LINKER-MM1 (NCT03761108) is a Phase 1/2 study of linvoseltamab, a human BCMA×CD3 bispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) with ≥ 3 prior lines of therapy (3L+), or triple-class refractory (TCR). To contextualize efficacy data from LINKER-MM1, the Phase 2 linvoseltamab 200 mg cohort (N = 105) was compared with an international external control arm (ECA) comprising 203 patients from participating International Myeloma Working Group sites who met LINKER-MM1 eligibility criteria based on chart reviews. The ECA reflected real-world standard-of-care (RW SOC). An independent data review committee assessed data relevance, quality, and cohort comparability, while a separate independent central review committee evaluated response data. Inverse probability of treatment weighting was used to balance baseline characteristics between the linvoseltamab arm and the ECA. Linvoseltamab had a higher objective response rate (weighted odds ratio 3.0 [95% confidence interval (CI): 1.9-4.1]) and longer median progression-free survival (weighted hazard ratio [wHR] 0.33 [95% CI: 0.28-0.40]), time to next treatment (wHR 0.34 [95% CI: 0.29-0.44]), and overall survival (wHR 0.72 [95% CI: 0.58-0.98]) than RW SOC. These findings highlight linvoseltamab's potential as an effective treatment for 3L+ and TCE/TCR RRMM.

Introduction: MYC rearrangement (MYC-R), especially those involving the immunoglobulin loci (IGL, IGH, and IGK), are drivers of MM and other malignancies. IGL::MYC has been associated with hyperdiploidy and inferior outcomes. Despite this, MYC is not part of the recommended fluorescence in situ hybridization (FISH) panel at diagnosis. We describe the clinical impact of MYC alterations in newly diagnosed MM (NDMM) and the MYC-R prevalence in systematic MYC assessment by FISH and genomic proximity mapping (GPM). Methods: The Multiple Myeloma Research Foundation CoMMpass (MMRF-NGS cohort) was used to assess the frequency and impact of MYC rearrangements (MYC-R) on progression-free survival (PFS). FISH using a MYC break apart probe was part of the routine FISH panel at our center for MM starting in June 2023 in 133 patients (pts) (WCM-FISH cohort). GPM was performed on CD138+-selected cells from 50 pts who part of a prospective clinical trial of NDMM (NCT01559935 (CarBiRD cohort)) and in 37 pts from the WCM-FISH cohort. MYC-R breakpoints and gain (MYC-g) were identified. PFS was defined as the time from MM diagnosis to progression of disease or death, as determined by the International Myeloma Working Group. High-risk cytogenetics (HR-CG) were defined as any of del17p, t(4;14), t(14;16), or gain1q. Supported by R44CA268681 and WA Care Fund. Results: In the MMRF-NGS cohort, MYC-R was seen in 234/913 pts (25.6%), with most MYC-R having IGH/IGL/IGK (IG::MYC) as a partner in 52% of cases. IG::MYC pts had inferior PFS (25.4 months) when compared to MYC-R with non-IGH/L/K partners (MYC::non-IG) (42.2 months, pairwise p= 0.04) and MYC-negative (neg) (37.9 months, pairwise p= 0.04). There were no differences in PFS between MYC-neg and MYC::non-IG (p = 0.59). In a multivariable model, IG::MYC remained associated with inferior PFS (hazard ratio [HR] 1.39, 1.09-1.7, p = 0.01) after adjusting for age, transplant, triplet vs. duplet induction, and del17p, gain1q, del1p, and del13q status. 24 pts with IG::MYC had sequential samples available, and 22/24 (92%) IG::MYC was present at diagnosis, suggesting IG::MYC-Ris a truncal event and is often present at MM diagnosis. In the WCM-FISH cohort, MYC alterations were present in 44/133 pts with MM (33%). MYC-R was present in 35 pts (26%), while MYC-g was present in 13 (9.8%). Pts with MYC-R had significantly shorter PFS compared to MYC-neg (15.6 vs. 35.7 months, p = 0.017). Other variables associated with PFS included ISS, R-ISS, lactate dehydrogenase, albumin, del17p, and HR-CG. In the multivariable model, only MYC-R was associated with inferior PFS (HR 2.82, 95% CI 1.12-7.06, p = 0.02). When pts were stratified by MYC-R and HR-CG status, pts with MYC -R and no HR-CG had inferior PFS compared to MYC-neg/no HR-CG pts (p = 0.001) and had comparable PFS to HR-CG alone. Most MYC-R cases were not further assessed by standard FISH for, with MYC::IGH being the only partner genes identified (3/35 cases). In the CarBiRD cohort, GPM identified 17/50 (34%) pts with MYC alterations, including 12 pts (24%) with MYC-R. The MYC partner was identified in all cases, with 8 pts having IG::MYC. MYC-R, were associated with inferior PFS when compared to MYC-neg (HR 2.1, 1.06 – 4.4, p = 0.03), mainly driven MYC::IG cases, which had inferior PFS when compared to non-MYC-R pts (HR 4.27, 1.82 – 10.1, p < 0.001). In the pts who had GPM and FISH available (87 pts), GPM identified MYC alteration in 32/87 (37%) of cases, including MYC-R in 27/87 (31%) of pts. 48% of MYC-R involved the IGL, IGK or IGH (6, 4, and 3 cases, respectively). GPM identified the breakpoint in all cases, also identifying complex alterations involving several translocations or inversions in the same patient in addition to inversions of chromosome 8q. GPM detected all cases of t(11;14), t(4;14), MYC-R, and t(14;16) identified by FISH, in addition to 3 pts with t(11;14), t(14;16), and MYC-R that FISH missed due to atypical breakpoints. MYC alterations were associated with a higher rate of del1p, hyperdiploidy, and del17p, while mutually exclusive from t(11;14). Conclusion: MYC-R is common in NDMM and is associated with inferior PFS independent of other genomic variables. MYC FISH should be considered part of the standard risk stratification. MYC partner may have important prognostic implications. GPM provides higher resolution and can locate other recurrent abnormalities in MM, in addition to characterizing complex MYC alterations and breakpoints.

