After Autologous Stem Cell Transplantation Research Articles

GATA genotype and FY*B(-67T>C) polymorphism as a cheap and reliable tool to evaluate ethnicity in Brazilian patients submitted to autologous transplantation

Abstract Collecting high quality data on race and ethnicity is crucial for clinical research, notably in genetic association studies, to avoid confounding by different ethnic background among patients, a bias referred to as population stratification. In Brazil, to describe race we commonly use the National Institute of Geography and Statistics (IBGE) classification, so-called “self-declared color”, but it is acknowledged that defining ancestry by phenotypic characteristics, especially in countries with highly mixed population like Brazil, can be misleading. We aimed to evaluate the relationship between the GATA FY*B(-67T>C) polymorphism and self-declared race in Brazilian patients undergoing autologous transplantation and verify the feasibility of using this test as a more reliable tool to evaluate ethnicity in this population. Methods: We conducted a study to evaluate the association of candidate-gene polymorphisms and toxicities after autologous stem-cell transplantation (ASCT) in adult patients with lymphoma or myeloma from 2015 to 2021 in two Brazilian transplant centers. All patients with available DNA to study genetic polymorphisms were included. In this analysis we evaluate the association between GATA polymorphism and self-declared color in this cohort. Results: A total of 217 patients were included in this analysis. Median age at transplantation was 56 years (21-79) and 130 patients (59.9%) were male. Most patients were self-declared white (n=175, 80.6%) and the most common genotype was GATA67T/T (wild type/wild type) (n=142, 65.4%). Among the self-declared white patients, 73.1% were genotyped as GATA67T/T and 4.0% as GATA-67C/C, while among the non-white patients 21.4% were genotyped as GATA-67C/C (p<.001). The allele FY*B(-67T>C) frequency was 0.22 in the whole population; it was identified in 26.9% of the self-declared white patients and in 66.6% of the non-white (p<.001). Twelve-month overall survival was 86.6% (95% CI 79.9 - 91.2%), with no difference according to self-declared race (86.8% vs 85.5% for white and non-white patients, respectively, p=0.81) or the presence of the allele FY*B(-67T>C) (85.2% vs 89.9% for non-mutated and mutated patients, respectively, p=0.27). Conclusion: GATA FY*B(-67T>C) polymorphism is associated to self-declared race in Brazilian patients submitted to ASCT. Given the importance of correctly evaluating ancestry in genetic association studies in transplantation, GATA FY*B(-67T>C) polymorphism can be used as a more accurate tool in populations with mixed ethnic/racial background.

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma—a randomized, open-label phase III trial of the European mantle cell lymphoma network

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47–1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29–0.79) and without previous ASCT (aHR 0.52, 0.28–0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344.

The therapeutic effect and prognostic value of oligoclonal bands after autologous stem cell transplant in patients with multiple myeloma

Objective: To investigate the therapeutic effect and prognostic value of oligoclonal bands (OB) in multiple myeloma (MM) patients after autologous stem cell transplant (ASCT). Methods: The data of 156 patients with MM who underwent ASCT after inductive treatment in the Department of Hematology, Jiangsu Provincial People's Hospital from December 2013 to February 2022 were retrospectively analyzed, including 91 males and 65 females. The median age was 56 (26, 71) years. Patients were divided into two groups according to OB formation after ASCT treatment, including OB group (n=60) and non-OB group (n=96). The last follow-up date was August 31, 2023, and the follow-up period was 42 (18, 117) months. The clinical baseline characteristics and efficacy of the two groups were compared. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups by Kaplan-Meier method. Cox risk regression modal was used to analyze the risk factors associated with prognosis. Results: There were no significant differences in age, type, stage, risk stratification, extramedullary disease (EMD), proportion of circulating plasma cells and induction therapy regimen between OB and non-OB groups (all P>0.05). The proportion of patients in OB group who achieved complete response (CR) or above after ASCT treatment was 93.3% (56/60), which was higher than that in non-OB group (80.2%, 77/96) (P=0.024). The negative rate of minimal residual disease (MRD) in OB group was 66.7% (40/60), which was higher than that in non-OB group (34.4%, 33/96) (P=0.001). The median PFS and OS in the OB group were not reached, and the median PFS and OS in the non-OB group were 28 (2, 80) months and 86 (2, 100) months, respectively. The PFS (P<0.001) and OS (P=0.017) of patients with OB were considerably longer. In the Cox multivariate analysis, OB was an independent prognostic factor for PFS in MM patients (HR=0.314, 95%CI: 0.153-0.644, P=0.002). Subgroup analysis showed that among high-risk patients with mSMART, the OS of patients in OB group was not reached, which was significantly better than that of non-OB group [71 (2, 90) months, P=0.046]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in standard risk group (not reached vs not reached, P=0.103). In those with EMD at diagnosis, patients with OB had significantly better OS than those with non-OB [not reached vs 47 (6, 74) months, P=0.037]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in those without EMD at diagnosis [not reached vs 86 (2, 100) months, P=0.130]. Conclusions: OB formation after ASCT treatment in MM patients is related to the efficacy and prognosis. OB formation can increase the negative MRD rate, prolong the OS and improve the prognosis, especially for newly diagnosed patients with extramedullary disease or patients with high-risk genetic characteristics.

Immune Graft Composition Is Important for Deepening Response and Outcome after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma Who Do Not Receive Maintenance Therapy

Maintenance therapy with Lenalidomide or proteasome inhibitors after autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is an important component of first line treatment, resulting in deepening response (DR), converting PR to VGPR/CR or VGPR to CR in most patients and, in significantly longer PFS and OS. Of note, randomised clinical trials and real-world data confirm that DR also occurs in about 30% of patients receiving placebo or no maintenance at all. We analysed 90 patients with MM treated with first line ASCT in Hammersmith Hospital between 2017 - 2020, who did not receive maintenance therapy. We observed DR in 20 patients (22%) in the first two years. Patients achieving a DR had significantly higher PFS at 36 months post ASCT (89.4% v 41.1%, p=0.001 - Figure 1A). Baseline and ASCT characteristics, including high-risk cytogenetics, ISS, induction therapy and conditioning were comparable in DR and non-DR patients, however the use of the CXCR4 antagonist Plerixafor plus G-CSF vs G-CSF alone in the mobilisation regimen was associated with a higher probability for DR in the first 24 months post ASCT (58.3% v 23.2%, p=0.011 - Figure 1B). We suggest that improvement in depth of response after ASCT without pharmacological intervention indicates an immune anti-MM effect, underpinned by the immune composition of autologous grafts. We used 14-colour flow cytometry to analyse the immune cell frequencies in graft in 59 of the above patients, including 17 patients mobilised with Plerixafor plus G-CSF and 42 with G-CSF alone. The cell dose of each cell population was calculated from the relative frequency of CD34 cells in the graft and the CD34 cell dose infused in ASCT. In line with previous reports, the use of Plerixafor results in higher frequency and cell dose (in x10^6 cells/kg) of T cells in the graft (70.6% v 61.3%, p=0.015 and 306.2 v 161.4, p=0.007), driven mostly by a higher frequency (67.8% v 48.7%, p= 0.001) and dose (224 v 78.2, p=0.001) of central memory (CM) CD4 T cells. On the contrary, frequency and cell dose of effector memory (EM) CD4 T cells in Plerixafor plus G-CSF mobilised grafts were lower (6.7% v 21.5%, p=0.006 and 15.5 v 34.7, p=0.063). Apart from mobilisation regimen, univariate analysis showed a higher probability of achieving DR in grafts with high frequency of CD4 CM T cells (p= 0.012), NK cells (p=0.018 , Figure 1C), CD8 CM cells (p=0.06), higher dose of CD8 memory stem cells (p=0.033), lower frequency and dose of CD4 EM (p= 0.017 and p=0.007) and a lower dose of CD4 terminal effectors (TE) (p=0.039). In multivariate analysis, only a high NK cell frequency (p=0.011) and low CD4 TE cell dose (p=0.01), driven by their PD1 expression, predicted a higher probability for DR. Tregs frequency and cell dose were not affected from mobilisation regimen. However, Tregs dose was the stronger predictor of PFS at 36 months (75% with dose &amp;lt;5.06 x10^6/kg v 34.5% with dose &amp;gt;5.06 x10^6/kg, p= 0.001). Similarly, lower cell doses of CD4 EM (p=0.012) and frequency of CD4 TE (p=0.034) predicted a higher probability of PFS, but only Tregs cell dose retained significance in multivariate analysis (Figure 1D, p=0.001). In conclusion, spontaneous DR occurs in the first 2 years post ASCT in the absence of maintenance therapy and is associated with better PFS. CD4 memory subsets and NK cell graft composition appears significant for a potential immunological effect in DR. Additionally, a lower cell dose of immunosuppressive Tregs appears more important for sustaining long-term remission post ASCT.

