Dimopoulos, Meletios Α.

Introduction Linvoseltamab is an investigational, BCMA×CD3 bispecific antibody designed for the treatment of RRMM. High objective response rates (ORR) to linvoseltamab 200 mg in the LINKER-MM1 trial (NCT03761108) were demonstrated across high-risk subgroups, including patients aged ≥75 years, patients with high-risk cytogenetics, and patients with penta-class refractory status. The aim of this study was to compare ORR, overall and in key subgroups, between patients in Phase 2 of the LINKER-MM1 trial and patients in an international RW SOC external control arm (ECA). Methods The ECA was derived from a chart review of 16 academic sites across 10 countries that are part of the International Myeloma Foundation (IMF)-International Myeloma Working Group (IMWG) and 2 US electronic health record databases (COTA and Guardian Research Network [GRN]). Included patients initiated ≥1 anti-MM treatment after meeting key eligibility criteria of LINKER-MM1. Weighted random sampling and inverse probability of treatment weighting (IPTW) were used to select 1 line of therapy (LOT) per patient and balance the overall ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). For ORR assessment, LINKER-MM1 and IMF-IMWG used independent central review committees per IMWG criteria, COTA used algorithmic assessment based on IMWG criteria, and GRN used physician-assessed responses. Prior to conducting comparative analyses, an independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments, and approved study continuation. ORR among patients in LINKER-MM1 and patients in the ECA was compared overall and across prespecified subgroups (≥10 patients per subgroup), including age, race, cytogenetic risk score, international Staging System (ISS), presence of extramedullary plasmacytoma (EMP), refractory class, bone marrow plasma cell (BMPC) proportion, and number of prior LOTs. Results Median duration of follow-up was 14.3 months (data cut-off: January 6, 2024) for patients receiving linvoseltamab (n=105) and 13.6 months for the ECA (n=307; n=194, n=72, and n=41 from IMF-IMWG, COTA, and GRN, respectively). Following IPTW, 13 prognostic factors with <30% missingness were balanced between cohorts, with an effective sample size in the ECA of 197. After adjustment, ORR was significantly higher in patients who received linvoseltamab compared with patients in the ECA (69.5% vs 45.7%, odds ratio [OR] 2.5 [95% confidence interval (CI) 1.6-4.1]) and in key subgroups with age 65-74 years (76.9% vs 48.3%, OR 3.6 [1.6-8.6]), age ≥75 years (72.4% vs 48.5%, OR 2.8 [1.1-7.4]), Black or African American race (82.4% vs 25.0%, OR 14.0 [3.0-85.4]), White race (68.9% vs 49.7%, OR 2.2 [1.3-4.0]), standard cytogenetic risk (72.3% vs 51.3%, OR 2.5 [1.3-4.8]), ISS stage III (58.8% vs 19.7%, OR 5.8 [1.5-25.2]), absence of EMP (71.6% vs 49.3%, OR 2.6 [1.5-4.6]), triple-class refractory status (68.2% vs 45.7%, OR 2.6 [1.5-4.4]), quadruple-class refractory status (66.7% vs 45.9%, OR 2.4 [1.3-4.3]), 4-5 prior LOTs (65.1% vs 40.4%, OR 2.8 [1.3-6.0]), and >5 prior LOTs (75.7% vs 36.1%, OR 5.5 [2.4-13.6]). Numerically higher (not statistically significant) or similar ORR was observed for patients receiving linvoseltamab compared with patients in the ECA with age <65 years (59.5% vs 46.8%, OR 1.7 [0.79-3.6]), high-risk cytogenetics (65.0% vs 63.1%, OR 1.1 [0.41-2.9]), ISS stage I (73.3% vs 64.6%, OR 1.5 [0.62-3.7]), ISS stage II (67.6% vs 53.5%, OR 1.8 [0.72-4.7]), presence of EMP (58.8% vs 56.9%, OR 1.1 [0.32-3.8]), penta-class refractory status (64.3% vs 48.5%, OR 1.9 [0.78-4.8]), BMPC <50% (77.0% vs 67.2%, OR 1.6 [0.61-4.3]), BMPC ≥50% (41.7% vs 36.0%, OR 1.3 [0.36-4.7]), and ≤3 prior LOTs (68.0% vs 66.4%, OR 1.1 [0.43-2.9]). Separate findings will be presented for IMF-IMWG and COTA/GRN data at the congress. Conclusions Linvoseltamab induced better ORR vs RW SOC treatments overall, and better or similar ORR in the key subgroups assessed, highlighting its therapeutic value across a range of patients with RRMM with heterogeneous risk profiles and levels of disease burden.

ImportanceKidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes.ObjectiveTo validate graded kidney response criteria and their association with kidney and overall survival (OS).Design, Setting, and ParticipantsThis retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023.ExposureFour kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, >60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response.Main Outcomes and MeasuresCumulative incidence of progression to KRT and OS.ResultsSeven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS.Conclusions and RelevanceThe results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.

AbstractObjectivesCluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi‐centre, Phase 1, single‐agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)‐modified anti‐CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc‐gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM.MethodsThis study comprised two parts: Part‐A (dose‐escalation involving anti‐CD38 mAb pre‐treated and naïve patients) and Part‐B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D).ResultsThirty‐seven heavily pre‐treated patients were treated in Part A. Part‐B (dose‐expansion) was not studied. Seven dose‐limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5–7·5 mg/kg. Most common treatment‐emergent adverse events were infusion‐related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti‐CD38 mAb naïve and 4% in anti‐CD38 pre‐treated patients, with a median progression‐free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively.ConclusionsThe efficacy of SAR442085 was promising in anti‐CD38 mAb naïve patients but did not extend to the larger cohort of anti‐CD38 mAb pre‐treated patients. This observation, along with transient high‐grade thrombocytopenia, could potentially limit its clinical use.

7510 Background: The randomized Phase 3 CANOVA study’s (NCT03539744) primary analysis showed multiple numerically improved efficacy endpoints with VenDex v PomDex, but the primary endpoint of mPFS by IRC was not statistically significant. Here, we report correlative biomarker analyses from CANOVA. Methods: CANOVA is a randomized, global, open-label Phase 3 study of VenDex v PomDex in pts with t(11;14)+ RRMM and ≥2 prior lines of therapy (LOTs). The primary endpoint was mPFS by IRC. Key secondary endpoints included ORR, ≥VGPR, mOS, and MRD negativity (<10-5). In post hoc mPFS sensitivity analysis, disease progression, death, and start of next LOT were defined as events. BCL2 gene expression by RNAseq (3.7 log2 FPKM prespecified median cutoff for BCL2high v BCL2low) and chr1q abnormalities by whole-exome sequencing (normal, gain, or amp) were assessed centrally from pretreatment, CD138-enriched BM aspirates. Results: mPFS, post hoc mPFS, and mOS in the VenDex arm were similar by BCL2 status, with numerically higher ORR, ≥VGPR, and MRD negativity rates in the BCL2highsubgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2lowsubgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2high v BCL2low subgroups in the VenDex arm (51% v 45%) but not in the PomDex arm (59% v 31%). Normal 1q and gain(1q) subgroups had numerically improved mPFS, mOS, ORR, ≥VGPR, and MRD negativity with VenDex; pts with amp(1q) had poor outcomes regardless of treatment, albeit the sample size was small. Conclusions: Pts with BCL2high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2high or BCL2low) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744 . [Table: see text]

Background: Liver involvement in light chain amyloidosis (AL) is seen in up to 20% of patients and is typically encountered as part of multi-organ involvement. Liver involvement is associated with a poor prognosis. The goal of this study was to assess the prognostic impact of the hepatic response criteria, which were published in 2005 and were not broadly assessed for their prognostic value. Patients and methods: Ten centers across the USA and Europe participated in this study.AL amyloidosis patients who were diagnosed between 2010 and 2015, had liver involvement with serum alkaline phosphatase (AP) &gt;1.5 upper reference limit (URL), and achieved hematologic response to therapy were included in this study. Hepatic response was assessed at 6, 12, and 24 months from therapy initiation and at best response. Based on a receiver operation characteristic analysis, a 50% reduction in AP was set as the optimal cut point for discrimination of 5-year overall survival (OS) in the 12-months response assessment landmark (area under the curve 0.67). Therefore, hepatic response was defined as a reduction in AP &gt;50% from baseline value in addition to AP normalization, regardless of AP percentage reduction. Hepatic progression was defined as &gt;50% increase in serum AP. OS was assessed from therapy initiation until death or last follow-up and was plotted using the Kaplan-Meier method. The log-rank test used to compare survival between groups. For fixed-time point survival analysis, patients who died before the landmark were excluded. Hepatic response at a fixed time points, when missing, was imputed based on available data from adjacent time points (imputation of hepatic response was performed in 15%, 23%, and 22% of evaluable patients at 6-, 12-, and 24-month landmarks, respectively). Multivariate Cox proportional models were set to determine independent prognostic factors for OS using variables with p-value &lt;0.1 in a univariate analysis. P-values &lt;0.05 were considered significant. Results: One hundred and sixteen patients (n=116) are included. The median age was 60 years, and the median serum AP was X2.6 URL. Concomitant kidney involvement was present in 63.8% of patients, while coexisting heart involvement was seen in 56% of patients. Hematologic VGPR or better was achieved in 69% of patients. AP decrease deepened with time, with a median reduction at 6-, 12-, 24-months and best response being 22%, 34%, 53%, and 56%, respectively. Overall, 65% of patients (n=75) achieved hepatic response, of whom 71 patients based on reduction in AP &gt;50% and 4 patients for reaching AP within normal reference but not meeting &gt;50% reduction in AP (40- 46% reduction in AP). The median time to hepatic response was 13.8 months, longer for patients undergoing autologous stem cell transplantation (ASCT) as their primary therapy compared to non-transplant therapies (24 vs 12.6 months, P=0.1). With a median follow-up of 105 months, 42 patients died (36.2% of the study cohort). The 2-, 5- and 10-year OS rates were 83%, 67%, and 61%, respectively. Achievement of hepatic response as early as 12 months and at best response was associated with a longer survival (Figure). Hepatic response was an independent prognostic factor in a multivariate analysis, after adjusting for other known prognostic factors (age, cardiac stage, hematologic response, and primary therapy). Predictors of hepatic response include higher baseline AP level, lower total bilirubin, hematologic ≥VGPR, and cardiac and renal responses, when applicable. Hepatic progression was borderline associated with inferior OS (5-year OS 47% vs 70% among non-progressors, P=0.08). Conclusions: Hepatic response and progression measured by the change in alkaline phosphatase are prognostic in AL amyloidosis. These criteria are independent of other prognostic markers, and thus may have clinical implications for patients' care.