Patients participating in clinical trials are highly selected and may not represent the general population. The pivotal study of teclistamab (MajesTEC-1), a B-cell maturation antigen (BCMA)xCD3 bispecific antibody, demonstrated impressive response rates and progression free survival in relapsed/refractory multiple myeloma (RRMM) with acceptable toxicity. We performed a retrospective study of 58 patients treated as standard of care at four US academic centers to determine how these results translated to the real-world. Most patients (87.9%) would not have been eligible for the MajesTEC-1 study due to either disease related factors, patient related comorbidities or socio-economic/geographical factors. Despite these 'less-favorable' characteristics we observed similar efficacy and toxicity to MajesTEC-1. A meta-analysis with six other published real-world series (n = 546) confirmed these results. These data support the significant clinical activity of teclistamab in RRMM and highlights the importance of real-world data to accompany the pivotal trial data to further inform daily clinical practice.

Background Relative Dose Intensity (RDI) affects the outcomes of several neoplasms, including Multiple Myeloma (MM). However, due to the mechanism of action of Bispecific Antibodies (BsAbs), RDI may not necessarily be as relevant. Our objective is to describe clinical characteristics, prognostic factors and survival impact of RDI in a cohort of MM patients treated with BsAbs. Materials and Methods MM Patients treated in a single institution with BsAbs between oct/2021 and apr/2024 were included. Demographic, treatment and outcomes characteristics were collected with REDCap®. RDI was estimated based on the Prescribing Information for each BsAb, and calculated multiplying by 100 the total amount of dose received over the total expected dose during the treatment time [PMID: 30696949] without an expected number of cycles. Day 1 of treatment was the day of first given dose, and last day of treatment was the day of last dose given when treatment was interrupted due to dose-limiting toxicity, progression or death. Progression Free Survival (PFS), defined from the time from first dose of BsAb until progression of disease (based on IMWG criteria) or death, and Overall Survival (OS), were analyzed. Results 40 MM patients treated with BsAbs were identified. Median age at diagnosis was 61.9 years (IQR=15) and median age at time of BsAbs administration was 71.5 years (IQR=14.5). 65% of patients were female. Most patients were Non-Hispanic White (NHW, 60%) followed by Non-Hispanic Blacks (10%) and Hispanics (5%). ECOG <2 was seen in 67.5%. 50% were ISS stage II. High-Risk Cytogenetic Abnormalities (HRCA) were seen in 42.5%. Median follow up since diagnosis was 117.8 months, and since starting the BsAbs was 12 months. Median of lines of treatments prior to BsAbs were 7 (IQR=6) and 65% of cases were Triple-Class Refractory. Elranatamab was received by 42.5%, followed by Teclistamab (40%) and Talquetamab (17.5%). 45% of patients reached complete response with the BsAbs. Median PFS was 8.9 months (CI95%=0.0-18.5) and median OS was not reached, with 3-year OS of 60%. Median RDI was 93.4% (IQR=33.2). Median duration of treatment was 99.5 days (IQR=245). The median time to loss the 100% compliance with treatment was 42 days (IQR=65.2). 87.5% of patients with low RDI (<95%) had a treatment duration ≥100 days, meanwhile 89.5% of patients with high RDI (≥95%) had a duration of treatment of <100 days (p<0.001). RDI ≥95% was seen in patients with high CAR-HEMATOTOX score compared to low (77.8% vs 23.1%, p=0.011), early (≤1 month) vs late onset (>1 month) of neutropenia (87.5% vs 12.5%, p<0.001) and in patients without severe neutropenia compared with those with severe neutropenia (75.0% vs 16.7%, p=0.009). No difference in RDI was seen by gender, race, ISS stage or BsAb. The most frequent reasons for any treatment interruption (70% each) were CRS/ICANS, neurotoxicity, renal failure, liver toxicity and osteomuscular problems. Treatment was stopped due to progression of disease in 35% of cases, followed by toxicity in 35.2%. 17.5% of cases received another different BsAbs after our analyzed first course of treatment. Median PFS for patients with RDI ≥95% was 1.1 months (CI95%=0.15-2.01) vs the PFS for RDI<95% was 27.1 months (CI95%=9.48-44.66), p=0.003. Multivariate Cox regression for PFS showed that RDI ≥95% is an independent prognostic factor for survival (HR=18.1, p<0.01). Also, worse PFS is associated with female gender (HR=17.6, p<0.01), ECOG ≥2 (HR=16.2, p<0.01), ISS stage III (HR=8.8, p=0.02), HRCA (HR=7.6, p<0.01), linfopenia prior to BsAbs (HR 8.0, p=0.03) and teclistamab compared with elranatamab (HR=6.3, p=0.01). Better prognosis was seen for Hispanic when compared to NIW (HR=0.008, p<0.01). no significant effect of age at time of administration of BsAbs was observed. Conclusions In this retrospective cohort, achieving a high RDI was associated with worse PFS, and does not seem to be essential in BsAb, potentially due to the longstanding therapeutic effect of BsAb even after holding the medication. Lower RDI benefit seems to be driven by longstanding responders that receive treatment with less RDI due to dose-limiting toxicity or preference, meanwhile a high compliance (RDI 100%) is more frequently seen in patients with early relapse. This is translated in improved PFS in this cohort. Impact of RDI on outcomes can help guide treatment length in immunotherapy.