Isolated and Dynamic Peripheral Blood Residual Disease Status Characterized By Mass Spectrometry Predicts Outcome in Patients with High Risk Smoldering Multiple Myeloma Treated in the GEM-CESAR Trial

Background: GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the rate of minimal residual disease (MRD) negativity in the bone marrow (BM) assessed by next generation flow (NGF) after autologous stem cell transplantation (ASCT) and sustained 3 and 5 years afterwards. Here, we update the preliminary results presented at ASH2019 about the clinical value of quantitative immunoprecipitation mass spectrometry to assess treatment response in this group of patients. Methods: Pts received induction with six 4-week cycles of KRd (K: 36mg/m 2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d: dexamethasone 40mg po weekly), high-dose melphalan followed by ASCT, consolidation with two further cycles of KRd and up to 2 years of maintenance with Rd (R: 10mg po od, d: 20mg po weekly). Peripheral blood Residual Disease(PRD) was analyzed post-ASCT and at treatment completion (after 2 years of maintenance) using Quantitative Immunoprecipitation Mass Spectrometry with anti IgG/A/M, total k and total l beads using the EXENT ® Solution (The Binding Site, part of Thermo Fisher Scientific). From the 90 pts enrolled in the trial, 61 were analyzed post-ASCT and 35 at the end of treatment. Isotype-matched immunoparesia (IMI) was also evaluated post-ASCT using the heavy/light chain pairs. Kaplan-Meier curves were plotted either from the specific time point investigated or from the last one if dynamics were analyzed. Results: First,PRD was analyzed post-ASCT and at treatment completion and deemed to be positive in 54% (33/61) and 20% (7/35) of patients, respectively. At both time points, PRD assessment discriminated two groups of patients with a very significantly different prognosis: median PFS in PRD+cases post-ASCT was 4.27 years vs not reached in PRD- cases (p=0.0071) (Fig 1A) and after 2 years of maintenance, the median PFS in PRD- cases was not reached vs 1.43 years in PRD+ cases (p=0.0011) (Fig 1B). Importantly, standard response criteria and, more specifically, the achievement of complete response (CR) or better, was not associated with disease outcome. And further, among samples in ³CR, PRD+ was also able to discriminate a group of patients with poorer outcome, with a median PFS of 4.42 years vs not reached in PRD- cases (p=0.0136) Interestingly, when we combined the analysis of the M-protein by mass spectrometry with the identification of severe isotype-matched suppression (uHLC &amp;lt; 50%), PRD+ patients post-ASCT could be further stratified in two subgroups with significantly different median PFS (not reached in those with no severe IMI vs 3.85 years in those with severe IMI, p=0.0384) (Fig 1C). A similar tendency was observed among PRD+cases after 2 years of maintenance (mPFS in those with no severe IMI of 2.5 years vs 9 months in those with severe IMI) although the difference did not reach statistical significance. Then, we analyzed PRD dynamics after ASCT and at the end of treatment. Sustained PRDnegativity during this period was observed in 12 pts (33.3%), and sustained positivity in 6 (16.6%). In 5 pts (13.8%) PRD converted from positive to negative, and in 1 (2.7%) from negative to positive. Whereas sustained PRD+ was associated with a very short median PFS of 1.66 years, patients with sustained PRD- or who converted from PRD+ to PRD- displayed a very favorable outcome with median PFS not reached and significantly different compared to the sustained PRD+ group (p&amp;lt;0,0001) (Fig 1D). Interestingly, the only patient that converted from PRD-to PRD+ had a very poor outcome with a mPFS 3.8 months. By contrast, sustained CR or better according to standard response criteria was not significantly associated with clinical outcome. Conclusion: In this cohort of high-risk smoldering MM patients treated intensively with a curative intention, whereas standard CR or better was not associated with clinical outcome, PRD status defined by mass-spectrometry segregated two groups of patients with different PFS at the 2 time points analyzed. Furthermore, this outcome was better predicted when PRD dynamics were analyzed and/or with the evaluation of severe IMI on PRD+ patients, highlighting once again the relevance of immune recovery as a determinant factor in the evolution of the disease.

The Impact of Continuous Lenalidomide Maintenance Treatment on People Living with Multiple Myeloma - a Single-Centre Qualitative Service Evaluation

