Citations

Abstract Introduction: IEC-HS is an emerging and potentially life-threatening complication in multiple myeloma (MM) patients (pts) treated with CAR-T therapies. We conducted a retrospective, multi-institutional analysis to define the features and outcomes of IEC-HS after ide-cel or cilta-cel in the real-world setting. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium for patients with relapsed/refractory MM (RRMM) who received commercial cilta-cel or ide-cel. IEC-HS was defined by each center based on diagnostic criteria (Hines et al, TCT 2023). Kaplan-Meier and multivariable Cox models were used for time-to-event outcomes while logistic regression was used for categorical outcomes. Results: Of 1502 RRMM pts who received either ide-cel (n=712) or cilta-cel (n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. Product-specific incidences were 2.9% for ide-cel and 6.7% for cilta-cel. The median time from CAR-T infusion to IEC-HS onset was 9.5 days (range 2-37 days). IEC-HS-related clinical findings (Hines et al, 2024) included cytopenias (95%), elevated soluble IL-2R levels (79%), fever (76%), elevated LDH (71%, median 1,800 U/L), hypofibrinogenemia (70%), hypertriglyceridemia (65%), ICANS (63%), hepatic transaminase elevation (56%), pulmonary involvement (46%), renal insufficiency (29%), hyperbilirubinemia (22%), and hemophagocytosis in bone marrow (6%). The median interval from peak CRS to IEC-HS onset was 4 days (IQR 1–6). Some variables, such as splenomegaly and coagulopathy, were not systematically collected. Nearly all pts received pharmacologic intervention: corticosteroids (94%, n=59), anakinra (76%, n=48), tocilizumab (71%, n=45), emapalumab (13%, n=8), ruxolitinib (16%, n=10), or etoposide (3%, n=2). Only one pt (2%) did not receive any IEC-HS therapy. Among those evaluable for outcomes, 58% (n=35) improved, 12% (n=7) developed further CAR-T-related complications (e.g., recurrent IEC-HS, delayed neurotoxicity), and 30% (n=18) had no therapeutic response and died. Compared to non-IEC-HS pts (n=1,428), those with IEC-HS were younger (median age 63 vs 66), male (61% vs 57%), and more frequently received cilta-cel (72% vs 52%, all p<0.01). They had higher rates of triple-class (81%) and penta-refractory (43%) disease, greater pre-treatment bone marrow plasma cell burden (40% vs 6%), and higher baseline ferritin (1058 vs 208 ng/mL). Prior autologous SCT was less common, and advanced R-ISS stage was more prevalent. IEC-HS was associated with dramatically worse PFS and OS: with cilta-cel, median PFS was 6.5 months (mo) with IEC-HS (vs 33.1 without); for ide-cel, 8.9 vs 11.4 mo. Median OS for cilta-cel IEC-HS pts was 9.6 mo (not reached in non-IEC-HS pts); for ide-cel IEC-HS, 19.6 mo (vs 40.8 mo). Multivariable analysis confirmed IEC-HS as an independent predictor of shorter PFS (HR 1.88, 95% CI 1.29–2.74, p=0.0011) and OS (HR 2.30, 95% CI 1.39–3.83, p=0.0013). Notably, IEC-HS was not associated with lower response rates – either best CR (63.9% vs 64.0%, p=0.71) or ORR (91.8% vs 90.9%, p=0.97). Cilta-cel pts had a higher probability of achieving a deep (CR) response, regardless of IEC-HS status. Grade > 3 CRS occurred in 14% (n=3/21) of ide-cel and 15% (n=8/52) of cilta-cel IEC-HS pts, versus 2% (n=12/691) and 2% (n=13/737) in non-IEC-HS pts, respectively. Any-grade ICANS was observed in 67% (n=14/21) of ide-cel and 55% (n=29/52) of cilta-cel IEC-HS cases, compared to 26% (n=179/690) and 20% (n=148/738) in non-IEC-HS. Grade ≥3 ICANS occurred in 29% (n=6/21) of ide-cel and 26% (n=14/52) of cilta-cel IEC-HS cases, relative to 4% (n=25/690) and 4% (n=27/738) in pts without IEC-HS. Severe infections were also more common: 71% (n=15/21) of ide-cel and 53% (n=28/52) of cilta-cel IEC-HS pts experienced at least one infection, compared to 31% (n=214/691) and 29% (n=217/737) in non-IEC-HS groups. Conclusions: IEC-HS is an uncommon but severe and early complication after CAR T-cell therapy for RRMM. Despite similar ORRs with or without IEC-HS, IEC-HS was associated with significantly worse PFS and OS for both ide-cel and cilta-cel. These findings support the need for vigilant monitoring and potential preemptive treatment strategies to better manage this syndrome.