Introduction: Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb), recently approved by EMA and FDA. Approval was based on the MajesTEC-1 study showing high overall response rates (≥PR in 63.0%) in heavily pretreated patients with relapsed multiple myeloma (RRMM). Few reports have described Real-World experience despite that TEC can induce unique side effects including cytokine release syndrome (CRS), neurotoxicity (ICANS) and a high incidence of infection (MajesTEC-1: incidence 76.4%; ≥Gr3: 44.8%). Thus, we performed a Real-World analysis of TEC therapy from 7 International Myeloma Foundation (IMF) associated MM academic centers. Methods: Patients treated with standard-of-care TEC were included. Data was collected until 7/28/2023. Results: 103 pts were included; median age 63 (range 33-91y); 15 pts. (14.5%) &gt;75 yrs; 56.5% were male, 71.8% Caucasian, 11.6% Hispanic, and 12.6% Asian. Pts received a median of 6 PLT (range 1-16); 75% were triple-class-refractory (n=41/52 (79%), 30/85 (35%) had high-risk cytogenetics/FISH and 32/80 (40%) had 1q21 gain. At least 57/76 (75%) of pts would not have been eligible for MajesTEC-1 (mostly from prior BCMA (n=28 CAR-T, n=14 ADC; n=3 BsAb; n=5 CAR-T+ADC). 14 pts had CrCl &lt;30ml/min with 2 on HD. Median number of hospital days was 8 (n= 72) but 31 patients were treated entirely as outpatients (Mayo clinic (MN, AZ, FL)). CRS was seen in 52 (50.4%) (all grade 1: except 6 Gr2, 1 Gr4), generally resolved within 24 hrs and was managed with tocilizumab alone (n= 27) or dex alone (n=9) or dex+toci (n=12). CRS was more common with inpatient (56.9%) vs outpatient (35.4%) TEC Rx. CrCl &lt;30 ml, did not appear to alter the incidence or severity of CRS (50%; 1 Gr4). ICANS was infrequent (n=5; 4.85%), 1 pt with Gr 4-Sz requiring HD-steroids and TEC discontinuation). Infections were common, seen in 54 (52.4%) of patients, the majority were viral URI or CMV reactivation (n=26; 3 pts receiving CMV Rx, 1 pt with CMV organ disease). IVIG was given in 43/67 (64%) pts. The overall response rate for evaluable patients (n=82) was 63%; (sCR/CR 14; VGPR 23; PR 15; MR 2, SD 14; PD 14). In evaluable pts treated with prior BCMA (n=43), the ORR was 53% (sCR/CR 4; VGPR 14; PR 5; 1 MR; SD 10; PD 9). The most common reason for treatment discontinuation was PD (26.2%). 14 pts have died by the time of data cut-off (7/28/23), with the most common cause of death being disease progression. Conclusions: In this Real-World evaluation of TEC, a high ORR was seen, similar to the MajesTEC-1 study. Responses were rapid and are expected to deepen over time (median f/u 5m). CRS rates were similar to MajesTEC-1 and no new toxicity signal was noted. The rates of infection appear low but may be related to short follow-up. Details regarding the incidence and types of infection and the global use of IVIG will be described. With longer follow-up, additional efficacy/toxicity data will be presented.

PURPOSE Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide. PATIENTS AND METHODS This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival. RESULTS 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation. CONCLUSION Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.