Background: Randomised trials examining continuous lenalidomide maintenance after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) have demonstrated progression free survival (PFS) and overall survival benefit compared to placebo. In 2021 the UK National Institute of Clinical Excellence (NICE) approved lenalidomide maintenance for all newly diagnosed National Health Service (NHS) patients receiving ASCT after induction chemotherapy. Patient-reported outcomes from observational studies suggest lenalidomide causes tolerable adverse effects. However, clinical trial data demonstrate that neutropenia, fatigue, neuropathy, and gastrointestinal issues are common, particularly in the first six months of treatment, and that lenalidomide increases the risk of secondary malignancies. Before lenalidomide maintenance was used in this setting, individuals would typically enter a treatment-free phase after ASCT, where they might experience a reasonable quality of life (QoL) without treatment burden. Studies suggest that medication breaks allow patients to detach from the ‘illness’ experience, but with continuous lenalidomide that opportunity is lost. Whilst the PFS benefit of lenalidomide maintenance is proven, both short- and longer-term toxicities reported in clinical trials suggest the trade-off between efficacy and harm should be considered. In-depth information about how continuous lenalidomide impacts individuals' QoL is scant. The overall objective of this qualitative service evaluation was to examine patients' experience of lenalidomide maintenance, including perceived impact on QoL and experience of side-effects. It was anticipated that findings would result in clinical service improvement through the delivery of communication better suited to patients' needs and priorities when facing treatment choices. Methods: We conducted 20 one-to-one semi-structured interviews with purposively selected patients (10 female and 10 male) from a specialist MM center in London. All participants had undergone induction chemotherapy followed by ASCT and were receiving continuous lenalidomide. Ages ranged from 45 to 71 years (median 58). The sample comprised 12 White British, 2 Black Caribbean, 1 Black African, 1 Asian Indian, 2 from other ethnic groups and 2 with undisclosed ethnicity. Lenalidomide treatment duration varied; seven patients had received lenalidomide for 1-6 months, five for 7-12 months, five for 13-18 months, one for 19-24 months, and two for over 24 months. Reflexive thematic analysis was used for data analysis. Results: Four themes were developed from the data: 1) Lenalidomide: understanding its role and rationale, 2) Reframing the loss of a treatment-free period to a return to normal life, 3) The reality of being on continuous lenalidomide maintenance: balancing hopes with hurdles, 4) Gratitude and Grievances: Exploring patients' mixed perceptions of care and communication. Most patients believed lenalidomide maintenance would double remission time and were compelled by the relative certainty it offered, which contrasted with the unpredictability of MM. Many participants reported that lenalidomide helped to diminish fears about relapse, and thus most did not feel they were missing out on a treatment break. The impact of lenalidomide maintenance on patients' QoL varied; younger patients reported no/negligible side-effects, while several older patients with comorbidities described significant symptom burden, such as skin rashes, debilitating fatigue, unpredictable gastric disturbances and bone pain, occasionally leading to treatment discontinuation which caused distress at the perceived loss of prolonged remission. The transition from frontline to maintenance treatment required a return to greater patient autonomy as medical support was reduced. Some patients described anxiety and depression in this period, suggesting the need for greater support. The study also highlighted specific challenges that younger patients experience, such as concerns about sexual transmission and fertility, which merits further research. Conclusions: Understanding the real-world symptom burden in MM is key as continuous treatment becomes routine. Qualitative research on the impact of treatment could lead to a more comprehensive understanding, helping patients cope with the increasingly chronic nature of this disease.

The Temporal Evolution of Chromosome 1q Gain and Hyperdiploidy and Its Impact on Clinical Outcomes in Multiple Myeloma

INTRODUCTION: Multiple myeloma (MM) evolution is shaped by the acquisition and selection of distinct genomic events over time. While various temporal patterns have been identified, the precise chronological order in which key clonal genomic defining events are acquired, and their specific impact on clinical outcomes remain to be fully elucidated. METHODS: To decipher the genomic life history of MM and its impact on clinical outcomes, we interrogated the high coverage (80X) whole genome sequencing (WGS) of 378 MM patients. Overall, 319 and 59 WGS were generated from samples collected at diagnosis and at relapse, respectively. Newly diagnosed MM (NDMM) patients were treated upfront with proteosome inhibitors, lenalidomide, dexamethasone, +/- monoclonal antibodies. To estimate the relative and absolute temporal relationship among clonal events, we leveraged the molecular time approach, based on the corrected ratio between duplicated and non-duplicated single nucleotide variants (SNV). RESULTS: Overall, 300/378 (79%) patients had at least one large chromosomal gain defined as &amp;gt;1Mb with &amp;gt;50 clonal SNV eligible for molecular time analysis, for a total of 1493 events tested. Consistent with recent findings, using clock-like mutational signatures SBS1-SBS5, we estimated that the first gain in MM is typically acquired around the second or third decade of life, with a median time lag of approximately 33 years between acquisition and diagnosis. In 158/178 (89%) of hyperdiploid (HRD) patients, all trisomies of odd-numbered chromosomes were acquired simultaneously. Among patients with canonical IGH translocations and HRD, the molecular time when trisomies were acquired was usually late compared to HRD without canonical IGH translocations (p&amp;lt;0.0001). Next, we examined the temporal relationship between IGH canonical translocations and gains linked to the same IGH canonical translocation in 29 patients. We consistently observed that when IGH canonical translocations co-occurred with HRD (n=7), and/or 1q gain (n=8) in the same patient, the canonical IGH translocation was always found to be the initiating event, occurring earlier than the chromosomal gains. Interestingly, in 104/178 (58.4%) HRD patients, the earliest multi-gain event was not always restricted to odd chromosomes, but in involved other non-HRD chromosomes such as: 6p (n=43) and 1q (n=32), demonstrating that gain 1q, which is assumed to occur at progression, can also be acquired very early in disease life history. A total of 92 and 21 patients with 1q gain and 1q amp (&amp;gt;3 copies) were identified, respectively. In 14/21 (66%) with 1q amp, the first and second 1q extra copies were acquired in two distinct and independent time windows. Interestingly, patients with early 1q gain showed the same clinical outcomes as 1q amp, and inferior progression free survival outcomes compared to late 1q gain (p=0.01; Figure 1). In 18/21 1q amp the first 1q duplication was acquired early, suggesting that the adverse prognostic effect of 1q gain/amp in NDMM may be more dependent on the timing of its acquisition rather than the number of extra copies gained. To investigate late temporal patterns and differentiate selection versus acquisition of large gains at relapse after autologous stem cell transplant (ASCT), we interrogated 25/59 (42%) RRMM patients exposed to melphalan with detectable SBS-MM1. To establish the temporal order of events, we employed the melphalan mutational signature, SBS-MM1, as a unique temporal barcode (Diamond et al. Blood 2023). Overall, we observed that 21% of all loss of heterozygosity (LOH) events and 15% of all gains were acquired after ASCT (i.e., SBS-MM1 mutations were only detectable in the pre-gain/duplicated SNV). Notably, among these events, 1q gain was acquired after ASCT in 3/4 patients, indicating that the acquisition of 1q gain can occur even after administration of first-line therapy. CONCLUSIONS: In our study, we have uncovered distinct temporal patterns in the acquisition of early genomic drivers in MM. These patterns contribute to the reconstruction and better understanding of the life history of MM and may hold potential clinical and prognostic implications.

Favezelimab (anti-LAG-3) Plus Pembrolizumab in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Cohort 3 of a Multicohort Open-Label Phase 1/2 Study