BACKGROUND:Multiple myeloma (MM) is a plasma cell neoplasm, which accounts for 1-2% of cancers and approximately 17% of hematological malignancies in the United States each year. Fifty percent of patients with symptomatic MM have three or more primary care visits before being referred to a specialist, which is greater than any other cancer. A delay in the diagnosis of multiple myeloma has been shown to negatively impact the clinical course of the disease; patients with longer diagnostic intervals have been shown to experience shorter disease-free survival and higher rates of treatment-related complications. RESEARCH DESIGN AND METHODS:We performed a retrospective analysis of patients diagnosed with MM in our institution, to determine the time from the first detectable lab abnormality to the diagnosis of MM. RESULTS:We included 92 patients in this study. Fifty-two percent of patients had isolated anemia at the time of diagnosis. Twenty-nine percent of patients had a delay in diagnosis of ≥1 year, while 18% had a delay of ≥3 years. Nine patients in our cohort had anemia and an elevated serum total protein (31%). This group had the longest time to diagnosis with a median of 38 months. CONCLUSIONS:Our results did not show any difference in time to diagnosis by race, ethnicity, gender, or socioeconomic status.

Introduction: Teclistamab is a B cell maturation antigen (BCMA)-targeting bispecific antibody (bsAb) that is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy. In this study, we report long-term follow-up data regarding the safety and efficacy of teclistamab in a real-world multi-institutional cohort. Methods: We performed a retrospective cohort study on 168 patients with RRMM who received at least one dose of teclistamab across 5 academic medical centers in the US. Infection incidence was evaluated from the date of teclistamab initiation through the date of last follow-up or 60 days after discontinuation of therapy. Responses were adjudicated as per International Myeloma Working Group (IMWG) criteria. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Results: The median age of our cohort was 70 years (range: 31- 89) and 49% were female. Black patients constituted 25% of the cohort. Most patients (65%) had high risk cytogenetics and either triple-class refractory (83%) or penta-refractory (52%) disease. Extraosseous extramedullary disease (EMD) was seen in 43 patients (28%) prior to starting teclistamab, and relatively few patients had CNS involvement (1.8%), plasma cell leukemia (6.5%), or concomitant AL amyloidosis (4.2%). The median prior lines of therapy were 5 (range 1-12) with the majority having received at least one prior autologous stem cell transplantation (95%). At the time of teclistamab initiation, 92% of patients had evidence of progressive disease and 55 patients (33%) had received prior BCMA-targeted therapy. Among those with prior BCMA exposure, the most common therapy used was BCMA CAR T-cell therapy (n=34; 62%), followed by BCMA antibody-drug conjugate (ADC) (n=18; 33%), and BCMA bsAb (n=5; 9.1%). Notably, 2 patients received both prior BCMA CAR T and ADC. Patients received a median of 15 teclistamab doses (range 1 - 49) and were followed for a median of 8.5 months from treatment initiation. The overall response rate (ORR) in our cohort was 71%, with a very good partial response (VGPR) or better in 60% of patients. The median time to best response was 2.94 months. No baseline clinical characteristic demonstrated a statistically significant association with ORR on multivariable analysis. Specifically, age (odds ratio (OR) 0.99, 95% CI 0.94-1.04, p = 0.67), prior BCMA-targeted therapy (OR 0.85, 95% CI 0.29-2.54, p = 0.77), and the presence of high-risk cytogenetics (OR 0.48, 95% CI 0.17-1.23, p = 0.14) were not significant predictors. In our cohort, the estimated PFS rates at 6 and 12 months were 58% and 49%, respectively, while the OS rates were 81% and 68%, respectively. The median PFS and OS was 12 months (95% CI, 7.1-15) and 18 months (15-NR) respectively. The incidence of grade 1/2 cytokine release syndrome (CRS) was 53%, with only 1 patient (0.6%) experiencing grade 3 CRS. The incidence of grade 1/2 immune effector cell-associated neurotoxicity syndrome (ICANS) was 7.2%, with 3 patients (1.8%) experiencing grade 3 ICANS. Of those with CRS/ICANS, 29 patients (17%) received systemic steroids and 45 patients (27%) received tocilizumab. Within this cohort, 99% of patients received herpes prophylaxis, 73% pneumocystis prophylaxis, 43% primary or secondary prophylaxis with intravenous immunoglobulin, 19% prophylactic antibiotics, and 16% antifungal prophylaxis. Overall, a total of 181 infections were diagnosed in 92 patients in this cohort, with 100 of these being ≥ grade 3 infections (55.2%), and 79% of infections confirmed microbiologically. The cumulative incidence of all-grade infections at 3 months and 6 months was 43% and 54% respectively, with the respective cumulative incidence of grade ≥3 infections being 23% and 34%. The estimated rate of all-grade and grade ≥3 infections per 100 days was 0.61 (±0.07) and 0.33 (±0.06) respectively. There were four grade 5 infections (2.2%) observed. Conclusion: Despite a significantly higher proportion of patients with triple-class refractory and penta-refractory disease in our cohort compared to the MajesTEC-1 trial, teclistamab demonstrated a comparable ORR and ≥VGPR rate. Additionally, with the implementation of robust infection prophylaxis, the rates of all-grade and grade 3-5 infections were favorable compared to clinical trial data. Further follow-up data will be presented at the meeting.