Abstract Background: Real-world data suggest that safety and efficacy of ide-cel and cilta-cel mirror data from pivotal trials, yet older adults remain underrepresented. We report outcomes of the largest cohort of RRMM patients aged ≥75 years receiving CAR-T and compare them with propensity-matched younger patients. Methods: We retrospectively analyzed RRMM patients receiving standard-of-care BCMA CAR-T at 15 centers from the US Myeloma Immunotherapy Consortium between May 2021 and December 2024. Patients ≥ 75 years were 2:1 propensity-matched to patients < 75 based on CAR-T product, sex, performance status, extramedullary disease, baseline ferritin, penta-refractory status, bridging therapy, prior autologous SCT and lines of therapy. Continuous outcomes were analyzed with multivariable linear regression, binary outcomes with logistic regression, and time-to-event endpoints with Cox proportional-hazards models. We estimated average treatment effects via G-computation, using cluster-robust standard errors to account for the matched sets. Results: After 2:1 propensity matching, the cohort included 194 patients ≥ 75 years (cilta-cel: 64 and ide-cel: 130) and 388 patients < 75 years (cilta-cel: 128, ide-cel: 260). Median ages were 78 (range: 75-90) for the older cohort vs 65 (range: 35-74) for the younger cohort. The older cohort had a higher frequency of t(14;16) (9% vs. 3%, p = 0.005), lower baseline ferritin (151 vs. 196 ng/mL, P = 0.046), and lower likelihood of prior ASCT (57% vs. 71%, P = 0.001). Median prior lines of therapy were 5. Median follow-up time for ≥ 75 and < 75 groups for cilta-cel was 11.5 and 11 months and for ide-cel was 16 and 24.3 months, respectively. ORR did not differ amongst the older vs younger patients: cilta-cel (97% vs. 97%) and ide-cel (90% vs. 88%).For patients ≥ 75 years, median PFS with cilta-cel was 28.7 months (95% CI: 13.3–NR) and with ide-cel was 16.4 months (95% CI: 12.1–22.4). In patients < 75 years, median PFS was not reached for cilta-cel but was 11.5 months (95% CI: 9.6–12.7) for ide-cel, reflecting inferior PFS with ide-cel in the younger group (HR 0.4, 95% CI 0.3–0.6). On sensitivity analysis by Cox proportional hazards model, we did not observe any statistically significant differences in PFS in older vs younger patients receiving cilta-cel, although older patients paradoxically had better PFS with ide-cel compared to their matched younger cohort. In the cilta-cel cohort, HR for PFS for older vs younger patients was 1.48 (95% CI:0.77-2.84; p=0.2) and in the ide-cel cohort it was 0.7 (95% CI: 0.5, 0.98; p=0.04). Median OS was reached only in the < 75-year ide-cel cohort at 40 months (95% CI: 32.5–43.5). Rates of CRS were similar, with any-grade (grade ≥3) CRS seen in 74% vs 78% (0% vs. 0.8%) of cilta-cel recipients and 86% vs. 87% (3.1% vs. 1.5%) of ide-cel recipients in the older vs younger groups, respectively. ICANS rates were 21% vs. 20% for cilta-cel (p = 0.79) and 29% vs 20% for ide-cel (p = 0.07), with similar rates of grade ≥ 3 ICANS. In the cilta-cel cohort, Parkinsonian delayed neurotoxicity (DNT) occurred in 3/62 (4.8%) older patients and 6/128 (4.7%) younger patients. Similarly, other non-Parkinsonian DNT rates were similar across age groups, with 6.4% vs 5.5% in older vs younger cilta-cel cohort and 0% vs 1% in the older vs younger ide-cel cohort. Rates of IEC-HS, and infections were comparable across the cohorts. There was no difference in hospital length of stay and ICU admission rate between products within either age cohort. The overall non-relapse mortality (NRM) was 6.7% for patients ≥ 75 years and 6.2% in patients < 75 years. For cilta-cel, NRM in older vs younger cohort was 9.4% vs 4.7% (p= 0.96) and for ide-cel it was 5.4% vs 6.9%, respectively (p= 0.65). Conclusion: Appropriately selected older adults (≥75 years) receiving CAR-T therapy for RRMM can derive a similar efficacy benefit with CAR-T as a propensity-matched younger cohort, without any increased signal of toxicity including CRS, ICANS or delayed NT. NRM was numerically greater, but not statistically significant, in older adults receiving cilta-cel. Median PFS with cilta-cel and ide-cel in older adults were 28.7 months and 16.4 months with median OS not reached and 40 months, respectively. Older adults, ≥75 years old, should not be excluded from CAR-T therapy solely due to advanced age. Overall, cilta-cel was not associated with worsened toxicities in older adults and may offer better PFS.