Background: Lymphocyte-activation gene 3 (LAG-3) is involved in the regulation of T-cell function and is commonly coexpressed with PD-1 on anergic T cells. Favezelimab (MK-4280), a humanized IgG4 anti-LAG-3 monoclonal antibody, plus pembrolizumab (anti-PD-1) is being investigated in the multicohort phase 1/2 MK-4280-003 efficacy and safety study (NCT03598608) in patients with relapsed or refractory (R/R) hematologic malignancies. Prior analyses of the combination demonstrated antitumor activity and manageable safety in patients with anti-PD-1-naive R/R classical Hodgkin lymphoma (cHL; cohort 1; ORR, 73%; CR, 30%) (Johnson NA et al. Blood. 2022;140(suppl 1):6540-2) and anti-PD-1-refractory cHL (cohort 2; ORR, 29%; CR, 9%) (Timmerman J et al. Blood. 2022;140(suppl 1):768-70). We present results from analysis of patients with R/R DLBCL enrolled in cohort 3. Methods: In this study, a safety lead-in phase (part 1) to determine the recommended phase 2 dose (RP2D) was followed by a dose-expansion phase (part 2). In cohort 3, eligible patients were ≥18 years old, had histologically confirmed R/R DLBCL that had progressed after ≥2 lines of previous therapy, including progression after autologous stem cell transplant (ASCT), had declined ASCT, or were ineligible for ASCT. Patients with Richter transformation were not permitted. In part 1, patients received favezelimab at a starting dose of 200 mg that was escalated to 800 mg plus pembrolizumab at 200 mg IV every 3 weeks (Q3W) per the modified toxicity probability interval method. In the dose-expansion phase, patients received favezelimab at the established RP2D of 800 mg plus pembrolizumab 200 mg Q3W for ≤35 cycles (~2 years). Response assessments were performed at weeks 12 and 24 (PET) and Q12W (CT). Adverse events (AEs) were graded per the NCI CTCAE v4.0. The primary end point was safety. ORR per IWG 2007 criteria by investigator review was a secondary end point. Exploratory end points included duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS). Results: A total of 25 patients with R/R DLBCL were enrolled. Patients had a median age of 73 years (range, 25-87), 10 (40%) had ECOG PS 0, and 15 (60%) had ≥3 prior lines of therapy. Most common subtypes of DLBCL were unspecified DLBCL (n = 12; 48%) and germinal center B-cell DLBCL (n = 6; 24%). At database cutoff (March 2, 2023), 1 patient (4%) was ongoing on treatment and 24 (96%) had discontinued because of progressive disease (n = 14), AEs (n = 2), clinical progression (n = 5), or patient noncompliance/nonstudy anticancer therapy (n = 3); 1 patient (4%) discontinued because of treatment-related AEs. No treatment-related deaths occurred. Sixteen patients (64%) had a treatment-related AE; the most common (≥5%) were cough (16%), increased blood alkaline phosphatase (12%), and hypothyroidism, constipation, infusion related reaction, increased AST, muscle spasms, headache and pruritis (8% each). Grade 3 or 4 treatment-related AEs occurred in 4 patients (16%; 1 grade 3 lymphocytic hypophysitis, 1 grade 3 infectious enterocolitis, 1 grade 3 increased AST, 1 grade 3 increased ALT, 1 grade 3 increased amylase, and 1 grade 4 decreased neutrophil count). AEs of clinical interest occurred in 5 patients (20%); only one grade ≥3 occurred (grade 3 hypophysitis). The median (range) time from first dose to data cutoff was 25.9 (19.7-52.1) months. The objective response rate was 12% (95% CI, 2.5-31.2; [2 CR, 1 PR]). Among 17 patients with a postdose scan, 7 (41%) had a reduction from baseline in target lesion size, and 6 (35%) had ≥50% reduction from baseline. Median DOR was not reached (range, 3.0+ to 16.9+ months); 1 responder had an observed response duration of ≥12 months. Median PFS was 2.1 months (95% CI, 1.1-2.7); 12-month PFS rate was 12%. As of the data cutoff, 20 patients (80%) had died. Median OS was 6.4 months (95% CI, 2.3-15.8); 12-month OS rate was 43%. Conclusion: Favezelimab 800 mg plus pembrolizumab 200 mg had limited antitumor activity in patients with DLBCL in cohort 3. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. The safety profile was manageable and consistent with that observed in other cohorts in the study.

Favezelimab in Combination with Pembrolizumab in Patients with Heavily Pretreated Anti-PD-1-Refractory Classical Hodgkin Lymphoma: Updated Analysis of an Open-Label Phase 1/2 Study

Background: Programmed cell death protein 1 (PD-1) inhibitors are a standard of care for relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but better treatment options are needed for patients with anti-PD-1-refractory disease. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor with a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity in patients with advanced melanoma. Combination therapy with favezelimab (anti-LAG-3) and pembrolizumab (anti-PD-1) is currently being investigated in a phase 1/2 study (NCT03598608) in patients with R/R hematologic malignancies. Prior analyses showed that the combination had antitumor activity and manageable safety in patients with heavily pretreated anti-PD-1-refractory cHL (cohort 2). Updated results for this cohort are presented. Methods: The study consisted of a safety lead-in (part 1) followed by a dose-expansion phase (part 2). Eligible patients were ≥18 y; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had an ECOG performance status of 0 or 1; and had experienced disease progression after ≥2 doses of anti-PD-1-based therapy and within 12 weeks of the last dose of anti-PD-1 therapy. In part 1, patients received pembrolizumab 200 mg IV Q3W + favezelimab starting at 200 mg and escalating to 800 mg IV Q3W per a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D of 800 mg Q3W for ≤35 cycles (~2 y). The primary end point was safety. ORR per IWG 2007 criteria by investigator review was a secondary end point. DOR and PFS per IWG 2007 criteria by investigator review and OS were exploratory end points. Results: 34 patients with anti-PD-1-refractory cHL were enrolled in cohort 2. The median age was 37.5 y (range, 25-79), 16 patients (47%) were male, 21 (62%) had an ECOG performance status of 0, and 94% had received ≥4 prior lines of therapy. Seventeen patients (50%) had received an anti-PD-1-based regimen as their most recent therapy. At database cutoff (March 2, 2023), 8 patients (24%) had completed 35 cycles of treatment and 26 (76%) had discontinued treatment (14 [41%] progressive disease, 7 [21%] AEs, 5 [15%] other reasons). The median time from first dose to data cutoff was 35.3 mo (range, 15.0-49.4). Treatment-related AEs occurred in 28 patients (82%), of which the most common (≥15%) were hypothyroidism (18%), nausea (18%), and fatigue (15%). Grade 3/4 treatment-related AEs occurred in 6 patients (18%). 6 patients (18%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 17 patients (50%); 2 patients (6%) had grade 3 events (encephalitis, hepatitis) and 1 patient (3%) had a grade 4 event (type 1 diabetes mellitus). Of the 2 patients who underwent allogeneic hematopoietic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3 AE (acute graft versus host disease) unrelated to study treatment that resolved. The ORR in cohort 2 was 29% (10/34; 95% CI, 15-48), with 3 (9%) complete responses (CR) and 7 (21%) partial responses (PR). Of the 10 responders, 7 had received ≥5 prior lines of therapy (3 CR/4 PR). The ORR in patients with anti-PD-1 as their most recent therapy was 35% (6/17; 95% CI, 14-62; 1 CR/5 PR); the ORR in patients with non-anti-PD-1 as their most recent therapy was 24% (4/17; 95% CI, 7-50; 2 CR/2 PR). Of 28 patients with a baseline and postbaseline assessment available, 25 (89%) had any reduction in target lesion size from baseline, and 12 (43%) had ≥50% reduction. Median DOR was 21.9 mo (range, 0.0+ to 26.1+) and an estimated 17% of responders remained in response ≥24 mo. Median PFS was 9.7 mo (95% CI, 5.1-14.7); 24-mo PFS rate was 21%. Median OS was 34.3 mo (95% CI, 25.7-NR); 24-mo OS rate was 76%. Conclusion: After additional follow-up, the combination of favezelimab + pembrolizumab continued to demonstrate manageable safety and antitumor activity in patients with heavily pretreated anti-PD-1-refractory cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. The phase 3 KEYFORM-008 study (NCT05508867) is being conducted to evaluate a coformulation of favezelimab and pembrolizumab in patients with anti-PD-1-refractory cHL.