Introduction Multiple myeloma (MM) is considered incurable. Despite improved outcomes with novel agents, including BCMA-targeted chimeric antigen receptor (CAR) T-cell therapies, antibody-drug conjugates (ADCs), and bispecific antibodies, patients with relapsed/refractory MM (RRMM) often have poor prognoses. LINKER-MM1 (NCT03761108) is a global, single-arm, Phase 1/2 study of linvoseltamab, a BCMA×CD3 bispecific antibody, in patients with RRMM who were either triple-class exposed (TCE; previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody) during ≥3 prior lines of therapy (LOTs), or triple-class refractory to these therapies. Here, we present comparisons of clinical outcomes from LINKER-MM1 with those of a current, international, real-world (RW) external control arm (ECA; NCT05673967). Methods The ECA was derived from 16 academic sites of the International Myeloma Foundation International Myeloma Working Group (IMWG) (N=203; 309 eligible LOTs) and compared with linvoseltamab (N=105; Phase 2 200 mg cohort). Patients in the ECA initiated ≥1 anti-MM therapy after meeting key LINKER-MM1 eligibility criteria. Weighted random sampling and inverse probability of treatment weighting were used to select 1 LOT per patient and balance the ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). The primary endpoint was objective response rate (ORR; IMWG criteria) determined by an independent central review committee (ICRC) based on myeloma laboratories. An independent data review committee reviewed comparability of cohorts and endpoint assessments prior to conducting comparative analyses. Results Median follow-up was 14.3 months for the linvoseltamab cohort (data cutoff: Jan 6, 2024) and 13.4 months for the ECA. After weighting, 15 prognostic factors were balanced between cohorts. Patients in the ECA received 68 distinct regimens, most commonly CAR T-cell therapies (11.3%) and ADCs (10.3%). After balancing the cohorts, patients in the ECA evaluable for response had ICRC-assessed ORR of 46.3% (40.8% by treating physician assessment), among whom 24.0% had very good partial response or better (≥VGPR). When including patients who died without evaluable response, ECA ICRC-assessed ORR was 44.2%. Linvoseltamab induced significantly higher ICRC-assessed ORR (69.5% vs 46.3%, odds ratio [OR] 2.65 [95% confidence interval (CI) 1.66-3.69]) and rate of ≥VGPR (62.9% vs 24.0%, OR 5.37 [95% CI 3.61-8.49]) compared with ECA regimens. Conclusion Despite current use of novel therapies, there is no well-established RW standard of care (SOC) for patients with TCE RRMM treated at IMWG sites. To our knowledge, this is the first RW ECA study in MM with a high percentage of anti-BCMA therapies and response ascertainment for all patients by ICRC. Linvoseltamab induced significantly higher response rates, including rate of ≥VGPR, compared with current RW SOC therapies, highlighting its potential as a highly effective treatment in patients with TCE RRMM.