Abstract Introduction : Current standard of care for smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), is observation until progression to active MM. Increasing evidence suggests that patients (pts) with SMM at high risk for progression to active MM may benefit from early treatment (tx). In AQUILA, a phase 3 study in pts with high-risk SMM (NCT03301220), daratumumab (Dara) monotherapy significantly reduced risk of progression to active MM or death with a trend of extending overall survival (OS) vs active monitoring (ActMon), with no new safety concerns. Given the evolution in SMM risk stratification, a post hoc analysis was performed to assess outcomes using the IMWG 2020 and IMWG 2020 plus cytogenetic risk models to assess which AQUILA pts benefited most from Dara monotherapy. Safety and efficacy analysis by age and stem cell collection outcomes were also assessed. Methods: Eligible pts with a confirmed diagnosis (≤5 y) of high-risk SMM per IMWG 2014 criteria, defined as clonal bone marrow plasma cells (BMPC) ≥10% and ≥1 risk factor (IgA SMM, serum protein ≥30 g/dL, serum involved:uninvolved free light chain [I/U FLC] ratio ≥8 and <100, immunoparesis with reduction of 2 uninvolved Ig isotypes, and/or clonal BMPC >50% to <60%) at study entry, were randomized 1:1 to receive subcutaneous Dara or ActMon for 39 cycles, 36 months, or until confirmed disease progression (PD), whichever came first. Primary endpoint was progression-free survival (PFS) assessed by independent review committee, defined as progression to active MM (based on IMWG SLiM-CRAB diagnostic criteria) or death. Secondary endpoints included time to first-line (1L) MM tx and OS. For this post hoc analysis, we assessed outcomes by age, IMWG 2020 high-risk SMM criteria (BMPC >20%, monoclonal spike >2 g/dL, serum FLC ratio >20; ≥2 factors=high risk; also known as the Mayo 2018 or the 20-2-20 criteria), and the IMWG 2020 plus cytogenetic criteria (IMWG 2020 criteria + presence of ≥1 high-risk cytogenetic abnormalities [t(4;14), t(14;16), +1q and/or del13q]; ≥3 factors=high risk). Results : Dara tx showed a PFS benefit across all IMWG 2020 risk subgroups (low: hazard ratio [HR], 0.59; intermediate: HR, 0.70), with the largest benefit in the high-risk subgroup, where the PD/death rate in the ActMon arm was ~1.6-fold that in the Dara arm (62.8% vs 37.5%; HR, 0.36). This benefit of Dara vs ActMon was preserved over time, with 5-year PFS rates of 78.2% vs 71.6%, 56.2% vs 42.9%, and 60.4% vs 23.6% in IMWG 2020 low-, intermediate-, and high-risk groups, respectively. There was a positive trend favoring Dara for time to 1L MM treatment across all IMWG 2020 risk groups (low-risk HR, 0.63; 95% CI, 0.22–1.80; intermediate-risk HR, 0.57; 95% CI, 0.35–0.92; high-risk HR, 0.39; 95% CI, 0.25–0.62). IMWG 2020 plus cytogenetic risk classification results will be available at the time of presentation. When comparing the younger (<65y HR, 0.51; 95% CI, 0.32–0.79) vs the older (≥65y, HR, 0.50; 95% CI, 0.32–0.77) pt population, a PFS benefit was observed regardless of age. Similarity was also observed in TEAE incidence rate when looking into <65, 65 to <75, and ≥75 y subgroups (82.7%, 81.1%, and 87.5% with ActMon; 96.2%, 98.5%, and 95.2% with Dara); however, serious TEAEs were more frequently observed in older ActMon pts (12.2%, 18.9%, and 50.0% with ActMon; 24.8%, 35.8%, and 28.6% with Dara). Across all pts treated/monitored in AQUILA, 23 (11.9%) and 41 (20.9%) pts in the Dara and ActMon arms, respectively, received autologous stem cell transplant as part of their first tx after progressing to active MM, with very limited plerixafor use (Dara, 3 [1.6%] vs ActMon, 9 [4.6%]). Median (range) CD34+ cell yield was 5.0 (2–20)×106 cells/kg body weight among 22 pts in the Dara arm and 5.1 (2–21)×106 cells/kg body weight among 39 pts in the ActMon arm. Conclusions : In this analysis, pts with high-risk SMM from the phase 3 AQUILA study treated with Dara monotherapy experienced long-term PFS benefit across IMWG 2020 subgroups, with the most pronounced benefit in the high-risk subgroup. No notable differences in PFS or safety were observed across age subgroups. Early Dara tx for high-risk SMM did not have a detrimental impact on stem cell yield. Although mature OS analyses are forthcoming, overall, these results further support early intervention with Dara monotherapy vs ActMon among pts with high-risk SMM, regardless of risk stratification criteria used.

Abstract Background Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare blood disease characterized by uncontrolled complement activation with potentially life-threatening complications. Therapeutic options comprise both terminal complement inhibition, targeting C5 to prevent intravascular hemolysis (IVH), and proximal complement inhibition, intervening upstream within the complement cascade to address IVH and extravascular hemolysis (EVH). Pegcetacoplan, the first C3 and C3b inhibitor, demonstrated efficacy and safety in complement inhibitor (CI)–experienced (CIexp) and –naïve (CInaive) patients in two phase 3 studies with a three year follow up (PEGASUS [NCT03500549] and PRINCE [NCT04085601]). The aim of this study was to describe real world clinical and treatment outcomes in CIexp and CInaive PNH patients prescribed pegcetacoplan. Methods Data were drawn from the Adelphi PNH II Disease Specific Programme™, a real-world cross-sectional survey of hematologists and their consulting PNH patients. Data were collected from November 2023–January 2025 in Canada, France, Germany, Italy, Spain, the UK, and the US. Patients prescribed pegcetacoplan for ≥3 months were included and described as CIexp if they had previously been treated with CI, or CInaive if patients had never been prescribed CI therapy. Physicians reported patient demographics, clinical characteristics, and treatment outcomes. Patients provided data on patient-reported outcomes, including the EQ-5D-5L and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Response to pegcetacoplan was categorized as no, minor, partial, good, major or complete response per SAAWP-response criteria (Risitano et al, 2019). Analyses were descriptive. Results Overall, 54 physicians provided data for 77 patients prescribed pegcetacoplan (54 CIexp patients and 23 CInaive patients). Median (interquartile range [IQR]) age was 45.0 (33.5–55.0) years (CIexp, 47.0 [37.0–60.8]; CInaive, 39.0 [30.0–45.0]), 63.6% (Cexp, 64.8%; Cnaive, 60.9%) were male, 57.9% (CIexp, 50.9%; CInaive, 73.9%) were in employment. Median (IQR) time since diagnosis was 2.4 (1.3–4.9) years (Cexp, 3.1 [2.0–5.5]; Cnaive, 1.3 [0.8–2.3]) with median (IQR) time since start of pegcetacoplan initiation being 0.6 (0.4–1.0) year (CIexp, 0.6 [0.4–0.9]; CInaive, 0.6 [0.5–1.2]). Clinical outcomes were measured at treatment initiation and the time of survey, and reported as median (IQR). Hemoglobin levels increased from 9.0 (8.0–9.2) to 11.0 (10.3–12.1) g/dL, and 9.0 (7.0–10.5) to 11.5 (10.6–12.0) g/dL, for Cexp (n=52) and Cnaive (n=21), respectively. Lactate dehydrogenase levels decreased from 490 (295–594) to 260 (189–377) U/L for Cexp (n=53), and 275 (214–775) to 220 (187–278) U/L for Cnaive (n=18). Absolute reticulocyte counts decreased from 200 (135–275) to 113 (105–217) x109/L for Cexp (n=19) and 160 (113–250) to 110 (100–134) x109/L for CInaive (n=7). Positive movement by at least one response category since pegcetacoplan initiation were observed in 85.2% CIexp (n=27) and 61.5% CInaive (n=13); with patients classified as having a ‘good’, ‘major’ or ‘complete’ response increasing from 3.7% to 74.1% for CIexp and 23.1% to 69.2% for CInaive. Perceived severity of PNH improved after pegcetacoplan initiation, with ‘mild’ severity increasing from 13.0% to 68.5% and 34.8% to 87.0%; patients experiencing no fatigue increased from 5.6% to 57.4% and 8.7% to 65.2%, for CIexp and CInaive, respectively. For both CIexp and CInaive, complete treatment adherence was reported for 87.0% of patients. Since pegcetacoplan initiation, proportion of ‘well’ or ‘very well’ controlled PNH patients increased from 14.8% to 96.3% for CIexp and 52.2% to 100.0% for CInaive. Overall, 25 patients self-reported data (n=14 CIexp; n=11 CInaive). Patients reported a mean (Standard Deviation [SD]): EQ-5D VAS score of 66.8 (16.0) and 76.7 (18.7); EQ-5D utility score of 0.86 (0.16) and 0.91 (0.13); FACIT-Fatigue 41.1 (9.5; n=13)and 37.1 (12.2; n=11) for CIexp and CInaive, respectively. Conclusion Improvements in clinical values, perceived PNH severity, control of PNH, and both physician and patient-reported fatigue were observed in CIexp and CInaive patients. These data suggest that pegcetacoplan has positive outcomes regardless of prior CI exposure. These findings indicate that the efficacy of pegcetacoplan in a real-world clinical practice is consistent with results from clinical trials and other real-world evidence for both CIexp and CInaive patients.

Abstract Background: Multiple myeloma (MM) is always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage or high tumor cell burden (i.e. SLiM criteria, SV Rajkumar Lancet Onc 2014), as morphology and cytogenetics cannot reliably distinguish them. Methods: To identify genomic features underlying clinical behavior in MGUS and SMM, a total of 374 patients with SMM (n= 290) or MGUS (n=84) with available whole exome (whole exome sequencing, WES, n=190) or whole genome sequencing (whole genome sequencing WGS, n=184) were included in the study. Overall, none of the patients had evidence of SLiM or CRAB criteria at the time of the biopsy. Based on the center of origin and availability of WES and WGS, 227 and 97 patients were used to form our study training and validation set. The study was designed in two parts: 1) defining a new classification for MM precursor conditions; 2) integrating genomics to existing prognostic score to improve accuracy in identifying patients at imminent risk of progression. Overall, 68 patients in the training set were either lost to follow-up or enrolled in a clinical trial and they were only included in the classification part of the study. Results: By leveraging the distribution of established MM-defining genomic events (Maura et al. JCO 2024) in the training set, we developed a workflow that differentiates MGUS and SMM into two genomically distinct entities: one with evidence of neoplastic transformation (i.e., genomic MM) and one without (i.e., genomic MGUS). Overall, 39% of MGUS and 91% of SMM cases had genomic evidence of neoplastic transformation in the training set (i.e., genomic MM). When we applied the same workflow and classification to the validation set, 46% and 83% of MGUS and SMM had evidence of neoplastic transformation, respectively. Importantly, none of the patients classified as genomic-MGUS progressed to MM in either the training or validation cohorts, with a median follow-up of 40 and 61 months, respectively. Moreover, all patients with IMWG 2/20/20 high risk SMM were classified as genomic MM in both the training and validation set. Interestingly, 5 out of 62 (8%) patients enrolled in early intervention trials for high risk SMM were genomically classified as genomic-MGUS. Overall, these data demonstrated that the MM genomic background and neoplastic transformation can be acquired very early in time, even before the SMM phase, in line with what observed in solid tumors. To avoid overestimating the prognostic impact of myeloma-defining genomic events—which are, by definition, enriched in the genomic-MM group compared to genomic-MGUS—we restricted our prognostic analysis to patients in whom transformation has already occurred (genomic-MM). In fact, distinct genomic drivers may predict malignant transformation but not necessarily the risk of imminent progression to MM once transformation has occurred. After running 5-fold cross validations corrected for IMWG 2/20/20, only presence of RAS mutations, genomic events involving MYC, presence of neoplastic copy number variant (CNV) signatures and APOBEC mutagenesis were predictive of early progression in the training set. Adding the presence of high-risk myeloma-defining genomic events to the IMWG 2/20/20 model (i.e., genomic-IMWG) significantly improves the accuracy of predicting MM progression in both the training (c-index 0.69 vs. 0.74) and validation sets (c-index 0.74 vs. 0.79), compared to the IMWG 2/20/20 alone. Conclusion: By leveraging comprehensive genomic profiling integrated with the clinical IMWG 2/20/20 risk score, we propose a novel classification and prognostication system for MM precursor conditions, which will better define patients who may benefit from early therapeutic intervention versus watch-and-wait monitoring.

