Citations

Introduction ABBV-383 is a differentiated BCMA x CD3 bispecific antibody (fully humanized IgG4) T-cell engager composed of a bivalent BCMA binding domain with high avidity, a low-affinity CD3-binding domain, and a present but silenced-Fc tail retaining the FcRn binding allowing for an extended half-life and thereby, enabling dosing convenience. ABBV-383 monotherapy has shown promising activity and improved CRS safety profile with modified dexamethasone (Dex) premedication in patients (pts) with RRMM (NCT03933735; Rodriguez et al., JCO 2024;42[suppl 16]:7531). Here, ER and CRS PK/PD analyses supporting the selection of optimal SUD for ABBV-383 are reported. Methods ER-efficacy (N=286) and -safety (N=290) analyses were conducted using logistic regression methodology (R version 4.3.2) combining data from escalation (0.025-120 mg Q3W) and expansion (20, 40, 60 mg Q3W and 60 mg Q4W) cohorts of phase 1 study NCT03933735 and Arm A of phase 1b study NCT05650632 evaluating step-up dose (2 or 4 mg on Day 1) with a full dose (60 mg on Day 4) in pts with RRMM. Pts received modified Dex with full dose in expansion cohorts of 60 mg Q4W and 2/60 mg Q4W. In all other cohorts with or without SUD, pts received low Dex. Based on prior knowledge (JCO 2024;42[suppl 16]:7541), the safety endpoints (CRS: any-grade and ≥ G2) were modeled with Cycle 1 total (unbound + bound to soluble BCMA) Cmax, while objective response rate (ORR) was modeled with free (unbound + partially bound to soluble BCMA) Cavg. CRS ER models included a priori selected Dex (low vs. modified) and SUD (yes vs. no) as predictors. Relevant pt-specific covariates were tested in all models. CRS PK/PD analyses included total PK, IL-6, and CRS data (N=199) from the first 3 cycles of the above phase 1/1b studies. A semi-mechanistic indirect response PK/IL-6 model was developed to correlate total PK and IL-6 (NONMEM 7.5). Maximal IL-6 concentrations were derived using post hoc estimates from the PK/IL-6 model and correlated with CRS events (logistic regression; R version 4.3.2). The models included effects of time-dependent Dex (low vs. modified) and SUD (yes vs. no). The overall modeling approach was assessed by comparing observed and predicted CRS rates. Simulations were conducted for various dosing regimens, including one or two SUD and Dex premedication scenarios to support the selection of the optimal SUD. Results Consistent with clinical observations (separate abstract submission), any-grade CRS model predicted probabilities suggested two key outcomes: 1) premedication with modified Dex improves the CRS safety profile compared to the low Dex (42% vs 69% for 60 mg Q4W); 2) modified Dex with SUD further improves the CRS safety profile of ABBV-383 compared to low Dex with SUD (29% vs 43% for 2/60 mg Q4W). Consistent with prior work, no ER relationship was observed for ≥ G2 CRS (p > 0.05). The ORR model resulted in a predicted probability of 68% ORR (closely matching with overall observed 64% ORR) with no impact of SUD and modified Dex. Only soluble BCMA was selected as a covariate in the ORR ER model. The final semi-mechanistic PK/IL-6 model well captured the observed IL-6 data, and the CRS rates (predicted by the logistic regression models) closely matched with the observed data. The CRS PK/PD analyses findings were consistent with the clinical observations and ER analyses key outcomes 1 and 2. The CRS PK/PD analyses predictions comparing the 1-SUD vs 2-SUD (untested) regimens with modified Dex suggested that 1) among the 2-SUD regimens with modified Dex, the 2/3/60 mg regimen would have the maximum reduction of 4% points in any-grade CRS compared to the 2/60 mg 1-SUD regimen, however, with substantial overlap of confidence intervals and with no decrease in ≥ G2 CRS (< 0.5% point); 2) 4 mg as an intermediate SUD in a 2-SUD regimen would lead to higher any-grade and ≥ G2 CRS rates (~9% and 3% points higher, respectively), compared to the 2/60 mg Q4W regimen. Conclusions ER and CRS PK/PD analyses suggested that modified Dex and SUD improve the CRS safety profile of ABBV-383 with no impact on efficacy (ORR) in pts with RRMM. The CRS PK/PD predictions indicated that implementation of 2-SUDs provide minimal additional or no improvement in CRS safety profile compared to 1-SUD. Overall, the 1-SUD dosing regimen of 2 mg with modified premedication prior to the full dose of 60 mg Q4W showed promising results and can be considered for future evaluation and studies.