Response and Safety of Selinexor with VRD Regimen in Newly Diagnosed Multiple Myeloma (NDMM) with Extramedullary Disease (EMD): A Prospective, Open-Label, Multicenter, Phase 2 Study

INTRODUCTION: Extramedullary disease (EMD) is a rare but increasingly recognized complication in newly diagnosed multiple myeloma (NDMM) patients, associated with a poorer prognosis and drug resistance. However, data on treatment outcomes for EMD are primarily based on retrospective studies, necessitating prospective studies with well-defined EMD to assess treatment efficacy and safety accurately. In this context, we present the preliminary findings from a prospective phase 2 study evaluating the safety and efficacy of selinexor in combination with VRd as a first-line treatment for NDMM patients with EMD(NCT05900882). METHODS: The study enrolled NDMM patients under the age of 75 who had measurable extramedullary disease (defined as paraosseous or extramedullary plasmacytoma ≥2cm. Patients received selinexor (60 mg QW) in combination with VRd (SVRD) regimen as induction therapy for 4 cycles (28 days of each cycle). Following the induction phase, patients underwent two cycles of VRd consolidation therapy after autologous stem cell transplantation (ASCT), while those who did not undergo ASCT received another 4 cycles of SVRD consolidation therapy. All pts received bortezomib plus lenalidomide for maintenance for at least 24 months. The primary endpoint of the study was the best response rate during induction therapy, and secondary endpoints included complete response (CR) rate, duration of response (DOR), safety, and survival outcomes. RESULTS: Between Oct 17, 2022 and May 12, 2023, a total of 10 NDMM pts with EMD were enrolled and received treatment at The First Affiliated Hospital of Nanjing Medical University. The median age was 62 years (range 48-70). Among them, 7 patients (70%) had RISS stage II/III disease, 7 patients (70%) were classified as high risk based on the mSMART stratification, and 3 patients (30%) had extra-osseous extramedullary plasmacytomas (EMP) as per Table 1. By the data cut-off date of July 15, 2023, at a median follow-up of 5.5 months (range 2.2-9.3 months), 5 pts completed 4 cycles of SVRd inductive treatment, 2 pts underwent ASCT, 1 pts discontinued the clinical trial due to progressive disease, and 3 pts were now receiving consolidation therapy ( Figure 1). Among the 10 evaluable pts for best serological response, 4 pts (40%) achieved serological CR/sCR, and 6 pts (60%) achieved VGPR. The depth of remission improved with the continuous treatment. Extramedullary disease evaluation in 9 patients showed complete disappearance of extramedullary lesions in 3 patients (30%), partial response in 5 patients (50%), and stable disease in 1 patient (10%). 8 (80%) pts experienced any grade AE. Grade 3 or 4 AEs were reported in 2 pts (9 events in total), with the most common being leukopenia (3), neutropenia (3) and thrombocytopenia (3). Non-hematological AEs were mainly grade 1-2, except for 1 pt with grade 3 anorexia. No pts required dose reductions or discontinuations due to AEs. CONCLUSIONS: The combination of selinexor with VRd regimen demonstrated early, deep, and durable responses in NDMM patients with extramedullary disease, both in serological and extramedullary responses, with a manageable safety profile. These results suggest that this therapeutic intervention holds promise as an effective and well-tolerated treatment option for multiple myeloma patients with EMD. Further studies are warranted to validate these findings and establish the long-term benefits of this combination therapy.

Selinexor Combined Bortezomib, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma with Extramedullary Disease(EMD) or High-Risk Cytogenetics

BACKGROUND: High-risk(HR) cytogenetics are significantly enriched in MM with EMD , and studies consistently showed EMD and HR cytogenetics were associated with poor outcome. To date, there is no established approach for treatment of newly diagnosed multiple myeloma (NDMM) with EMD. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, which leads to accumulation of tumor suppressor proteins in the nucleus and re-activation of cell cycle regulators such as p53, FOXO, IkB. Meanwhile, by forcing the nuclear retention of the eIF4E protein, Selinexor reduces the cytoplasmic ribosomal translation of oncoproteins, including c-Myc, Bcl-2 and Bcl-6. In the STORM study(NCT02343042), 122 patients(pts) with penta-exposed, triple-class refractory multiple myeloma were enrolled to receive Selinexor combined with low-dose dexamethasone. 27 patients were diagnosed with EMD at baseline. The median age of patients was 64 years, the median prior therapies were 7, and 8 pts had high risk cytogenetics. Follow-up evaluation of plasma cell tumor was performed in 16 cases, and complete disappearance or shrinkage of extramedullary lesions was observed in 9 cases. It indicates that Selinexor has clinical activity in the treatment of plasma cell tumor or EMD. The treatment of MM with EMD or HR cytogenetics still faces great challenges, because there is no uniform guideline and consensus to recommend standard protocols, and prospective clinical studies are urgently needed to explore new treatment strategies. METHODS: Eligible pts were aged≥18 years of NDMM with EMD or HR cytogenetics, and an Eastern Cooperative Oncology Group(ECOG) performance status of 0-2. For induction/consolidation(21-day cycles), pts received 8 cycles of SVRd (Selinexor 60 mg PO weekly, Bortezomib 1.3 mg/m2 SC days1, 4, 8, 11, Lenalidomide 25 mg PO days 1-14, and Dexamethasone 40 mg PO weekly. In maintenance (28-day cycles), pts received SR (Selinexor+ Lenalidomide) at least 2 years until disease progression, death or withdrawal. The primary endpoint was overall response rates (ORR) by end of induction. The secondary endpoints are complete response (CR), duration of response (DOR), progression free survival (PFS), overall survival (OS) and toxicity. This trial is registered with Chinese Clinical Trial Registry, number ChiCTR2200062860. RESULTS: 8 pts with previously untreated NDMM were included from August 2022 to July 2023 in 3 hospitals. Median age was 62 (range 55-81). R-ISS stage 3 was present in 2 (25%) pts(Table 1). Based on inclusion criteria, 7 pts had EMD and 1 patient had HR cytogenetic, including 17p deletion (n=2, 25%), 1q21 gain(n=2, 25%). According to IMWG criteria, the ORR of 8 pts with NDMM was 100%, including 2 stringent complete response(sCR), 3 CR, 2 very good partial response (VGPR) and 1 partial response (PR). 1 patient evaluated with sCR at the end of the induction period was evaluated with MRD negativity after autologous stem cell transplantation (ASCT). Median time to first response in patients with a partial response or better was 1 months (1-2). This result established that SVRd regimen has a prospective response for MM with EMD or HR cytogenetic. The most common grade 3-4 treatment-emergent adverse events (occurring in ≥10% of pts) were thrombocytopenia. The most common treatment-related adverse events were grade 1 or 2, including nausea (25%), fatigue (25%), and anorexia (25%). Overall, the severe toxicities are manageable. CONCLUSIONS: SVRd as induction prior ASCT is safe and allows deep responses in NDMM patients with EMD or HR cytogenetic profile. It is worthy of further study based on the preliminary efficacy results. Longer-term results still require more pts have been enrolled and further follow-up.

