of a Risk Evaluation and Mitigation Strategy (REMS) to monitor and manage these toxicities, which, while prudent, may add unnecessary challenges related to access and socioeconomic disparities. We sought to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world BCMA CAR T recipients in order to better inform future changes to the monitoring guidelines for CAR T recipients. This is a retrospective study across four academic centers that examined 129 ide-cel and cilta-cel recipients that received CAR T cell infusions from May 2021 to June 2023. Infusion and toxicities were managed per institutional guidelines in accordance with previously published guidelines. While differences were noted in the incidence and duration of CRS/ ICANS between ide-cel and cilta-cel, late-onset CRS and ICANS were rare after 2 weeks following infusion (0% and 1.6%, respectively). NRM was driven by hemophagocytic lymphohistiocytosis and infections in the early follow-up period (1.1% until Day 29), then by infections through three months post-infusion (1.2%). Our findings suggest that 25% of patients had to relocate for 4 weeks due to distance from the treatment center. With the low risk of CRS and ICANS after 2 weeks, a flexible shorter monitoring period may be reasonable, emphasizing collaboration with referring oncologists to improve NRM.

Comparison of biosimilar filgrastim and originator filgrastim for peripheral blood stem cell mobilization for allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Nivestym, a biosimilar granulocyte colony-stimulating factor (G-CSF) to the originator filgrastim (Neupogen), is now being used for the mobilization of peripheral blood stem cells (PBSC) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aim to compare the efficacy of Nivestym and Neupogen for PBSC mobilization in healthy allogeneic donors. METHODS: We conducted a retrospective single-center study including 541 adult allo-HSCT donors receiving Nivestym (January 2013-July 2020), or Neupogen (July 2020-June 2023) for donor PBSC mobilization. Bivariate analysis was conducted using SPSS version 28. Statistical significance was determined at a p-value <.05. RESULTS: Our study included 541 allo-HSCT donors who received Neupogen (n = 345, 64%) or Nivestym (n = 196, 36%) for PBSC mobilization. The median age was 47 years (range 17-76). The median donor weight was 86 kg (95% confidence interval [CI]: 87-91). Donors receiving Neupogen had similar pre-G-CSF white blood cell count, CD34+ percentages, and circulating CD34+ count compared with donors receiving Nivestym. The Neupogen group had similar median PBSC product total neutrophil count, CD34+ percentage, absolute CD34+ count, and infused CD34+ dose compared with the Nivestym group. For donors aged 35 years or younger, the median CD34+ dose was higher in donors who received Neupogen compared with Nivestym (6.9 vs. 6.3 million cells/kg, p = .044). CONCLUSIONS: Nivestym demonstrated similar efficacy for PBSC mobilization compared with Neupogen among allo-HSCT donors. In donors aged 35 years or younger, a slightly lower PBSC product CD34+ count was noted with Nivestym compared with Neupogen.

Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).

TACTUM: Trends in Access to Cellular Therapies in Multiple Myeloma, Perspectives of Treating Versus Referring Physicians.

Chimeric antigen receptor T cell therapy (CAR-T) and bispecific T cell engagers (TCE) for multiple myeloma (MM) are readily available at many large US medical centers. However, many potentially eligible patients may not be referred to the specialized centers administering these therapies. Perspectives regarding potential barriers for MM cellular therapy from referring-center oncologists (ROs) versus treating-center oncologists (TOs) have not been reported previously. We conducted TACTUM-23, a survey of US oncologists who treat MM, to identify perceived barriers to these cellular therapies. This 24-question survey, which focused on demographics and perceived barriers to CAR-T and TCE, was conducted between June and August 2023. Of 247 oncologists, 37 (15%) completed the survey including 26 (70%) TOs who prescribed both CAR-T and TCEs, 4 (11%) TOs who only prescribed TCEs, and 7 (19%) ROs who referred patients. The top RO-stated barrier to CAR-T was financial toxicity, while the top TO-stated barrier to CAR-T was leukapheresis/ manufacturing slot availability. The top RO-stated barrier to TCE was financial toxicity, while the top TO-stated barrier to TCE was the hospitalization requirement. In conclusion, financial concerns are perceived by ROs to be the top barrier to both CAR-T and TCEs in myeloma. In contrast, TOs perceive logistical concerns to be the top barrier. Interventions to lower financial toxicity during these therapies, and outreach to raise awareness of such interventions among ROs, are needed alongside strategies to streamline manufacturing (for CAR-T) and monitoring.

Impact of Extraosseous Extramedullary Disease on Outcomes of Patients with Relapsed-Refractory Multiple Myeloma receiving Standard-of-Care Chimeric Antigen Receptor T-Cell Therapy.

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.

Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience.

BACKGROUND: We aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). METHODS: We conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. RESULTS: The median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. CONCLUSIONS: CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.

Efficacy and safety of daratumumab, pomalidomide, and dexamethasone versus daratumumab, carfilzomib, and dexamethasone in daratumumab-naïve relapsed multiple myeloma.

OBJECTIVES AND METHODS: We conducted a multicenter retrospective study to analyze the safety and efficacy of DPd versus DKd in daratumumab naïve RRMM patients treated in real-world practice. RESULTS: A total of 187 patients with RRMM were included in the analysis; 128 patients received DPd, and 59 patients received DKd. A vast majority (80%) of patients had lenalidomide refractory disease and nearly 50% had bortezomib refractory disease. The overall response and complete response rates were 76% and 34% in the DPd group versus 80% and 51% in the DKd group, respectively. With a median follow up of 36 months for the entire patient population, median PFS and OS in the DPd versus DKd groups were 12, 12, 37, and 35 months, respectively. The most common grade 3+ adverse events in the DPd versus DKd groups were neutropenia (32% vs. 7%), anemia (14% vs. 10%), thrombocytopenia (13% vs. 15%), and cardiovascular events (4% vs. 15%), respectively. Both DPd and DKd appeared to be a safe and effective treatment options for RRMM. CONCLUSIONS: While there were more cytopenias associated with DPd and more cardiovascular side effects with DKd, there were no significant differences in the survival outcomes with these two regimens.

Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma.

PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

Efficacy and safety of idecabtagene vicleucel in patients with relapsed-refractory multiple myeloma not meeting the KarMMa-1 trial eligibility criteria: A real-world multicentre study.

Ide-cel received approval for relapsed-refractory multiple myeloma based on the results of the KarMMa-1 trial. However, patients with significant comorbidities, aggressive disease and prior B-cell maturation antigen-directed therapy (BCMA-DT) were excluded. This retrospective study evaluated real-world outcomes of patients who did not meet the KarMMa-1 eligibility criteria and were treated with standard of care (SOC) ide-cel. A total of 69 patients from three US centres who did not meet the KarMMa-1 criteria underwent ide-cel infusion. The main reasons for trial ineligibility included baseline grade 3-4 cytopenia (39%), prior BCMA-DT (26%), renal impairment (19%) and Eastern Cooperative Oncology Group performance status ≥2 (14.5%). Cytokine-release syndrome occurred in 81% vs. 84%, and immune effector cell-associated neurotoxicity syndrome occurred in 28% vs. 18% of SOC versus KarMMa-1 patients, respectively. Early infection (≤8 weeks post-infusion) and severe infection rates were 42% vs. 49% and 30% vs. 22% for the SOC versus KarMMa-1 cohorts, respectively. Grade 3-4 cytopenias for SOC versus KarMMa-1 cohorts were: neutropenia (87% vs. 89%), anaemia (51% vs. 60%) and thrombocytopenia (65% vs. 52%). Overall response rate was higher for the SOC cohort (93% vs. 73%), as was the complete response or better rate (48% vs. 33%). However, median progression-free survival and overall survival were comparable between the two groups. Our findings support broadening the inclusion criteria of future trials evaluating ide-cel.

Outcomes with HLA-matched unrelated donor versus haploidentical hematopoietic cell transplantation.

We investigated the outcomes after adult haploidentical (haplo) and matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) in a single-center study (n = 452) including 276 MUD and 176 haplo transplants. Myeloablative (37%) and reduced-intensity conditioning (63%) were performed. Graft sources included peripheral blood (50%) and bone marrow (50%). GVHD prophylaxis included tacrolimus/methotrexate (53%) and post-transplant cyclophosphamide-based (47%). In MUD versus haplo HCT recipients, a similar incidence of neutrophil engraftment (18 vs 17 days, p = 0.895), grade II-IV acute GVHD (51% vs 50%, p = 0.773), relapse (26% vs 23%, p = 0.578), non-relapse mortality (22% vs 23%, p = 0.817), 1-year disease-free survival (62% vs 63%. p = 0.921), and 1-year overall survival (73% vs 74%, p = 0.744) were observed. Earlier platelet engraftment (22 vs 27 days, p < 0.001) and higher chronic GVHD (45% vs 35%, p = 0.040) were noted in MUD as compared to haplo HCT. Allogeneic transplantation should be done promptly whenever indicated, utilizing either matched unrelated or haploidentical donors.

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma.

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

Safety and Efficacy of Teclistamab in Patients with Relapsed/Refractory Multiple Myeloma: A Real-World Experience.

Teclistamab is a B cell maturation antigen (BCMA)-directed bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM) on the basis of the phase I/II MajesTEC-1 trial. Here we report clinical outcomes with standard-of-care teclistamab in a real-world RRMM population. A total of 106 patients from 5 academic centers who received teclistamab from August 2022 to August 2023 were included in this retrospective analysis, 83% of whom would have been considered ineligible for the MajesTEC-1 trial. All patients were triple-class exposed, 64% were penta-class refractory, and 53% had received prior BCMA-directed therapy. Cytokine release syndrome was observed in 64% of patients, and only 1 event was grade ≥3, whereas immune effector cell-associated neurotoxicity syndrome was observed in 14% of patients (3 events were grade 3 or 4). One-third (31%) of patients experienced at least 1 infection, with nearly half of these infections graded as severe (grade ≥3). The overall response rate (ORR) was 66%, and the complete or better response rate was 29%. The ORR was 47% for patients with extramedullary disease (EMD), 59% for patients with prior BCMA-directed therapy exposure, and 68% for patients with penta-refractory disease. At a median follow-up of 3.8 months, the median progression-free survival (PFS) was 5.4 months (95% CI, 3.4 months to not reached), while median overall survival was not reached. Patients with Eastern Cooperative Oncology Group Performance Status ≥2, EMD, and age ≤70 years had inferior PFS on multivariable analysis. Our study demonstrates reasonable safety and good efficacy of teclistamab in patients with RRMM treated in a real-world setting.

Exploring the High-Grade and Refractory Neurotoxicity of Teclistamab: An Underreported Entity.

T-cell re-directing bispecific antibodies targeting B-cell maturation antigens have recently entered real-world use in relapsed/refractory multiple myeloma. While no head-to-head comparison has been done, they have generally been observed to have lower-grade toxicities compared with their chimeric antigen receptor T-cell (CAR-T) counterparts. However, in our real-world, single-institution experience, we have encountered two patients receiving teclistamab who experienced high-grade and refractory immune effector cell-associated neurotoxicity syndrome (ICANS) that did not respond to traditional toxicity mitigation strategies of high-dose corticosteroids or other immunosuppressive therapies. As we increase our use of these novel and vital agents, caution must be warranted.