Background: FL3B is the least common among FL subtypes, accounting for 5-10% of cases. Almost half of FL3B tumors have concurrent diffuse large B cell lymphoma (DLBCL) in the diagnostic tissue biopsy, while FL3B rarely coexists with FL1-2 or FL3A. Several lines of evidence suggest that FL3B displays distinct biological and clinical characteristics resembling aggressive DLBCL rather than the indolent FL1-3A. Accordingly, DLBCL anthracycline-containing regimens, such as R-CHOP, are the mainstay of therapy for FL3B with or without coexisting DLBCL. However, while some studies show that R-CHOP therapy in FL3B was associated with 5-year overall survival (OS) rate of 54%, others report outcomes comparable to FL3A with 79-90% survival. Additional controversy involves the clinical implication of pure FL3B (FL3Bp) vs FL3B with concurrent DLBCL (FL3Bc). Thus, it remains unclear if FL3B clinically resembles DLBCL or lower-grade FL and whether FL3Bp has a different prognosis from FL3Bc. To address these questions, we performed a pooled study of two large prospective multicenter study cohorts to compare the clinical characteristics and outcomes of newly diagnosed FL3B with FL1-2, FL3A and DLBCL patients, all of whom were uniformly treated with frontline R-CHOP. Patients and Methods: Weevaluated 469 newly diagnosed patients with FL1-2 (n=216), FL3A (n=170) and FL3B (n=83) who received R-CHOP within 6 months of diagnosis and 739 de novo DLBCL (GCB n=455 and non-GCB n=284) who were prospectively enrolled into the Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts between 2002 and 2021. FL3B cases were designated as FL3Bc and FL3Bp based on the presence or absence of coexisting DLBCL, respectively. Histologic diagnosis was determined by an expert pathologist at each participating center and centrally reviewed. Event free survival (EFS) and OS were defined as time from diagnosis to progression, relapse, retreatment or death, and early progression defined as failing to achieve EFS at 24 months (EFS24). Associations between clinical features and EFS or OS were evaluated using Kaplan Meier curves and Cox proportional hazards models unadjusted and adjusted for age and FLIPI (comparisons with FL1-2 and FL3A) or IPI (comparisons with DLBCL). Results: The median age was 61 years (range, 18-94 years). Among FL3B patients, 21 (25%) had FL3Bc and 62 (75%) FL3Bp. Baseline characteristics and outcomes were broadly similar between the two FL3B subtypes. We then compared all FL3B patients to those with lower-grade FL. Patients with FL3B showed similar clinical features to those with FL1-2 and FL3A, with exception for a lower tumor burden. After R-CHOP, FL1-2 patients had an inferior EFS (HR 2.13 95%CI 1.31-3.46) than those with FL3B, whereas there was no difference compared to FL3A. OS was similar across all FL grades. Although FL1-2 patients failed to achieve EFS24 more frequently than FL3B and FL3A (34% vs 18% and 15%, p<0.001), FL3B patients who did fail EFS24 had almost three folds higher risk of subsequent mortality (HR 2.84 95%CI 1.35-6.01) than other FLs. At 5-year follow-up, FL3B patients had twice the risk of relapse with an aggressive subtype (i.e., DLBCL, high-grade B-cell lymphoma) than those with FL1-2 and FL3A, who instead often recurred with indolent disease (i.e., FL1-2, FL3A; p<0.001). We further compared FL3B patients to those with DLBCL classified based on cell-of-origin into GCB and non-GCB subtypes. At diagnosis, patients with FL3B had more favorable clinical features than those with GCB and non-GCB DLBCL. Compared to FL3B, patients with non-GCB DLBCL had an inferior EFS (HR 1.73 95%CI 1.07-2.79) and OS (HR 2.04 95%CI 1.11-3.75), while those with GCB DLBCL did not show a significant difference in EFS (HR 1.41 95%CI 0.88-2.25) or OS (HR 1.69, 95%CI 0.93-3.06) likely due to insufficient statistical power. Patients with FL3B failed EFS24 less frequently than patients with GCB or non-GCB DLBCL (17% vs 25% and 32%; p=0.01). Among patients who failed EFS24, those with FL3B had a similar subsequent OS as both GCB (HR 1.41 95%CI 0.73-2.72) and non-GCB DLBCL (HR 1.27 95%CI 0.65-2.47). Conclusions: We report that FL3Bp and FL3Bc appear clinically similar. While most FL3B patients have a prognosis comparable to FL1-2 and FL3A, 18% exhibit aggressive behavior with poor outcome reminiscent of DLBCL. Future studies with a larger population will be needed to confirm our findings.