The Outcome of Tisagenlecleucel (Tisa-Cel) Vs Axicabtagene Ciloleucel (Axi-Cel) CD-19 CAR-T Cell Therapy in Relapsed/Refractory NHL, Real World Data, Single Institution Experience

ABSTRACT Background: In the Kingdom of Saudi Arabia, non-Hodgkin lymphoma (NHL) reported as 6.1%. The estimated age adjusted incidence is 6/100,000. The more advanced disease stage at presentation reaches up to 40% stage IV. The cure rate with first line of therapy (R-CHOP) reaches up to 70%. The CD 19 chimeric antigen receptor (CAR) T-cell therapy targets CD19-expressing B cells and shows efficacy against B-cell lymphomas. Objective: The registration of CAR-T therapy products at KSA was in 2020 for Tisa-Cel and 2022 for Axi-Cel. The objective is to describe the outcome of the more available CAR-T therapy products in relapsed or refractory NHL. Methods: Retrospective analysis of CAR-T therapy outcome in NHL and compare the outcome of the two products for the same patient's population, using patients' chart electronic file assessment in the tertiary institution treating over 500 new lymphoma per year. Patients: Between November 2020 and May 2023, 44 patients with relapsed or refractory NHL to ≥2 lines of therapy, Follicular lymphoma (FL) relapsed after three lines of therapy counted for four patients treated with Axi-Cel. All patients received an infusion were included in the analysis. Of the 44 patients, 54.5% were male (n=24), the median age was 51 (20-75), and ECOG was 0-3. NHL subtype includes germinal center B-cell (GCB) 52% (n=23) and activated B-cell (ABC) 38.6% (n=17); the disease stage by PET/CT scan was III (47.7%, n=21) and IV (47.7%, n=21). In Axi-Cel group, 9.1% (n=4) received CAR-T as second line for relapse refractory disease or relapse within 12 months of complete remission (CR) after 1 st line therapy. Other patients received at least two lines of therapy prior to CAR-T infusion; 65.9% received ≥ 3 lines of therapy. Seven patients (16%) relapsed after autologous stem cell transplantation (ASCT) have received CAR-T therapy Tica-Cel product (n=6). Four patients (9.1%) have controlled CNS involvement at the infusion time. All patients received lymphodepletion (LD) therapy with fludarabine and cyclophosphamide (Flu/Cy). 25% (n=11) needed bridging chemotherapy therapy before LD, radiation therapy (XRT) bridging was counted for 13 patients (29.5%). The patients' characteristics and disease in Table-1. Results: Overall response rate (ORR), complete responses (CR), partial responses (PR). The respective toxicities include cytokine release syndrome (CRS) and neurologic events namely ICANS. The best ORR was 68.2%; 43.2% of the patients had CR and 25% had PR. The disease progression (DP) was 29.5%. In Axi-Cel group, ORR, CR, PR, and DP was 84.2%, 52.6%, 31.6% and 10.5, respectively. In Tica-Cel group; ORR, CR, PR, and DP was 56%, 36%, 20% and 44%, respectively. The estimated 2 years overall survival was 75% in all patients; 89.5% and 64% in Axi-Cel and Tica-Cel, respectively (p=0.47), Figure1. The estimated overall progressive free survival (PFS) was 61.4% with 73.7% in Axi-Cel group and 52% in Tica-Cel group (p=0.2), Figure2, the best PFS was seen in GCB subtype 65.2% vs 47.1% in ABC, (p= 0.05), Figure4. In FL, PFS was 100%, the patient number is small. PFS was 62.5% in-patient with CRS compared with 50% on non-CRS patient, not statistically significant (p= 0.7), Figure3. The main toxicities post CAR-T cell infusion including cytokines release syndrome (CRS) was 90.9% with 9% grade ≥ 3. In Tica-Cel, grade CRS-IV was 9% while 0% in Axi-Cel. Neurotoxicity (NT)-ICANS was 27% with grade ≥ 3 of 13.6% in both groups (20% in Tica-Cel and 5.6% in Axi-Cel). Tocilizumab was used in 72.7% in all cohorts with higher number of patients in Axi-Cel 17/19 (98.5%). Dexamethasone (Dexa) was used in CRS in 36.4%, in Axi-Cel; 42% of patients received Dexa while 32% in Tica-Cel group. In addition, for treatment of ICANS; Dexa was needed in 31.6% of Axi-Cel patients and 20% in Tica-Cel group. Upon the latest patient's follow-up, two patients (10.5%) in Axi-Cel group and 36% (n=9) in Tica-Cel group died from DP. The outcome of both products is summarized in Table-2. Conclusions: In this single-center retrospective analysis of CAR T-cell therapy in relapsed or refractory NHL or FL in adults, the rates of durable responses were like the real-world data. The best response rate was higher in Axi-Cel group; however, the follow-up duration of disease response is shorter in Axi-Cel group. The toxicity profile is similar in both groups with a bit higher of Grade-III-IV ICANS in Tica-Cel group. Keywords NHL, FL, CAR-T, CRS, ICANS

Efficacy of Brentuximab Vedotin Maintenance Therapy Following Autologous Stem Cell Transplantation in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma with and without Pre-Transplant Exposure to Novel Agents

Background: Maintenance therapy with brentuximab vedotin (BV) after autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) among high-risk patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the phase III AETHERA trial. However, cHL treatment has changed significantly since that trial with frequent incorporation of BV and PD-1 inhibitors into earlier lines of therapy. The efficacy of BV maintenance may be different among pts who receive novel agents before ASCT. Methods: Pts with a diagnosis of R/R cHL who underwent ASCT between 2010 and 2022 were identified at 5 US transplant centers. Pts receiving no systemic post-ASCT maintenance or BV maintenance were included, while pts receiving investigational maintenance treatments were excluded. Medical records were reviewed to identify clinical variables. Results: 921 pts were identified. Median age was 32 yrs (IQR 24-44). 641 pts (70%) had primary refractory disease or relapsed within 12 months of frontline therapy, 326 (35%) had extranodal disease at relapse, and 173 (19%) had B symptoms at relapse. Pts received a median of 2 (1-9) lines of therapy before ASCT, including 295 (32%) who received ≥3 lines. 425 (46%) pts received BV before ASCT (including 24 pts as part of frontline treatment). 70 pts (8%) were BV-refractory (defined as failure to achieve an objective response to any BV-based treatment). 169 (18%) received a PD-1 agent with salvage treatment. 638 pts (69%) had a complete response on pre-ASCT positron emission tomography (PET). BEAM (71%) or CBV (21%) conditioning were used for most pts and 236 pts (26%) received peri-ASCT radiation. 224 pts (24%) received post-ASCT BV maintenance (including 37% of pts undergoing ASCT from 2015-2022). Compared to pts receiving no maintenance, pts receiving BV maintenance were more likely to have primary refractory/early relapsed disease (79% vs 67%, p&amp;lt;0.001), have received only 1 salvage regimen (79% vs 65%, p=0.001), and received BEAM conditioning (83% vs 67%, p&amp;lt;0.001). BV maintenance pts were less likely to receive peri-ASCT radiation (20% vs 28%, p=0.022). The median number of BV maintenance cycles was 10 (1-18) and the most common reason for discontinuation was neuropathy. Median post-ASCT follow-up was 4.9 yrs. 5-yr PFS and OS after ASCT were 70% (95% CI 67-74%) and 85% (83-88%), respectively. Because BV-refractory pts were much less likely to receive BV maintenance (p=0.0044) and had inferior PFS (HR 2.2, p&amp;lt;0.001) (and therefore would serve as a confounder), we excluded BV-refractory pts from additional analyses. Use of BV maintenance was associated with improved PFS (5-yr 81% vs 67%, HR 0.47 [0.33-0.69], p&amp;lt;0.001) and OS (5-yr 92% vs 83%, HR 0.38 [0.20-0.73], p=0.004). The benefit of BV maintenance depended upon pre-ASCT therapy. BV maintenance was associated with a significant improvement in PFS for pts who received no novel agents before ASCT (HR 0.41 [0.25-0.65], p&amp;lt;0.001), but not for BV-treated (HR 0.69 [0.38-1.25], p=0.22) or PD-1-treated pts (HR 0.63 [0.13-3.03], p=0.56) ( Figure). Among pts with 0-1 modified AETHERA risk factors, BV maintenance was not associated with a significant PFS benefit in any treatment subgroup (no novel agents, HR 0.50, p=0.087; BV-treated, HR 1.28, p=0.67; PD-1-treated, HR 2.97, p=0.44). For pts with 2+ modified AETHERA risk factors, BV maintenance significantly improved PFS in the no novel agent group (HR 0.35, p&amp;lt;0.001) but not in the BV-treated (HR 0.55, p=0.099) or PD-1 treated groups (HR 0.24, p=0.19). In multivariable analyses that included key variables (age, year of ASCT, conditioning regimen, peri-ASCT radiation, early relapse/primary refractory disease, B symptoms, extranodal sites, pre-ASCT PET, lines of therapy), BV maintenance was associated with a significant PFS benefit among pts who received no novel agents before ASCT (HR 0.27 [0.12-0.65], p&amp;lt;0.001), but not for pts treated with BV (HR 0.56 [0.28-1.10], p=0.091) or PD-1 blockade (HR 1.10 [0.22-5.56], p=0.91) before ASCT. Conclusions: In this large cohort, BV maintenance was associated with the clearest benefit among pts who received only chemotherapy before ASCT. We were unable to identify a significant improvement in PFS for pts receiving novel agents before ASCT (which could be due to insufficient power to detect a small benefit in this population), suggesting that if these pts benefit from BV maintenance, its impact is likely more limited.