Background Bispecific T-cell engagers (BiTEs) are effective in treating relapsed/refractory multiple myeloma (RRMM). This study examines the kinetics of absolute lymphocyte counts (ALCs) in RRMM patients (px) receiving BiTEs, hypothesizing that the stimulatory effect of BiTEs on T-cells would result in a higher ALC expansion in px with deeper and longer-lasting responses, aiding in predicting outcomes. Methods A retrospective study included all px with RRMM receiving a BiTE at one institution. We collected ALC data from 5 days prior to starting BiTE therapy (tx), during step-up dosing, and at every follow-up visit. Demographic data, baseline disease characteristics, previous lines of treatment (LOT), cytogenetics, staging at diagnosis, best response according to IMWG, progression (POD), and toxicities were recorded. We identified the minimum (ALCmin d1-22) and maximum ALC values (ALCmax d1-22) during the first 3 weeks after BiTE initiation. The difference between ALCmax and ALCmin during the first 3 weeks (deltaALC d1-22) was calculated to determine the expansion rate of ALCs early post-BiTE. Progression-Free Survival (PFS) was calculated from step-up dose 1 to either POD or last follow-up. Results As of April 2024, 48 BiTEs step-up dosing were initiated in 41 px. Clinical response was evaluated in 45 events. Anti-BCMA BiTEs were administered to 37 px, and anti-GPRC5D BiTEs to 9 px. Five px received a BiTE in more than one LOT, and two switched from a BCMA to a non-BCMA-targeted BiTE. Baseline disease characteristics and demographics were comparable across different BiTEs, except for race. Response rates were similar between anti-BCMA and non-BCMA agents, with CR/VGPR rates of 72% for elranatamab, 41% for teclistamab, and 56% for talquetamab. No significant difference was observed in the incidence of CRS, ICANS, or severe infections between anti-BCMA and non-BCMA BiTEs. However, severe cytopenias were significantly higher in subjects with elranatamab and teclistamab (65% and 53%, respectively). ALC kinetics were similar across all BiTEs, with a decrease in ALCs appearing early after starting tx. The median ALCs from day 1 to either POD or last follow-up while receiving a BiTE was 0.58 x109 cells/L [IQR 0.29, 1.07], and was significantly higher in px with CR/VGPR compared to those with ≤PR: 0.92 [0.57, 1.28] vs. 0.31x109 cells/L [0.22, 0.55]; p<0.001. Higher median ALCs were observed in px with CR/VGPR within the first 3 weeks post-BiTE tx vs. those with ≤PR: 0.39 [0.25, 0.57] vs. 0.27 [0.17, 0.55] in week 1, p=0.028; 0.34 [0.24, 0.57] vs. 0.25 [0.17, 0.4] in week 2, p=0.01; and 0.6 [0.38, 0.9] vs. 0.25x109 cells/L [0.12, 0.75] in week 3, p=0.005. During the first 3 weeks, the median ALCmin (d1-22) was 0.15x109 cells/L [0.07, 0.24], occurring at a median of 5 days [3, 7], while the median ALCmax (d1-22) was 0.70x109 cells/L [0.32, 1.00], appearing at a median of 15 days [11, 21]. The median deltaALC (d1-22) was 0.48x109 cells/L [0.26, 0.85]. The difference in deltaALC (d1-22) according to response group was not significant, but px with CR/VGPR took significantly longer to reach the max deltaALC (d1-22) vs. ≤PR: 11 [6, 15] vs. 6 days [2, 9]; p=0.011. Px with CR/VGPR more commonly developed CRS (81% vs. 47%; p=0.019), with higher ALCmax (d1-22) and deltaALC (d1-22) associating with CRS: 0.89 [0.54, 1.06] vs. 0.31x109 cells/L [0.20, 0.78]; p=0.02 and 0.61 [0.41, 0.91] vs. 0.24x109 cells/L [0.13, 0.58]; p=0.022, respectively. Px with overall median ALCs ≥0.5x109 cells/L had higher rates of CR/VGPR vs. those with median ALCs <0.5 (75% vs. 28%; p=0.003), but did not predict improved PFS in a multivariate analysis. Remarkably, the increased time to max deltaALC (d1-22) significantly associated with improved PFS (HR: 0.88; CI 0.78-0.9, p=0.03). Conclusion Higher median ALCs within the first 3 weeks following BiTE tx in RRMM associate with better clinical responses and increased incidence of CRS, but could not predict improved PFS. Px achieving CR/VGPR experienced a significant delay in ALC recovery post-BiTE initiation vs. those with ≤PR. A delayed time to maximum deltaALC (d1-22) was a protective factor for PFS, suggesting its potential as a predictive marker for treatment outcomes. The immunobiologic mechansisms underlying this protective delayed lymphocyte expansion remain to be elucidated and further research is required to optimize the use of ALC kinetics in guiding clinical decisions in px receiving BiTEs.

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T cells (CAR-Ts) used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (R/R) disease, and CAR-T expansion after infusion has been shown to inform depth and duration of response (DoR), but measuring this process remains investigational. This multicenter study describes the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the first 15 days after CAR-T infusion in 156 patients with relapsed MM treated with the BCMA-targeting agents ciltacabtagene autoleucel and idecabtagene vicleucel. Patients with higher maximum ALC (ALC(max)) had better depth of response, progression-free survival (PFS), and DoR. Patients with ALC(max) >1.0 x 10(3)/mu L had a superior PFS (30.5 months vs 6 months; P < .001) compared with those with <= 1.0 x 10(3)/mu L, whereas patients with ALC(max) <= 0.5 x 10(3)/mu L represent a high-risk group with early disease progression and short PFS (hazard ratio, 3.4; 95% confidence interval, 2-5.8; P < .001). In multivariate analysis, ALC(max) >1.0 x 10(3)/mu L and nonparaskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for international staging systemic staging, age, CAR-T product, high-risk cytogenetics, and the number of previous lines. Moreover, our flow cytometry data suggest that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report, to our knowledge, for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in patients with R/R MM.