Background: A donor search prognosis score based on HLA type and race/ethnicity can classify patients into 3 groups based on the likelihood of finding an HLA-matched (8/8) unrelated donor (MUD): Very Likely (44% of the population), Likely (41%) and Very Unlikely (15%). Previous studies showed that >90% of Very Likely, 26% of Likely and <10% of Very Unlikely patients used a MUD for their hematopoietic cell transplants (HCT), with the rest using other donor sources (mismatched unrelated donor, cord blood, or haploidentical relative). For some patients, prolonged efforts to identify a MUD might be futile and delay HCT, leading to increased morbidity, greater chance for relapse and disease resistance, and worse HCT outcomes. BMT CTN 1702 (NCT03904134) was the first national study to track the entire donor search identification process. Designed as a biologic assignment study, the goal was to estimate and compare overall survival between two arms: patients who are Very Likely to find a MUD versus those who are Very Unlikely to find a MUD. It tested whether provision of a donor search prognosis score to centers could prevent prolonged futile searches for the Very Unlikely group and improve their transplant rates and outcomes, compared to the Very Likely group. Methods: Eligible diagnoses included acute leukemia, myelodysplastic syndromes, lymphoma, acquired aplastic anemia and sickle cell disease. Patients could be consented at any time after diagnosis until an unrelated donor search was started. Consented patients became evaluable only after it was determined that no appropriate HLA-identical siblings were available. The primary endpoint was survival time after the patient was declared evaluable, regardless of whether HCT occurred, and was compared between the Very Unlikely and Very Likely groups. The target enrollment was 1732 evaluable patients. Because this was a biologic assignment trial and not a randomized trial, formal comparisons of overall survival between the Very Likely and Very Unlikely groups were done using a covariate-adjusted Cox proportional hazards model. The following covariates were a priori specified for adjustment in the model, according to the statistical analysis plan: sex, age, Karnofsky Performance Score (KPS), race/ethnicity, disease, disease status, and interval from consent to evaluability. Results: 1751 evaluable patients were enrolled at 47 centers: 44% female, median age 59.4 years (range 0.6-81.3 years), 73% were non-Hispanic White, 10% Hispanic White, 8% Black, 5% Asian/Native Hawaiian/Pacific Islander, 0.5% American Indian/Alaska Native. Among the evaluable patients, 1181 received a HCT, 827 died, and 924 are still alive with or without HCT, with a median of 25 months of follow up (range=6-54 months [mos], inter-quartile range [IQR]=25-34 mos). The distribution was: 958 Very Likely, 517 Less Likely, and 276 Very Unlikely. Individuals in the Very Unlikely group were younger and were less likely to be non-Hispanic White. The unadjusted cumulative incidences of undergoing HCT by 6 mos and 2 years [yrs], in the Very Unlikely group were 51% and 61% vs. 60% and 69% in the Very Likely Group; after adjustment, there was not a significant difference in the likelihood of undergoing HCT (Dehn et al, submitted). There was no difference in median time from evaluability to HCT: 3.4 mos Very Unlikely and 3.3 mos Very Likely. Unadjusted survival rates from the time of evaluability for the Very Unlikely and the Very Likely groups were: 6 mos (85% vs 84%), 1 yr (69% vs. 69%) and 2 yrs (55% vs. 56%). In the multivariate Cox model, there was no significant difference in the risk of death (HR = 1.07 for Very Unlikely vs. Very Likely, 95% confidence interval 0.86-1.33, p=0.56) adjusting for significant clinical covariates: age, KPS, disease status, and time from consent to evaluability were all significantly associated with overall survival. There was no significant center effect and no interaction between donor search prognosis group and clinical covariates. Conclusion: In this large multicenter BMT CTN study, using the donor selection strategy described, there was no difference in adjusted time to HCT or survival for patients Very Likely versus Very Unlikely to find an 8/8 MUD. These results suggest that patients Very Unlikely to identify a MUD should proceed to HCT using the best available alternative donor rather than delaying HCT to try to identify a MUD.