Mass Spectrometry-Based Assessment of M-Protein in Peripheral Blood during Maintenance Therapy in Multiple Myeloma (MM) in the Phase III ATLAS Trial

Introduction Minimal residual disease (MRD) assessment in bone marrow (BM) has emerged as one of the strongest prognostic factors in MM. Mass spectrometry (MS), capable of detecting MM-derived monoclonal proteins in peripheral blood with high sensitivity, has the potential to complement standard methods. While its role in evaluating residual disease and its prognostic performance compared to routine MRD assessments is not yet established, other unanswered questions remain: (1) What is the role of MS in response assessment for patients without a high disease burden baseline sample? (2) What is the optimal timing of MS assessment, considering the long half-life of immunoglobulins? Methods Stored serum samples collected at different timepoints [screening, cycle 6 (C6), C12, C18, C24, C36] from patients treated in the ATLAS trial, were analyzed using the EXENT® Immunoglobulin isotypes (GAM) assay (EXENT® Solution, in development by The Binding Site, part of Thermo Fisher Scientific), which utilizes MALDI-TOF MS. ATLAS is an ongoing phase 3 trial that randomized 180 patients with newly diagnosed MM after autologous stem cell transplantation (ASCT) to maintenance therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) or lenalidomide alone (R). In the KRd arm, patients with standard-risk cytogenetics who achieved MRD-negativity after cycle 6 de-escalated therapy to receive R, from C9. No baseline diagnostic samples were available, and samples were not available for every patient at every timepoint. A sample was called positive by MS when the EXENT® solution confirmed the presence of an M protein, matching the known (diagnostic) isotype. BM MRD was assessed at the same timepoints using multicolor flow cytometry (MFC) with a limit of detection (LoD) of 10 -5 and next-generation sequencing (NGS, clonoSEQ, Adaptive, LoD 10 -6). Progression-free survival (PFS) was analyzed using the Kaplan-Meier method, with log-rank test for comparisons between groups. The data cutoff (31-Dec-2021) was the same as was used in the ATLAS publication by Dytfeld et al. Lancet Oncology 2023. Results 585 samples from 138 patients were analyzed by MS. There were 349 paired BM MRD results by NGS; patients with MRD 10 -5 were considered MRD(+). The overall agreement between the two methods equaled 70%, with a comparable number of patients being MS+/NGS- (56/349, 16%) and MS-/NGS+ (50/349, 14%). The agreement at screening was 61%, but it improved at further timepoints and reached the highest level at C18 (74%). For BM MFC, there were 499 paired samples. There was 67% agreement, and the discrepancy was driven mostly by MS+/MFC- patients (125/499, 25%), whereas MS-/MFC+ was less frequent (40/499, 8%). The agreement was lowest at screening (60%), similarly to the NGS-based assessment, and reached the highest level at C18 (73%). Based on these findings, we concluded that C18 may be the optimal timepoint to assess prognostic role of MS results. Using the landmark method, MS(-) following C18 was associated with superior PFS compared to MS(+) [HR=0.39 (95% CI: 0.17-0.91), p=0.025; Figure 1]. MFC [HR=0.13 (0.04-0.35), p=0.0002], and NGS [HR=0.15 (0.03-0.63), p=0.003] statuses were also associated with PFS using this landmark method. Although small numbers of patients preclude definitive conclusions, we observed a similar effect size in outcomes among NGS(-)/MS(-) vs NGS(-)/MS(+) patients [HR=0.14 (0.01-1.58), p=0.06] and MFC(-)/MS(-) vs MFC(-)/MS(+) [HR=0.40 (0.13-1.27), p=0.11], both favoring BM MRD(-) with concurrent MS(-). Out of the 45 patients who were initially MS(+) and subsequently converted to MS(-), 23 (51%) occurred following C12 or later. Patients who converted from MS(+) to MS(-) had similar PFS to those with sustained MS(-) throughout the analyzed period [HR=0.74 (0.32-1.68), p=0.47; Figure 2], with the majority of PFS events in the converted group occurring during first 18 months of observation. Conclusions MS-based disease assessment in the post-ASCT setting is feasible in many cases, if information on the original MM clone is available by traditional methods. Our results suggest that the optimal timepoint for such evaluation can be as long as 18 months after ASCT. The EXENT® assay may be complementary to BM-based techniques for MRD assessment, allowing for more accurate prognostication when used in combination. Further studies are needed to confirm its exact timing and role in the disease evaluation algorithms.