Abstract Introduction: Expansion of chimeric receptor antibody (CAR)-T cells after infusion has been described as important marker in multiple myeloma (MM); however, the phenomenon of overt lymphocytosis has not been reported. We describe the kinetics of absolute lymphocyte count (ALC) after BCMA CAR-T in MM as a marker of depth of response and progression-free survival (PFS). Methods: 158 patients (pts) were included (93 pts ciltacabtagene autoleucel (cilta-cel) and 65 pts idecabtagene vicleucel (ide-cel) from three institutions. Baseline characteristics, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), ALC on day -5 through 14, and outcomes were collected. A cohort of 84 pts who received CD19 CAR-T for non-Hodgkin lymphoma (NHL) as comparator. Peripheral blood (PB) flow cytometry was performed on days 7, 14 and 21 in 4 patients. Results: Early ALC increase after BCMA CAR-T was frequent, with a median max ALC 1.3 × 103/uL (IQR 1-4.4) from a median baseline of 0. However, when compared to ide-cel, cilta-cel had a higher median Max ALC (2 × 103/uL (1 - 4.4) vs 0.8 (0.7 - 2.8), p < 0.001), longer time-to-max ALC (11 vs 12 days, p = 0.003), and higher absolute ALC increase (2.1 × 103/uL vs 0.7 × 103/uL, p <0.001), while there were no differences in ALC before lymphodepleting conditioning or day 0. Higher max ALC was associated with CRS (OR 4.8, CI 1.3-17.2, p 0.01). Max ALC and absolute increase in ALC were significantly associated with deeper response (VGPR vs PR or less), improved PFS and duration of response (DoR) in univariable analysis. Max ALC >1 × 103/uL (HR 0.4, 0.2-0.7, p <0.001) and non-paraskeletal EMD (HR 2.1, 1.2-.4, p <0.01) remained associated with PFS/DoR in multivariable model after adjusting for CAR-T Product, high-risk cytogenetics, and number of previous lines. PB flow cytometry in 3 responder patients (max ALC range 2-14 × 103) showed expansion of CD3+ BCMA CAR-T from day 7 (BCMA CAR-T <0.2% of CD3+ cells) to day 14 (BCMA CAR-T range 54-88.6%), while a non-responder (max ALC 0.4 × 103) patient had no expansion despite presence of CD3+ BCMA CAR-T at day 7, 14 and 21. BCMA CAR-T had higher max ALC when compared to CD19 CAR-T (median 1.3 × 103 vs 0.4 × 103 (0.2-0.7), p < 0.001), while there were no differences in baseline ALC between BCMA and CD19 CAR-T. Median max ALC did not differ between response status after CD19 CAR-T (0.4 × 103 (0.2-0.7) vs 0.6 (0.3-0.7), p = 0.3). Discussion: Post-CAR-T lymphocytosis is common after BCMA CAR-T therapy for MM and is associated with response, PFS, and DoR after adjusting for other prognostic variables. A cut-off of max ALC > 1 × 103 identified patients with superior PFS, while max ALC <0.5 × 103 represents high-rates of poor response and early progression. ALC expansion correlated with BCMA CAR-T expansion as assessed by flowcytometry, supporting ALC assessment as an accessible surrogate that is clinically applicable and accessible. Citation Format: Mateo Mejia Saldarriaga, Darren Pan, Caitlin Unkenholz, Tarek Mouhieddine, Josh Fein, Jorge Monge, Cara Rosenbaum, Roger Pearse, David Jayabalan, Christian Gordillo, Hei Ton Chan, Markus Mapara, Giorgio Inghirami, Suzanne Lentzsch, Ren Reshef, Adriana Rossi, Samir Parekh, Sundar Jagannath, Shambavi Richards, Ruben Niesvizky, Mark Bustoros. Post CAR-T lymphocytosis as a surrogate of BCMA CAR-T expansion, response, and prognosis in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3619.

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.

The objective of our study was to report real-world data on the safety and efficacy of standard-of-care teclistamab in patients with relapsed/refractory multiple myeloma (MM). This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of teclistamab up until August 2023. One hundred and ten patients were included, of whom, 86% had triple-class refractory disease, 76% penta-refractory disease, and 35% had prior exposure to B-cell maturation antigen (BCMA)-targeting therapies. The overall response rate (ORR) in our cohort was 62%, with a ≥ very good partial remission (VGPR) rate of 51%. The ORR in patients with and without prior BCMA-targeted therapies was 54% vs 67%, respectively (p = 0.23). At a median follow-up of 3.5 months (range, 0.39–10.92), the estimated 3 month and 6 month progression free survival (PFS) was 57% (95% CI, 48%, 68%) and 52% (95% CI, 42%, 64%) respectively. The incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was 56% and 11% respectively, with grade ≥3 CRS and ICANS noted in 3.5% and 4.6% of patients respectively. 78 unique infections were diagnosed in 44 patients, with the incidence of all-grade and grade ≥3 infections being 40% vs 26% respectively. Primary prophylaxis with intravenous immunoglobulin (IVIG) was associated with a significantly lower infection risk on multivariate analysis (Hazard ratio [HR] 0.33; 95% CI 0.17, 0.64; p = 0.001).

Jorge Monge receives consulting fees from Bristol Myers Squibb. Meri Razavi, Liming Bao, and Sanjay S. Patel have no conflicts of interest to disclose.