Introduction Genomic alterations are common in multiple myeloma precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, commonly used stratification systems do not include somatic alterations that play a role in the disease. To address this clinical need, we generated a comprehensive genomic map of MM and precursors by harmonizing and analyzing mostly WGS data from 1,030 patients. We used these data to define a simple MM-like score, that is able to discriminate which premalignant patients are at risk to progress. Methods We collected, enriched, and performed WGS of tumor plasma cells and matched normals from 138 participants with MGUS or SMM, including those in low, intermediate, and high-risk groups. We combined our precursor dataset with genomic profiles from MM (n=20) and external sources of 872 individuals with MGUS (n=18), SMM (n=62), and MM (n=792) for a cohort of 1,030 individuals with MM or a precursor condition. In 16 patients, we could perform WGS serially from the bone marrow or circulating tumor cells (n=39) and reassess the presence of mutations. Results To develop a simple score that reflects the similarity of precursor genomes to full-blown multiple myeloma disease, we searched among the 107 common driver events (occurring in >1% of patients) and initiating translocations for ones that are differently altered in precursor conditions versus MM. We found 26 differentially altered events: only MAF and MAFB translocations were enriched in MGUS/SMM whereas 24 events were enriched in MM, including known drivers MYC, KRAS, FAM46C, del(1p) and gain(1q). We then defined a simple “MM-like” score for each tumor as the number of MM-enriched drivers minus the number of MGUS-enriched drivers. As expected, the MM-like score in our cohort increased throughout MM development (MM-like score median of 1 in MGUS, 2 in SMM, and 3 in MM). Even among SMM patients, we found a gradual increase of the MM-like score from low- (median=1), to intermediate (median=2), to high-risk (median=3) groups that match the overall medians in MGUS, SMM and MM (p=2e-5). We tested whether the MM-like score can be used to estimate risk of progression. Among untreated SMM patients characterized with WGS, an MM-like score greater than 2 was associated with a higher likelihood of progression (HR=5.3, P=0.03). Using an independent dataset of 87 patients with SMM, we were able to validate that a MM-like score greater than 2 was indeed associated with a higher risk of progression (HR=3.3, P=5x10-5). 11 patients who did not progress and for whom we performed longitudinal WGS, has stable MM-like scores over time, while three patients clinically progressed and their MM-like score increased at the time of progression (due to newly detected mutations in KRAS and NRAS). For the two remaining patients, their MM-like score increased, and we observed growth of the subclone that acquired the additional MM-like driver. In the first patient with MGUS/low-risk SMM, a novel hyperdiploid clone was detected in addition to a TP53 bi-allelic hit and t(11;14) translocation and was shown to increase in clonal fraction with tumor burden (light chains +104% within three years). In the second non-progressor with an increasing MM-like score, a novel del(1p) was detected, and other subclones in the phylogenetic tree either shrank or were stable over three years. Finally, because the MM-like score can place tumors on a gradual axis of evolution towards a more genomically-mature tumor, we tested whether the MM-like score was also predictive of survival in patients treated with a newly diagnosed MM. To do so, we calculated the MM-like score in patients from the publicly available CoMMpass database. We found that an increased score significantly correlated with shorter progression-free survival (median PFS1: 3 years in high score, versus 5 years in low/intermediate score; p=1e-3) and overall survival (median OS: 4.5 years in high score, versus not reached in low/intermediate score; p=1e-5). Conclusion Overall, we demonstrate that it is possible to stratify precursor stages of MM by discovering drivers, detecting those that are associated with the stage of the disease, and defining a genomically-based score that can be used to assess risk of progression and is easy to implement in the clinic.

Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on multiple myeloma (MM) cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-mediated killing of MM cells. In an ongoing Phase I dose-escalation and dose-expansion study (GO39775; NCT03275103), cevostamab monotherapy demonstrated target dose (TD)-dependent activity and manageable safety in patients (pts) with heavily pretreated RRMM (Trudel et al. ASH 2021). We report updated efficacy and safety data from pts who received cevostamab once every 3 weeks (Q3W) at the 160mg TD level. Methods: Eligible pts were those with RRMM for which no established therapy was available or appropriate. Cevostamab was initiated with Cycle (C) 1 single-step (SS) dosing, double-step (DS) dosing (Trudel et al. ASH 2021), or triple-step (TS) dosing (step doses on D1, D2 [or D3 or D4 depending on the emergence and resolution of cytokine release syndrome [CRS] with the previous administration], and D8, TD on D9 [or D10 or D11]). Cevostamab was then continued at the TD on D1 of each subsequent 21-day cycle. Cevostamab was continued for 17 cycles, unless disease progression or unacceptable toxicity occurred. Results: As of February 23, 2024, 167 pts (median age: 66 years, range: 40-90; ECOG PS: 0, 35% or 1, 65%; median time from first MM therapy: 6.3 years, range: 0.3-21.8) had received cevostamab at the 160mg TD level (SS: n=10; DS: n=97; TS: n=60); 28% of pts had extramedullary disease and 38% of pts with a conclusive assay result (38/100) had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). The median number of prior lines of therapy was 6 (range: 2-18). Almost all pts (95.8%) were triple-class refractory and 73.7% were penta-drug refractory; 85.0% were refractory to their last prior therapy. A majority (57%) of pts had received ≥1 prior B-cell maturation antigen (BCMA)-targeted therapy. Twenty four percent of pts had received ≥1 prior bispecific antibody. Median observation time was 11.3 months (range: 0.5-42.8). The overall response rate (ORR) in all pts who received cevostamab at the 160mg TD level was 43.1% (72/167 pts); 6.6% achieved a stringent complete response (CR), 6.6% a CR, 12.6% a very good partial response (VGPR), and 17.4% a partial response (PR). The VGPR or better rate was 25.7%. Median time to first response (PR or better) was 1.4 months (range: 0.6-4.6) and to best response was 2.4 months (range: 0.7-13.4). Median duration of response was 10.4 months (95% CI: 6.8, 10.5). ORR was 30.2% (29/96) in pts with ≥1 prior BCMA-targeted therapy and 60.6% (43/71) in those without. ORR was 30.0% (12/40) in pts with ≥1 prior bispecific antibody, 33.3% (20/60) with ≥1 prior chimeric antigen receptor (CAR) T-cell, and 41.2% (14/34) with ≥1 prior antibody-drug conjugate. Common (≥20%) adverse events (AEs) included CRS (74.3%; Grade [Gr] 1: 52.7%; Gr 2: 19.8%; Gr 3: 1.2%; Gr 4: 0.6%), neutropenia (31.1%; Gr 1-2: 3.0%; Gr 3: 12.0%; Gr 4: 16.2%), cough (30.5%; Gr 1-2: 29.9%; Gr 3: 0.6%), nausea (28.1%; Gr 1-2: 27.5%; Gr 3: 0.6%), diarrhea (24.0%; all Gr 1-2), anemia (23.4%; Gr 1-2: 5.4%; Gr 3: 17.4%; Gr 4: 0.6%), and fatigue (21.0%; Gr 1-2: 19.8%; Gr 3: 1.2%). Possible immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 13.2% of pts (Gr 1: 6.0%; Gr 2: 5.4%; Gr 3: 1.8%). Infections occurred in 53.9% of pts, with serious events and Gr ≥3 events in 22.2% and 19.2%, respectively. Treatment-related AEs leading to cevostamab discontinuation occurred in 11 pts (6.6%) and treatment-related Gr 5 (fatal) AEs in 3 pts (1.8%; hemophagocytic lymphohistiocytosis, n=2; disseminated intravascular coagulation and pseudomonal sepsis, n=1). In the 0.3/1.2/3.6/160mg TS cohort, CRS occurred in 19/30 pts (63.3%) and was all Gr 1 (46.7%) or Gr 2 (16.7%). Pts with CRS were managed with tocilizumab (47.4%), steroids (21.1%), or both agents (10.5%). No pts discontinued cevostamab due to CRS and all events were resolved at cut-off. Conclusions: Cevostamab demonstrates clinically meaningful activity and manageable safety at the 160mg TD level in pts with heavily pretreated RRMM. C1 TS dosing provides effective CRS mitigation. Cevostamab combination studies may use the 0.3/1.2/3.6mg TS regimen and the Q3W 160mg TD (or similar TD exposure).