Abstract Background B-cell maturation antigen (BCMA)-targeting immunotherapies represent a promising class of treatment for the management of immunoglobulin light chain (AL) amyloidosis, a disease that is related to clonal plasma cells. Etentamig is a 2nd generation, off-the-shelf, fully human BMCA X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing plasma cells and CD3-expressing T cells. Etentamig monotherapy is being studied in multiple myeloma (MM) in an ongoing phase 3 study (NCT06158841). Here, we report the first safety and efficacy results from M24-209, an open-label phase 1/2 study evaluating etentamig monotherapy in patients (pts) with relapsed/refractory (RR) AL amyloidosis from dose level 1 (DL1). Methods The phase 1 dose escalation (ESC) portion of the study (NCT06158854) with etentamig enrolled pts with RR AL amyloidosis with ≥1 prior lines of therapy (LOT), including a proteasome inhibitor and an anti-CD38 monoclonal antibody with no prior BCMA exposure. Eligible pts were required to have a difference in involved and uninvolved serum free light chain (dFLC) of ≥50 mg/L, and pts with Mayo Clinic 2004 cardiac risk stage IIIb with NT-proBNP ≥8500 pg/ml were excluded. Three dose groups were explored in dose ESC (etentamig dose levels [DL] 1, 2, and 3). In all cohorts, pts will receive up to 24 cycles of treatment and will be followed until disease progression. In dose ESC, the primary objectives are to determine safety/tolerability, pharmacokinetic/pharmacodynamic, and recommended phase 2 dose. The secondary objectives include evaluation of efficacy as measured by hematologic response and organ response. Responses are investigator assessed per consensus guidelines (Comenzo, et al. Leukemia. 2012. 26[11]:2317-25; Palladini G, et al. Amyloid. 2021 [Epub];28[1]:1-2). Results As of 17 July 2025, all DLs in dose ESC have been fully enrolled, and 12 pts have been treated with etentamig at DL1. Due to short follow-up, this initial report only includes data from DL1, with further follow-up data from ESC to be included at the time of presentation. Median duration of follow up in DL1 was 9.4 months (8.3–13.8) with 83% of pts continuing treatment. Median age for pts was 72 years (range, 56–85 years). Median number of prior LOT was 2 (range, 1–6), and median time from initial diagnosis was 3.6 years. Thirty-three percent have received a prior stem cell transplant and 50% previously received the regimen of daratumumab with cyclophosphamide, bortezomib, and dexamethasone in combination. Median dFLC at study baseline was 110. 5 mg/L (range, 56.6–617.5). At baseline, 83% of pts had cardiac involvement, 25% had renal involvement, and 8% had hepatic involvement. Eighty-three percent of pts had lambda AL amyloidosis. Treatment-emergent adverse events were reported in 100% (42% Grade ≥3) of pts at DL1. Cytokine release syndrome (CRS) occurred in 2 pts (17%, all Grade 1), with no instances of any grade immune effector cell-associated neurotoxicity syndrome (ICANS). CRS occurring after the first dose had median time to onset of 6.8 hours (range, 6.7–6.9). Grade ≥3 infections occurred in 1 pt (8%, all Grade 3). Grade ≥3 neutropenia also occurred in 1 pt (8%, all Grade 3), and no Grade ≥3 events of thrombocytopenia or anemia occurred. No Grade 5 events have occurred. Within the dose ESC DL1 cohort, the overall hematologic response rate was 100%, with all pts achieving ≥VGPR and 83% of pts achieving complete response (CR). The median time to CR was 0.9 months (0.3–9.3). The median duration of response has not yet been reached and 100% of pts remain in their best overall response by investigator assessment. To date, no pts have experienced hematologic progression on study. Cardiac response was observed in 30% of evaluable pts. Renal response was seen in 67% of evaluable pts. Conclusions In the DL1 cohort, etentamig showed a manageable safety profile in AL amyloidosis with low incidence and severity of CRS, no ICANS, and limited Grade ≥3 cytopenia events. Deep and rapid hematologic responses were observed with 100% ≥VGPR rate and 83% hematologic CR rate. Additional dose-level data will be presented at the time of the meeting. All pts remain in ongoing follow-up and evaluation, and the study will begin the dose expansion (EXP) portion after dose selection.