Background: The FDA-approved BCMA-directed immunotherapies, which consist of chimeric antigen receptor T (CAR T) cell therapies like idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), alongside the bispecific antibody teclistamab, have improved outcomes for patients with relapsed/refractory multiple myeloma (MM). Despite their effectiveness, these treatments have distinct toxicity profiles, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, and the risk of infections, all contributing to non-relapse mortality. In this study, we analyzed these adverse events using data from the FDA Adverse Event Reporting System (FAERS) database. Method: We conducted a comprehensive search of the FAERS database from 2019 to 2023 to identify adverse effect reports of interest, associated with ide-cel, cilta-cel, and teclistamab. To ensure data accuracy, we excluded duplicate reports and cases where multiple BCMA-directed agents were associated with a single incident. Reporting odds ratio (ROR) was calculated by dividing the odds of a certain event occurring with the agent by the odds of the same event occurring with all other BCMA agents in the same database. Furthermore, to assess NRM, we excluded reports of progressive or refractory MM from the analysis of fatal cases. Results: A total of 1314 individual cases, with 3377 reported adverse reactions, were identified. Among them, 353 cases were associated with cilta-cel, 496 with ide-cel, and 465 with teclistamab. The most frequently reported adverse events included CRS at 12.8%, followed by fatigue (3.9%), pyrexia (3.2%), ICANS (3.0%), and non-ICANS neurotoxicity (1.9%). Ide-cel showed the highest ROR for CRS (1.64, 95% CI 1.33-2.02), whereas the ROR for ICANS was lowest with teclistamab (0.55, 95% CI 0.32-0.93). Ide-cel showed the highest ROR for non-ICANS neurotoxicity (2.45, 95% CI: 1.86-3.23). Bell's palsy was exclusively associated with cilta-cel, with 11 reported cases, while Parkinsonism was reported in 6 cases with cilta-cel, 2 cases with ide-cel, and none with teclistamab.Teclistamab had a notably higher proportion of infection-related events, accounting for 23.7% of all reported cases, as compared to 13.7% for cilta-cel and 2.9% for ide-cel. The ROR for infection was highest with teclistamab at 5.21 (95% CI: 4.14 - 6.56). Out of the total reported deaths (n=225 cases), NRM was observed in 189 patients, accounting for 84% of all mortality cases. In the analysis of NRM , ide-cel was associated with 42 reported deaths, with CRS (n=17; 40%), ICANS (n=8; 19%), sepsis (n=7; 17%), and hemophagocytic lymphohistiocytosis (HLH) (n=6; 14%) being the most common reported adverse events in this group. For cilta-cel, 59 deaths were reported, with CRS (n=17; 29%), ICANS (n=13; 22%), and HLH (n=9; 15%) as the most common adverse events in patients who suffered NRM. In the case of teclistamab, among the 88 NRM cases, the most frequent adverse events reported were COVID-19 (11.4%), pneumonia (11.4%), sepsis (9.1%), and septic shock (9.1%). Teclistamab exhibited the highest OR for NRM at 1.73 compared to 1.28 with cilta-cel and 0.42 with ide-cel. The findings will be presented with updated data. Conclusion: Our analysis of the FAERS dataset demonstrates a prominent risk of CRS and ICANS with CAR-T therapy, as well as a high risk of infection related mortality with teclistamab. Non-ICANS neurotoxicity was more pronounced with ide-cel compared to cilta-cel, potentially influenced by the longer follow-up period and wider uptake of ide-cel as it was the first FDA-approved CAR T therapy. We also note a higher NRM with both cilta-cel and teclistamab compared to ide-cel. While the exact attributes of NRM cannot be accessed in the database, complications of CAR T therapy and infections were the most common events noted in the group with NRM. Our analysis is limited by the nature of the FAERS database, where reporting is not mandatory, and selection bias cannot be eliminated. Since these agents share a similar indication for MM, clinicians will need to carefully consider their distinct toxicity profiles when choosing and sequencing treatments.

BACKGROUND In the phase 2, registrational MagnetisMM-3 (NCT04649359) trial, patients with RRMM who had not previously received a B cell maturation antigen (BCMA)-directed therapy (n=123) achieved an objective response rate of 61% with single-agent elranatamab (ELRA), a BCMA-CD3 bispecific antibody. Common treatment-emergent adverse events (TEAEs) included infections (70%; 40% grade [G] 3/4) and CRS (58%; all G1/2). Here we report on the safety of ELRA in the MagnetisMM-17 (MM-17; NCT05462639) trial, a North American Expanded Access Protocol (EAP). METHODS MM-17 is an ongoing, single-arm, open-label study for patients with triple-class refractory RRMM (refractory to ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody), and who had no prior BCMA-directed therapy. Patients must be ≥18 years of age and have a confirmed diagnosis of MM, measurable disease by IMWG criteria, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, adequate organ function, and no active, uncontrolled infection. The study is being conducted in the US and Canada. The primary objective is to provide access to ELRA for patients with RRMM and no access to comparable/alternative therapy. The secondary objective is to evaluate the safety and tolerability of ELRA. Patients received subcutaneous ELRA 76 mg once every week on a 28-day cycle after step-up doses of 12 and 32 mg during week 1. Dose frequency was reduced to once every 2 weeks (Q2W) after ≥6 cycles in patients with persistent response (≥partial response), and then from Q2W to Q4W after ≥6 Q2W cycles. Patients received ELRA until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or ELRA becomes commercially available. TEAEs were graded by NCI CTCAE v5.0, except cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which were graded according to the American Society for Transplantation and Cellular Therapy criteria (ASTCT). RESULTS As of April 28, 2023, 20 patients had enrolled in the trial. Median patient age was 72.5 years (range 53-82); 50% male, 85% white, and 15% Black/African American. At baseline, most patients had an ECOG PS of 1 (95%), and 40% had R-ISS disease stage III. Patients had a median of 4 prior lines of therapy (range 2-8); 95% and 35% of patients had triple-class and penta-drug refractory disease, respectively. At the time of data cut-off, 2 patients had discontinued due to progressive disease. Median treatment duration was 0.95 months (range 0.26-2.83); median relative dose intensity was 98.3% (range 48-105). TEAEs were reported in all 20 patients, with G3 or G4 events reported in 13 (65%). There were no G5 events. Thirteen (65%) patients developed CRS, all events were G1 (50%) or G2 (15%); no events G ≥3 were reported. After the first step-up dose, 11 (55%) patients had a CRS event. CRS events occurred in 3 patients (15%) and 1 patient (5%) after the second step-up dose and first treatment dose, respectively. The median time to onset was 2 days (range 1-4), and the median time to resolution was 3 days (range 1-5). ICANS occurred in 2 of the 20 patients (10%), both events were G1, with 1 occurring after the first step-up dose and the other after the second step-up dose. The median time to onset was 3 days (range 3-3) and the median time to resolution was 2.5 days (range 2-3). Four (20%) patients had infections, including 1 event each of G1 sinusitis, G2 acute sinusitis, G2 folliculitis, G2 upper respiratory tract infection and G3 bacterial conjunctivitis. Cytopenias were reported in 11 (55%) patients. The most common (occurring in ≥3 [15%] patients) cytopenias were neutropenia (30%; G3/4 25%), lymphopenia (20%; G3/4 15%), and thrombocytopenia (15%; G3/4 10%). CONCLUSIONS Early safety data (median treatment duration <1 month) from this ongoing expanded access protocol of elranatamab in patients with RRMM are consistent with results from the phase 2, registrational MagnetisMM-3 trial, with no new safety signal identified.