Introduction: Phase I trials are designed to evaluate the safety and tolerability of new treatments. Review of adverse events (AEs) experienced by trial participants is a critical aspect of these early phase trials. Current practice for safety and tolerability data collection is for clinicians to evaluate AEs using the Common Terminology Criteria for Adverse Events (CTCAE). Past work has demonstrated that clinicians may miss or underreport symptomatic AEs. The Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) is an item library of questions for patients to self-report symptomatic AEs in clinical trials that is complementary to the CTCAE. PRO-CTCAE offers a patient-centric method for capturing symptomatic AEs, which may be missed or underreported by clinicians. The PRO-CTCAE library includes questions using patient friendly terms to assess frequency, severity, and interference of symptomatic AEs on 0-4 verbal descriptor scales (e.g., severity is rated by patients as none, mild, moderate, severe, or very severe). The goal of the current work was to demonstrate how to incorporate AE information from PRO-CTCAE and CTCAE into a Phase I dose review report. Methods: We used data from a Phase I clinical trial of patients with relapsed or refractory acute myeloid leukemia. Therapy was administered on 28-day cycles. Patients completed questionnaires on an electronic device on days 1, 8, 15, and 22 of the first cycle of treatment. Through iterative feedback from clinicians and statisticians, we developed an example dose review report. The report summarized data for one dose level in which 4 patients were treated. These 4 patients comprised the first patient cohort enrolled in the available Phase I clinical trial. The report was intended to be representative of the type of report that would be reviewed to make a decision about the next dose level for a new cohort of patients. Results: The final dose review report included narratives for each patient generated by the statistical team based on patient-reported and physician-graded AEs in cycle 1, tabular summaries integrating CTCAE and PRO-CTCAE, and novel graphical presentation of PRO-CTCAE and CTCAE, including swimmer plots and butterfly plots for symptoms listed as dose limiting toxicity criteria. In this cohort, 3/4 (75%) patients had at least one grade 3+ AE, as assessed by CTCAE, and 4/4 (100%) patients had at least one score 3 symptomatic AE, as assessed by PRO-CTCAE. All 4/4 (100%) patients had at least one reported symptom on the PRO-CTCAE that was not captured by CTCAE or was reported at a lower grade by CTCAE. Multiple versions of the example dose review report were presented to the study team and iterative feedback was solicited from clinicians and statisticians. Feedback highlighted the usefulness of narratives and patient-level graphical displays. Narratives within the dose review report were refined to focus on treatment emergent AEs, minimizing text and succinctly presenting baseline symptoms where relevant. Symptom-level graphics of combined PRO-CTCAE scores and CTCAE grades were preferred over graphics consolidating data for multiple symptoms. Final graphics and report will be presented. Conclusions: We demonstrated that PRO-CTCAE, which captures patient-reported symptoms, complements traditional AE reporting and that reporting PRO-CTCAE and CTCAE jointly in a Phase I dose level report can provide a more complete picture of safety and tolerability in the Phase I setting.

Introduction: High-risk smoldering multiple myeloma (SMM) is an asymptomatic precursor disorder to active multiple myeloma (MM) without approved treatment options. However, recent evidence suggests patients at high risk of progression to MM may benefit from early treatment. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA is approved as monotherapy for relapsed/refractory MM (RRMM) and in combination with standard-of-care regimens for RRMM and newly diagnosed MM. Based on the encouraging activity and tolerability observed with DARA monotherapy in patients with intermediate- or high-risk SMM in the phase 2 CENTAURUS study, the phase 3 AQUILA study sought to determine if DARA could delay progression to MM versus active monitoring. Here we report the primary analysis from the AQUILA study. Methods: Eligible patients had a confirmed diagnosis of high-risk SMM for ≤5 years, defined as clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 risk factor (serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 and <100, and/or clonal BMPCs >50% to <60%). Focal and lytic lesion assessment was performed in screening by CT and MRI and centrally reviewed prior to study enrollment. Patients were randomized 1:1 to receive DARA SC versus active monitoring. DARA (QW in Cycles 1 and 2, Q2W in Cycles 3-6, and Q4W thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SLiM-CRAB) or death. Major secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS). Results: A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized. Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months). At a median (range) follow-up of 65.2 (0-76.6) months, PFS was significantly improved with DARA versus active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P <0.0001). Median PFS was not reached in the DARA group versus 41.5 months for active monitoring; estimated 60-month PFS rates were 63.1% versus 40.8%, respectively. Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups. ORR was 63.4% with DARA versus 2.0% with active monitoring (P <0.0001). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment. Median time from randomization to the date of first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI, 0.33-0.62; nominal P <0.0001). There was a positive trend in favor of DARA for PFS2 (HR, 0.58; 95% CI, 0.35-0.96) and OS (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%). Conclusions: DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by positive trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.