Abstract Introduction Although chemo-free regimens are increasingly used in elderly patients with large B-cell lymphoma (LBCL), most still receive conventional chemoimmunotherapy. Patients up to 75–80 years old are usually treated with full-dose R-CHOP, while 80+ patients receive the attenuated R-miniCHOP regimen as standard of care. Prior studies have shown that in patients aged 65+ years, R-CHOP was associated with improved survival based on propensity score matching (PSM) analysis (Al-Sarayfi, Am J Hematol, 2023), though this did not include comorbidity data. Furthermore, no formal studies have focused specifically on 80+ patients. We aimed to perform a PSM comparison of R-CHOP versus R-miniCHOP to better inform treatment decisions in this population. Methods We harmonized and pooled data from 237 LBCL patients receiving chemotherapy with rituximab (out of all 263 80+ patients) from the prospective LEO cohort (USA, n=147; 2015–2020) and NiHiL registry (Czech Republic, single center, n=116; 2010–2023). Of them, 205 (86%) receiving anthracycline(A)-based regimens were included. Baseline characteristics, comorbidities, treatments, and outcomes were collected. PSM (1:1, caliper 0.2) was performed to compare R-CHOP and R-miniCHOP using age, ECOG performance status (PS), clinical stage, lactate dehydrogenase (LDH), and major comorbidities (heart disease, history of stroke, and other recent cancer) as matching variables. The endpoints were overall survival (OS), event-free survival (EFS), and lymphoma-specific survival (LSS, defined as death attributed to lymphoma progression). Results Among 205 A-treated patients, median age was 83 years (range 80–99); 30% had ECOG PS 2–4, 67% clinical stage III–IV, 34% ≥2 involved extranodal sites, 59% elevated LDH, and 58% had International Prognostic Index (IPI) scores 3–5. Median follow-up was 5.5 years; median OS and EFS were 4.1 and 3.4 years, resp. A-based regimens comprised full-dose R-CHOP-like (n=79; 39%; R-CHOP n=74, DA-EPOCH-R n=5) and R-miniCHOP (n=126; 61%). Patients receiving R-CHOP-like regimens had more favorable baseline characteristics (median age 82 vs 83 years, P=0.04; ECOG PS 2–4: 16% vs 39%, P<0.01; IPI 3–5: 46% vs 66%, P=0.03) and a lower, though not statistically significant, comorbidity burden (mean 1.14 vs 1.39; heart disease 35% vs 45%, P=0.22; history of stroke 4% vs 6%, P=0.64; other cancer 6% vs 5%, P=0.87). R-CHOP-like regimens vs R-miniCHOP had superior OS (median 6.3 vs 3.4 years; HR=0.61, 95% CI 0.42–0.90; P=0.01) and EFS (median 5.3 vs 2.1 years; HR=0.58, 95% CI 0.40–0.83; P<0.01), with no significant difference in LSS (2-year 89% vs 82%, HR=0.77, 95% CI 0.39–1.54, P=0.46). To mitigate selection bias, we performed PSM on patients with available baseline characteristics treated with R-CHOP (n=69) and R-miniCHOP (n=121), resulting in 63 matched pairs. Matched cohorts were well-balanced on age (median 82 years in both cohorts; P=0.68), ECOG PS 2–4 (17% vs 19%; P=0.82), IPI 3–5 (52% vs. 59%; P=0.41), and comorbidity burden (mean 1.10 vs. 1.29; P=0.30). The presence of heart disease (40% in both cohorts), history of stroke (5% vs 6%), and cancer (5% vs 6%) were similar. Survival modestly favored R-CHOP, but differences were not significant: median OS 5.3 vs 3.5 years (HR=0.73; 95% CI 0.46–1.15; P=0.17), median EFS 3.8 vs 2.8 years (HR=0.76; 95% CI 0.49–1.18; P=0.23), and 2-year LSS 88% vs 84% (HR=1.09; 95% CI 0.45–2.63; P=0.85). Treatment-related mortality was similar in both cohorts (16%). Among R-miniCHOP patients, survival outcomes did not differ between matched (n=63) and unmatched (n=63) groups (OS P=0.72; EFS P=0.23; LSS P=0.27). Unmatched (n=16) R-CHOP patients had a trend toward improved survival compared to matched (n=63) individuals (OS P=0.10; EFS P=0.049; LSS P=0.24). Conclusion This is the first PSM-based analysis comparing R-CHOP and R-miniCHOP in LBCL patients 80+ years old. Despite inherent limitations of a non-randomized design and limited number of matched patients, our findings – derived from two prospective cohorts – suggest that R-miniCHOP may offer outcomes comparable to R-CHOP, particularly with respect to LSS. While these results support R-miniCHOP as an appropriate frontline option, treatment decisions remain highly individualized. These data may help inform clinical decision-making and provide a basis for designing future trials targeting this population, where R-miniCHOP could serve as a comparator arm. Funding: NU21-03-00411, U01 CA195568.