Introduction Although expansion of chimeric receptor antibody (CAR)-T cells after infusion has previously been described, overt lymphocytosis with atypical morphology has not been widely reported in multiple myeloma (MM). Here we describe the kinetics of absolute lymphocyte count (ALC), its relationship with immune mediated toxicities, and clinical outcomes. Methods Thirty-nine patients (pts) receiving BCMA CAR-T (25 pts ciltacabtagene autoleucel (cilta-cel) and 14 pts idecabtagene vicleucel (ide-cel)) from two institutions were retrospectively reviewed. Data on baseline characteristics, presence of extramedullary disease (EMD), conditioning regimen, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), severity of CRS/ICANS (according to American Society of Transplantation and Cellular Therapy (ASTCT) classification), ALC on day -5 through 14, time to best response (TBR), time to first response (TFR), depth of response, and outcomes were collected. Response was evaluated in pts with >3 months of follow up. Peripheral blood flow cytometry was performed in 3 cases at time of highest ALC. ALC data for 84 pts who received CD19 CAR-T (77 pts with axicabtagene ciloleucel and 7 pts with brexucabtagene autoleucel) for non-Hodgkin lymphoma (NHL) were included as a comparison. Maximum ALC (max-ALC) was defined as the highest ALC between day 0 and +15, baseline ALC was defined as the lowest ALC during day 0 through +3, and absolute ALC increase was defined as the difference of max-ALC and baseline ALC. Results Baseline characteristics of the cohort are described in Table A. Pts who received cilta-cel had earlier onset of CRS (median day +6 (IQR 2 - 8) vs +2 (IQR 1 - 2), p = 0.02), had higher max-ALC after CRS (median 1.7 cel/uL (IQR 0.8 - 5.3) vs 0.81 cel/uL (IQR 0.6 - 1.1), p = 0.02), and had a trend towards later max-ALC (median day +12 (IQR 11 - 13) vs +10 (IQR 9 - 13), p = 0.1). Baseline ALC did not differ by BCMA CAR-T product or number of previous lines of therapy. When compared to the NHL cohort, patients who received BCMA CAR-T had higher max-ALC (1.01 cel/uL (IQR 0.6 - 1.9) vs 0.4 cel/uL (IQR 0.2 - 0.7), p < 0.001) and this max-ALC occurred later (median day max-ALC +12 (IQR 10 - 13) vs day +10 (8 - 10), p < 0.01) Figure C. Higher max-ALC and absolute ALC increase were associated with depth of response and occurrence of CRS/ICANS. Pts who had a deeper response (VGPR/CR) had a higher median max-ALC (1.2 cel/uL (IQR 0.77 - 1.81) vs 0.5 cel/uL (IQR 0.2 - 0.7) p < 0.01) and absolute ALC increase (1.2 cel/uL (IQR 0.7 - 1.8) vs 0.6 cel/uL (IQR 0.2 - 0.7) vs, p = 0.01) compared to those with PR or worse Figure B. Similarly, pts who did not progress on follow-up had higher median max-ALC (0.58 cel/uL (IQR 0.4 - 0.8) vs 1.3 cel/uL (IQR 0.9 - 1.9), p < 0.001) and absolute ALC increase (1.3 cel/uL (0.9 - 1.8) vs 0.6 cel/uL (0.5 - 0.8), p < 0.01) compared to progressors. Pts who experienced CRS had a higher absolute ALC increase i(1.05 cel/uL (0.7 - 2.7) vs 0.27 cel/uL (0.2 - 0.5), p = 0.02), and pts who had ICANS had higher max ALC (3.2 cel/uL (0.8 - 6.4) vs 1.01 cel/uL (0.6 - 1.8), p = 0.2). These results were consistent across BCMA CAR-T product, and there were no differences in baseline ALC across CAR-T product, response, disease progression, or number of previous lines. Furthermore, higher max-ALC was associated with higher odds of having VGPR/CR (OR 32.3 (2.23 - 240), p = 0.04) in univariable logistic regression. Flow cytometry data on 3 pts showed expansion of CD8+ T Cells during peak ALC with increase of CD8:CD4 ratio. Multicolor flow cytometry using an antibody BCMA at time of peak ALC showed expansion of CD4+ and CD8+ CAR-T, and further immunophenotypic characterization (differentiation, maturation, exhaustion) is currently being performed. Conclusions Post-CAR-T lymphocytosis was a common event after BCMA CAR-T therapy for MM, which presented a higher max-ALC, and at a later day when compared to CD19 CAR-T for NHL. Furthermore, ALC dynamics differed by BCMA CAR-T product, with cilta-cel exhibiting later CRS with higher max-ALC peaking at a later day when compared to ide-cel. Furthermore, higher max-ALC and absolute ALC increase were associated with deeper response (VGPR/CR) and sustainable response on follow up. Our findings suggest that peripheral lymphocytosis after CAR-T is disease specific (NHL vs MM) and post CAR-T lymphocytosis in peripheral blood is a potential biomarker for clinical outcomes and toxicity.