Background: Teclistamab (Tec), a first-in-class BCMA bispecific T-cell antibody, received regulatory approval for the treatment of RRMM based on the MajesTEC-1 study [Moreau et al, NEJM, 2022] which demonstrated an overall response rate (ORR) of 63% and median progression free survival (PFS) of 11.3 months. However, less than 15% (N=24) of patients (pts) enrolled in MajestTEC-1 were ≥75 years, an age cohort that is often underrepresented in clinical trials and comprises approximately one third of MM pts at diagnosis [SEER 22 2017-2021]. In this multicenter retrospective study, we report the real-world safety and efficacy of a large cohort of elderly (≥75 years) RRMM pts treated with Tec. Methods: Pts with RRMM who received standard-of-care Tec across 13 U.S. academic institutions were included in the study. The follow-up data cutoff was 30 April 2024. Pts were divided by age into two groups: age <75 years (<75 group) and age ≥75 years (≥75 group). High-risk cytogenetic abnormalities (HRCA) were defined as the presence of del(17p), t(4;14), t(14;16) and/or gain or amplification of 1q21. Disease response and progression was evaluated using IMWG criteria. Time-to-event analyses were evaluated using the Kaplan-Meier method. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) assessment was based on the American Society for Transplantation and Cellular Therapy consensus grading. Results: Among 385 pts, 83 (22%) were in the ≥75 group (median age 78, range 75-92) and 302 (78%) in the <75 group (median age 65, range 31-74). Compared to pts in the <75 group, those in the ≥75 group were more often white (78% vs. 63%, p=0.009). Both the ≥75 and <75 age groups had a median of 6 prior lines of therapy, a similar proportion with ECOG ≥2 at start of Tec (29% vs. 24%, respectively; p=0.37), and a high proportion of pts with triple-class-refractory disease (77% vs. 85%, p=0.06) and pts who would have been ineligible MajesTEC-1 (73% vs. 80%, p=0.20). In contrast, pts in the ≥75 group had a lower incidence of adverse MM risk factors compared to the <75 group, including HRCA (44.6% vs. 57.9%, p=0.03), ultra high-risk (≥2 HRCA) MM (12% vs. 24%, p=0.02), extramedullary disease (22% vs. 40%, p=0.02), hemoglobin <8 g/dL (10% vs. 21%, p=0.02) or albumin <3 g/dL (6% vs. 19%, p=0.04) at the time of starting Tec. Moreover, a lower proportion of pts in the ≥75 group had prior autologous stem cell transplantation (43% vs. 72%, p<0.0001) or prior BCMA-directed therapy (33% vs. 55%, p=0.0003). The median time from diagnosis to start of Tec was longer for pts in the ≥75 group (7.21 years vs. 5.81 years, p=0.02). There was no significant difference in rates of any-grade CRS (52% vs. 59%, p=0.27), CRS grade 2-4 (10% vs. 11%, p=0.74) or any-grade ICANS (19% vs. 13%, p=0.12) between the ≥75 and <75 age groups, respectively. Four pts in the entire cohort developed CRS grade 3-4, one of whom was in the ≥75 group. Ten pts developed grade 3 ICANS (none grade 4), three of whom were in the ≥75 group. There was no significant difference between the ≥75 group and <75 group in ORR (62% vs. 53%, p=0.17) and ≥very good partial response (VGPR) rate (53% vs. 44%, p=0.14). After a median follow-up period of 9.9 months (95% CI 9.6-10.6 months), the median PFS in the ≥75 group was 10.7 months (95% CI 6.6-NR) vs. 5.2 months (95% CI 6.6-NR) in the <75 group (p=0.005). At the time of data cut-off, the median overall survival (OS) for pts in the ≥75 group had not been reached (95% CI NR - NR) compared to 16.1 months (95% CI 14.0 - NR) in the <75 group (p=0.048). In multivariable analysis for the entire cohort, age ≥75 was not significantly associated with either PFS (HR 0.87, 95% CI 0.54-1.39; p=0.55) or OS (HR 0.60, 95% CI 0.30-1.19; p=0.15). Conclusions: This analysis of a large cohort of RRMM pts treated with Tec in the real-world setting demonstrates comparable efficacy and safety outcomes in elderly (aged ≥75 years) pts to those reported in the overall study population of MajesTEC-1. The adverse baseline disease characteristics and inferior efficacy in pts <75 years age compared to ≥75 years likely reflect patient selection and prescribing patterns in the early era of access to commercial BCMA bispecific therapy with Tec. In multivariable analysis there was no significant impact of age ≥75 on survival outcomes. OP, DD & LF: co-first authors. KKP, HCL & AGC: co-senior authors