Abstract Introduction CAR T cell treatment is the standard of care for patients (pts) with primary refractory and relapsed large B-cell lymphoma (LBCL) within the first 12 months of chemoimmunotherapy, or for those unfit for autologous stem cell transplant (ASCT) regardless of timing of relapse. Consequently, the role of ASCT is limited to pts with late relapse (>12 months) who achieve a complete or partial response (CR or PR) to salvage therapy and are deemed eligible for ASCT based on comorbidities and performance status. In this report, we evaluated post-ASCT outcomes in this population of pts. Methods We conducted a retrospective cohort study using publicly available data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult pts (age ≥18 years) with DLBCL, NOS, and high-grade large B-cell lymphomas (HGBL) who relapsed after having responded to initial treatment and who remained on response for at least 12 months since diagnosis were selected. We considered for this analysis only pts who achieved a CR or PR after salvage treatment at the time of relapse, documented on pre-ASCT CT or PET scan (per the 2014 Lugano definition). CIBMTR databases used for this study included pts who received ASCT from 2013 to 2021. We compared baseline characteristics between ASCT in CR vs PR using the Wilcoxon rank sum test for continuous variables and the Pearson's χ2 test for categorical variables after ignoring missing data. Primary endpoints included Progression-free survival (PFS) and overall survival (OS). Non-relapse mortality (NRM) and relapse rate were among the secondary endpoints. Results 182 were included in the analysis: 100 were in CR and 82 in PR before ASCT. The median age at ASCT was 60 years (range, 26-79). Race distribution was similar across CR and PR pts. Advanced-stage disease at diagnosis (stage III–IV) was seen in 61% of CR pts and 55% of PR pts. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements was similar in the CR and PR groups (7% vs 4%). The median number of lines of treatment before ASCT were identical in CR and PR pts (N=2). BEAM was the most frequently used transplant conditioning regimen in both groups (80%). Median follow-up after ASCT was 34 months (range, 1–95): it was 37 months (range 1-95) in the CR group and 26 months (range 1-79) in the PR group For the entire cohort, OS at 3 years was 67.6% and PFS was 50.6%. NRM was 1.7% at 100 days and 3.4% at 1 year. Cumulative incidence of relapse at 3 years was 43.9%. The NRM analysis showed no statistically significant difference between pts in CR and PR. The 3-year OS for CR pts was 73.9%% compared to 59.4% for PR pts (95% CI, 0.334-0.99; p=.044). The 3-year PFS for CR pts was 59.8%, compared to 38.6% for PR pts (95% CI, 0.321-0.784; p=.001). The median PFS for CR pts was 52.01 months, compared to 14.05 months for PR pts. The cumulative incidence of relapse at 3 years in CR and PR pts was 35.2% vs 55.7%, respectively (95% CI, 0.311-0.811; p=.003.). Higher age (HR 1.03; p=.026) and number of previous lines of treatment (HR 1.43; p=.002) were associated with inferior OS. For PFS, no variables showed any significant impact in univariable analysis. The stepwise multivariable analysis showed that only the number of previous treatments had a significant impact on the OS (p=.009), while undergoing ASCT on a PR was the only factor significantly associated with shorter PFS (HR 1.41; 95% CI, 1.09-1.82; p=.029). Conclusion This dataset supports that ASCT provides high efficacy in pts experiencing late relapses (after 12 months) achieving CR following pre-transplant savage and validates the value of achieving CR. Outcomes for PR are inferior, and this analysis provides a benchmark for future investigations. At this time, until convincing on other non-transplant treatment show superior outcomes in this setting, ASCT remains a standard of care for fit pts with chemo-sensitive late relapsed DLBCL. In this group of patients, who have a better prognosis compared to patients who relapse within a year the major hurdle is achieving a remission pre-ASCT.

Abstract Introduction: IRAKLIA is an international, open-label, non-inferiority (NI) trial (NCT05405166) investigating isatuximab (Isa) subcutaneous (SC) vs intravenous (IV) administration, plus pomalidomide-dexamethasone (Pd) and the first Phase 3 multiple myeloma (MM) trial using an on-body injector (OBI). IRAKLIA demonstrated NI in its co-primary endpoints: overall response rate (ORR) and steady state trough concentration (Ctrough; Cycle(C) 6 Day(D) 1 predose). IsaOBI offers hands-free administration of flat-dose Isa, a small, hidden, retractable needle to prevent sharps injury and low-pressure delivery. Here, we examine the effect of body weight (BW) on pharmacokinetics (PK) as well as efficacy and safety outcomes with flat-dose IsaOBI vs IV + Pd in IRAKLIA. Methods: Patients (pts) with relapsed/refractory MM ≥18 years (yr) with ≥1 prior line of therapy (LOT) were randomized 1:1 to IsaOBI (1400mg; n=263) or IV (10mg/kg; n=264 weekly in C1, then every 2 weeks + P (4mg/day, D1–21) + d (40mg [20mg if ≥75yr] weekly) in 4-week cycles. This analysis is run by BW (≤65kg, >65–≤85kg, >85kg) which was a stratification factor, and extreme BW (≤50kg, >50–≤100kg, >100kg). Results: Number of pts per BW group were: ≤50kg [OBI n=16, IV n=14], ≤65kg [OBI n=84, IV n=85], >65–≤85kg [OBI n=117, IV n=118], >85kg [OBI n=62, IV n=65], and >100kg [OBI n=22, IV n=22]. Baseline (BL) demographic and disease characteristics were generally balanced across BW groups for IsaOBI vs IV, including age (median 66yr) and prior LOT (median 2). However, in the >100kg group, more IsaOBI vs IV pts exhibited poor prognostic characteristics including plasmacytoma, International Staging System Stage II/III disease, beta 2-microglobulin level ≥5.5mg/L, estimated glomerular filtration rate <60mL/min/1.73m2 and a lower very good partial response (VGPR) rate as best overall response at last regimen. Flat-dose IsaOBI showed adequate exposure (C2D1 Ctrough) for all BW groups, with geometric mean ratios (90% CI) vs