Favezelimab in Combination with Pembrolizumab in Patients with Anti-PD-1-Naive Relapsed or Refractory Classical Hodgkin Lymphoma: Updated Analysis of an Open-Label Phase 1/2 Study

Introduction: Programmed cell death protein 1 (PD-1) inhibitors such as pembrolizumab play an important role in the treatment of patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but treatment failure remains a significant challenge. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that downregulates T-cell activity and plays a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 demonstrated antitumor activity in patients with advanced melanoma in the RELATIVITY-047 trial, which led to FDA approval in this setting. Favezelimab is a humanized IgG4 monoclonal antibody directed against LAG-3 that is being investigated in combination with pembrolizumab in patients with R/R hematologic malignancies in a multicohort phase 1/2 study (NCT03598608). Prior analyses of this study demonstrated that pembrolizumab 200 mg plus favezelimab 800 mg every 3 weeks (Q3W) exhibited sustained antitumor activity and acceptable safety in the cohort of patients with anti-PD-1-naive R/R cHL (cohort 1). We present updated results from this cohort. Methods: A safety lead-in phase to determine the recommended phase 2 dose (RP2D) was followed by a dose-expansion phase. Eligible patients were ≥18 years of age; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had not received prior anti-PD-1 therapy; and had an ECOG performance status of 0 or 1. In the safety lead-in, patients received pembrolizumab 200 mg IV Q3W and favezelimab at a starting dose of 200 mg that was escalated to 800 mg IV Q3W using a modified toxicity probability interval method. In the dose-expansion phase, patients received pembrolizumab 200 mg Q3W plus favezelimab at the established RP2D of 800 mg Q3W for up to 35 cycles (~2 years). CT was performed every 12 weeks and PET at weeks 12 and 24. The primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Thirty patients with anti-PD-1-naive cHL were enrolled in cohort 1. The median age was 40.5 years (range, 19-82), 17 patients (57%) were male, 16 (53%) had an ECOG performance status of 0, and 24 (80%) had received 3 or fewer prior lines of therapy. At data cutoff (March 2, 2023), 13 patients (43%) had completed 35 cycles of study treatment, 16 (53%) had discontinued treatment (10 [33%] progressive disease, 5 [17%] adverse event [AE], 1 [3%] noncompliance with study drug), and 1 (3%) was ongoing on treatment. The median time from first dose to data cutoff was 31.5 months (range, 24.0-43.2). Treatment-related AEs occurred in 27 patients (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3/4 treatment related AEs occurred in 9 patients (30%). Five patients (17%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 patients (67%); 3 patients (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 patient (3%) had a grade 4 event (hepatitis). Of 5 patients who received allogeneic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3/4 AE (increased blood bilirubin) that was unrelated to study treatment and resolved. The ORR was 80% (n = 24; 95% CI, 61-92); 10 patients (33%) had a complete response and 14 (47%) had a partial response. Twenty-nine patients (97%) had any reduction in target lesions size from baseline, and 25 (83%) had a reduction of ≥50%. Median DOR was 17.0 months (range, 2.6-30.2), and an estimated 47% of responders remained in response ≥24 months. Median PFS was 19.4 months (95% CI, 9.0-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusion: With additional follow-up, the combination of favezelimab and pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in patients with anti-PD-1-naive R/R cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. Further studies to investigate this combination are warranted.

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

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

Overall survival of patients with cHL who progress after autologous stem cell transplant: results in the novel agent era

AbstractIn the pre–novel agent era, the median postprogression overall survival (PPS) of patients with classic Hodgkin lymphoma (cHL) who progress after autologous stem cell transplant (ASCT) was 2 to 3 years. Recently, checkpoint inhibitors (CPI) and brentuximab vedotin (BV) have improved the depth and durability of response in this population. Here, we report the estimate of PPS in patients with relapsed cHL after ASCT in the era of CPI and BV. In this multicenter retrospective study of 15 participating institutions, adult patients with relapsed cHL after ASCT were included. Study objective was postprogression overall survival (PPS), defined as the time from posttransplant progression to death or last follow-up. Of 1158 patients who underwent ASCT, 367 had progressive disease. Median age was 34 years (range, 27-46) and 192 were male. Median PPS was 114.57 months (95% confidence interval [CI], 91-not achieved) or 9.5 years. In multivariate analysis, increasing age, progression within 6 months, and pre-ASCT positive positron emission tomography scan were associated with inferior PPS. When adjusted for these features, patients who received CPI, but not BV, as first treatment for post-ASCT progression had significantly higher PPS than the no CPI/no BV group (hazard ratio, 3.5; 95% CI, 1.6-7.8; P = .001). Receipt of allogeneic SCT (Allo-SCT) did not improve PPS. In the era of novel agents, progressive cHL after ASCT had long survival that compares favorably with previous reports. Patients who receive CPI as first treatment for progression had higher PPS. Receipt to Allo-SCT was not associated with PPS in this population.

Survivin Dendritic Cell Vaccine Safely Induces Immune Responses and Is Associated with Durable Disease Control after Autologous Transplant in Patients with Myeloma.

We investigated whether a dendritic cell (DC) vaccine transduced with an adenoviral vector encoded with full-length survivin (Ad-S), with mutations neutralizing its antiapoptotic function, could safely generate an immune response and deepen clinical responses when administered before and after autologous stem cell transplant (ASCT) for multiple myeloma. This phase I first-in-human trial (NCT02851056) evaluated the safety of DC:Ad-S in newly diagnosed multiple myeloma not having achieved complete response with induction, given 7 to 30 days prior to stem cell collection and 20 to 34 days after ASCT. Anti-survivin antibodies and CD4+ and CD8+ specific T cells were quantified. A total of 14 patients were treated and 13 included in the primary efficacy analysis. No serious adverse events were attributed to DC:Ad-S vaccine. Detectable anti-survivin antibodies increased from baseline in 9 of 13 (69%) patients, and 11 of 13 (85%) mounted either a cellular or humoral immune response to survivin. Seven patients had an improved clinical response at day +90, all of whom had mounted an immune response, and 6 of 7 patients remain event-free at a median follow-up of 4.2 years. Estimated progression-free survival at 4 years is 71% (95% confidence interval, 41-88). Two doses of DC:Ad-S, one given immediately before and another after ASCT, were feasible and safe. A high frequency of vaccine-specific immune responses was seen in combination with durable clinical outcomes, supporting ongoing investigation into the potential of this approach. See related commentary by Dhodapkar, p. 4524.

P-131 Daratumumab (dara) as maintenance therapy after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM): results of a phase 2 study

P-131 Daratumumab (dara) as maintenance therapy after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM): results of a phase 2 study

Cost-effectiveness of brentuximab vedotin in Hodgkin lymphoma: a systematic review.

This study aimed to systematically review and critically appraise cost-effectiveness studies on Brentuximab vedotin (BV) in patients with Hodgkin lymphoma (HL). The PubMed, Scopus, Web of Science core collection, and Embase databases were searched until July 3, 2022. We included published full economic evaluation studies on BV for treating patients with HL. The methodological quality of the studies was assessed using the Quality of Health Economic Studies (QHES) checklist. Meanwhile, we used qualitative synthesis to analyze the findings. We converted the incremental cost-effectiveness ratios (ICERs) to the value of the US dollar in 2022. Eight economic evaluations met the study's inclusion criteria. The results of three studies that compared BV plus doxorubicin, vinblastine, and dacarbazine (BV + AVD) front-line therapy with doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) showed that BV is unlikely to be cost-effective as a front-line treatment in patients advanced stage (III or IV) HL. Four studies investigated the cost-effectiveness of BV in patients with relapsed or refractory (R/R) HL after autologous stem cell transplantation (ASCT). BV was not cost-effective in the reviewed studies at accepted thresholds. In addition, the adjusted ICERs ranged from $65,382 to $374,896 per quality-adjusted life-year (QALY). The key drivers of cost-effectiveness were medication costs, hazard ratio for BV, and utilities. Available economic evaluations show that using BV as front-line treatment or consolidation therapy is not cost-effective based on specific ICER thresholds for patients with HL or R/R HL. To decide on this orphan drug, we should consider other factors such as existence of alternative treatment options, clinical benefits, and disease burden.