Introduction. Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two anti-B-cell maturation antigen (BCMA) CAR T therapies, have demonstrated remarkable responses and improved survival among patients with relapsed/refractory multiple myeloma (RRMM) in the clinical trials and standard of care (SOC) setting. Here, we compare safety, efficacy, and survival for patients treated with SOC ide-cel and cilta-cel. Methods. Data were from a retrospective chart review of RRMM patients leukapheresed by 12/31/2022 with the intent to receive SOC ide- or cilta-cel at 19 institutions in the US Multiple Myeloma Immunotherapy Consortium. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type (cilta- vs. ide-cel), balancing on age, sex, race and ethnicity, performance status, extramedullary disease, high-risk cytogenetics, prior BCMA therapy, bone marrow plasma cells, penta-refractory status, lymphodepleting chemotherapy, baseline ferritin, low cell dose, and bridging therapy response. Logistic regression and Cox proportional hazard models were used to examine the association of treatment type with safety, efficacy, and survival accordingly, while adjusting for IPTW weights. We employed propensity score matching utilizing the same covariates to identify the association of treatment type with progression-free survival (PFS) within relevant patient sub-groups. Results. A total of 641 patients were leukapheresed by 12/31/2022 with ide-cel (n=386) and cilta-cel (n=255). 586 patients were infused (n=350 for ide-cel; n=236 for cilta-cel) with a median follow-up of 13.0 and 12.6 months, respectively. After IPTW, patient characteristics were well-balanced. Patients treated with cilta-cel were more likely to have grade ≥ 3 cytokine release syndrome (CRS) (OR=5.52, 95% CI=1.76-17.30, p=0.004), infections (OR=2.07, 95% CI=1.44-2.97, p<0.001), and delayed neurotoxicity (NT) (OR=20.97, 95% CI=4.75-92.42, p<0.001) compared to patients treated with ide-cel. In the cilta-cel cohort, 24 patients (10%) experienced delayed NT compared to 2 patients (1%) in the ide-cel cohort. Although not statistically significant, patients treated with cilta-cel were more likely to have any second primary malignancies (SPMs) (OR=1.87, 95% CI=0.94-3.71, p=0.08) and any SPMs excluding non-melanoma skin cancers (OR=1.78, 95% CI=0.78-4.10, p=0.2) but no association was observed for odds of hematologic SPMs (OR=0.98, 95% CI=0.26-3.61). No association was observed for therapy type with any or severe immune effector cell-associated neurotoxicity syndrome, any CRS, severe cytopenias, and non-relapse mortality. Compared to ide-cel, cilta-cel was associated with better treatment responses of ≥ complete response (OR=2.38, 95% CI=1.61-3.51, p<0.001) and ≥ partial response (OR=1.74, 95% CI=0.99-3.05, p=0.06). Patients treated with cilta-cel had a longer PFS and overall survival (OS) than ide-cel (HR=0.47, 95% CI=0.35-0.62, p<0.001 and HR=0.63, 95% CI=0.42-0.93, p=0.02, respectively), and these findings were similar in the intention to treat cohort (PFS: HR=0.44, 95% CI=0.34-0.55, p<0.001; OS: HR=0.55, 95% CI=0.41-0.73, p<0.001, respectively). We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time-period as FDA approval for cilta-cel (≥ March 2022), restricting to patients with data on all covariates, and restricting to sites that contributed data for both products. In a propensity matched population, (n=380; n=190 for cilta-cel and n=190 for ide-cel), patients treated with cilta-cel had superior PFS compared to those treated with ide-cel in most subgroups with respect to age and disease characteristics including extramedullary disease, high-risk cytogenetics, and elevated baseline ferritin (p<0.05). Conclusion. Our results suggest superior efficacy of cilta-cel with a higher incidence of certain toxicities compared to ide-cel in the SOC setting. This study provides valuable information for patient counseling and guiding the selection of CAR T-cell therapy for specific patient populations. Further validation through similar large-scale real-world experiences or prospective studies is needed to confirm our results and enhance applicability in the clinical setting. *DH, LP, & DD are co-first authors * YL, KP, & SS are co-last authors

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.