IV >1: ≤65kg (1.628 [1.294–2.048]), >65–≤85kg (1.303 [1.089–1.560]) and >85kg (1.006 [0.817–1.239]). IsaOBI ORRs were comparable to IV across BW: ≤65kg, 66% vs 71% (relative risk [RR]: 0.928), >65–≤85kg, 70% vs 70% (RR: 1.009), and >85kg, 81% vs 72% (RR: 1.115). For extreme BW groups, ORRs (95% CI) were similar between IsaOBI and IV for ≤50kg group [56% vs 60%] and for >50–≤100kg [72(66–78)% vs 70(63–76)%] but lower [68% vs 86%] in >100kg group. An exposure-response (E-R) analysis showed the impact of BW on response: IsaOBI pts ≤50kg tended to respond less vs IsaOBI pts >50kg despite correct exposure because they were confounded by BL disease characteristicsincluding a higher proportion of high-risk cytogenetics and plasma cells in the bone marrow vs other BW group pts. For IsaOBI and IV, Grade (Gr)≥3 treatment-emergent adverse events (TEAEs) and Gr≥3 treatment-related TEAEs decreased with increasing BW. They were similar between arms in ≤65kg group (OBI vs IV, Gr≥3 TEAEs: 87% vs 88%; Gr≥3 treatment-related TEAEs: 73% vs 77%). A similar trend was observed in extreme BW groups along with similar incidences between arms in ≤50kg group. While TE serious AEs (TESAEs) and treatment-related TESAEs decreased with increasing BW for IsaIV, incidence was stable in the IsaOBI arm. OBI arm OBI Gr5 TEAEs were similar between groups and arms, except for higher incidence in ≤65kg group (12% vs 5%) with OBI vs IV that was not reflected in ≤50 or >50–≤100kg groups. Treatment discontinuation rates for all drugs with IsaOBI vs IV were 14% vs 6% (≤65kg), 8% vs 10% (>65–≤85kg), and 2% vs 10% (>85kg). Similar incidence of Gr≥3 laboratory (lab) neutropenia was observed across BW in IsaOBI: 86.9% (≤65kg), 83.5% (>65–≤85kg) and 83.9% (>85kg). Higher rates of Gr≥3 lab neutropenia were observed in ≤50kg group (93.8%, IsaOBI vs 71.4%, IsaIV), which did not translate into higher rates of neutropenic complications (18.8% vs 14.3%). The E-R analysis revealed no relationship between Isa PK exposure and safety for OBI and IV arms. Conclusions: No notable impact from IsaOBI flat dosing was observed across BW groups. Flat-dose Isa OBI showed consistent safety and efficacy across different BW groups, with differences likely linked to BL disease characteristics according to the E-R analysis. The IsaOBI C2D1 Ctrough, a time-independent predictor of efficacy, was similar to, or higher vs IsaIV in each BW group, supportive of a flat dose providing adequate exposure without need for adjustment.

Abstract Background: Clonotypic peptide detection by mass spectrometry (MS) leverages monoclonal protein (M-protein) de novo sequencing and peptide quantification to enable ultra-sensitive blood-based monitoring of multiple myeloma (MM) patient M-protein kinetics. Etentamig is a 2nd generation BCMA x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pre-treated patients with relapsed or refractory (RR) MM (Journal of Clinical Oncology, 43;16:suppl.7527). In the current study, we explored the depth and kinetics of MS M-protein response to etentamig monotherapy in serum samples from Phase 1 M22-466 (NCT03933735) study patients. The correlation between blood-based MS M-protein levels and bone marrow minimal residual disease (MRD) negativity as determined by next generation sequencing (NGS) was also evaluated. Method: Clonotypic peptide MS using M-Insight (Sebia/Corgenix) was performed on serum samples from a subset of MRD evaluable patients enrolled into the Phase 1 (NCT03933735) clinical trial of etentamig monotherapy in patients with RRMM. Bone marrow MRD negativity (<10-5 and 10-6) analysis was determined by NGS (clonoSEQ, Adaptive Biotechnologies). Patient pre-treatment (Cycle [C] 1 Day [D] 1) serum samples were digested with proteolytic enzymes to permit sequencing of the M-protein heavy and light chain. Clonotypic peptides specific to the patient's complementarity-determining regions were selected for quantification by MS. Clonotypic peptide quantification by MS was performed on available tracking peripheral blood samples at C2D1, C3D1, C4D1, and C5D1 time points post etentamig monotherapy treatment. Results: Twenty patients who were MRD evaluable and treated with 40 mg and 60 mg doses of etentamig with available serum samples collected from C1D1–C5D1 time points were selected for M-Insight evaluation. Of the 20 patients, 16 (80%) had at least one clonotypic peptide identified prior to etentamig treatment that was utilized for tracking at subsequent time points. Rapid decline in MS M-protein levels was observed in patients treated with etentamig, which strongly correlated with the patients' best International Myeloma Working Group (IMWG) response. At C3D1 post etentamig treatment, patients with complete response (CR)/stringent CR (n=9) demonstrated a significant decline from MS M-protein levels (median: 1.8±0.9 g/dL at C1D1 to 0.03±0.2 g/dL at C3D1) (P<0.001). All evaluable subjects (n=16) had detectable MS M-protein at all time points (n=80). The lowest detectable M-protein level observed in the current dataset was 44 mg/dL (lower limit of quantitation of assay: 10 mg/dL). Subsequent analysis of differences in kinetics between MRD-negative (<10-5) (n=8) and MRD-positive (n=8) patients revealed a deeper reduction in M-protein levels for MRD-negative patients (median 0.02±0.2 g/dL at C3D1 compared with 0.4±0.3 g/dL at C3D1 for MRD-positive patients). Among the 8 patients who achieved MRD negativity at 10-5 threshold, 5 patients also achieved <10-6 threshold, and serum MS M-protein levels remained detectable in these patients (0.07±0.2 g/dL). Conclusions: Using MS-based clonotypic peptide detection, rapid and deep decline in serum M-protein levels was observed in RRMM patients treated with etentamig. Strong concordance was observed between MS M-protein levels and IMWG response, including in patients achieving MRD-negative CR at <10-5 and 10-6thresholds. Non-invasive and ultra-sensitive M-protein detection is feasible in MM and may serve as a key biomarker for enhancing the detection of residual disease in the future.