Lee, Hans C.

Autologous stem cell transplantation (ASCT) in AL amyloidosis effectively produces a high overall hematological response rate, complete response rate, and durable remissions. However, it is a high-dose chemotherapy-based therapy with high morbidity which can be offered only to a subset of AL amyloidosis patients who are considered fit for this therapy. Transplant-related mortality (TRM) in AL amyloidosis has decreased over the past three decades due to improvement in patient selection. New therapeutic options question the utilization of ASCT. A model to predict TRM can improve the decision-making process, patient selection and further reduce TRM. AL amyloidosis patients (n=1718) from 9 centers globally, transplanted in the years 2003-2020 were included. Pre-ASCT variables of interest were assessed for association with Day-100 all-cause mortality, including age at ASCT (≥ 60 years), sex, light chain isotype, ECOG performance status (ECOG PS; 0, 1 and 2/3), the difference between involved and uninvolved light chains (dFLC; ≥180 mg/L), N-terminal prohormone of B natriuretic peptide (NT-proBNP; ≥1800 pg/mL) or B-type natriuretic peptide (BNP; ≥400 pg/mL), left ventricle ejection fraction (LVEF, <50%), interventricular septum (>16 mm), corrected diffusing capacity for carbon monoxide (cDLCO; ≤65% of predicted), forced expiratory volume in one second (FEV1; ≤65% of predicted), serum albumin (<2.5 g/dL), estimated glomerular filtration rate (eGFR; <30 mL/min/m2), alkaline phosphatase (>X2 upper limit of normal), and systolic blood pressure (<100 mmHg). Troponins could not be included in our modeling given the multitude of assays used across institutions and periods that could not be reconciled. A random forest (RF) classifier with 10-fold cross-validation was used to assist in variable selection. The final model variables were selected based on statistical performance and clinical relevance. The model was fitted using logistic regression. The median age at ASCT was 58, and 40% of patients were women. The most frequently involved organs were the kidneys (69%) and the heart (52%). Mayo 2004 stages I and II were collectively present in 83% of patients. Day-100 TRM occurred in 75 patients (4.4%) with the 3 main causes being shock (n=27), cardiac arrhythmia (n=26), and organ failure (n=22). Age at ASCT, sex, and light chain isotype were not predictors of Day-100 TRM. Across the other pre-ASCT variables, adverse features were present from 6.9% (LVEF <50%) to 25.8% (dFLC ≥180 mg/L) of patients. Ten factors were associated with Day-100 TRM on univariate analysis. The odds ratio of these variables ranged from 1.6 to 10.2. RF classifier using all these variables identified a model with an area under the curve (AUC) of 0.72±0.12. Using the importance hierarchy function to refine the model selection, a 4-variable model [NT-proBNP/BNP ≥1800/400 pg/mL, serum albumin <2.5 g/dL, ECOG PS 1 or 2/3, and systolic blood pressure <100 mmHg] was built with an AUC of 0.70±0.12. Based on logistic regression coefficients, ECOG PS 2/3 was assigned two points, while other adverse predictors were assigned 1-point each (model score range 0-5). We then applied the model scoring to our study population. Score distribution was as follows: 0 (n=431, 25.1% of patients), 1 (n=688,40.1%), 2 (n=413, 24.0%), and 3 and above (n=186, 10.8%). Day-100 TRM rates were 0.46%, 3.2%, 5.8%, and 14.5% for 0, 1, 2, and ≥3 points, respectively. The respective rates for the years 2003-2011 were 1.1%, 3.3%, 6.4%, and 19.2%, while for the years 2012-2020 0%, 3.1%, 5.2%, and 8.4%. We developed a simple clinical tool to predict the Day-100 TRM risk in AL patients undergoing ASCT. This tool will allow more informed decision making weighing the individual benefits and risks of ASCT compared to other therapies.

Background: Teclistamab (Tec) received regulatory approval for the treatment of relapsed refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. The risk of CRS and ICANS with Tec is well established with a manufacturer's recommendation of inpatient observation for 48-hours for CRS/ICANS monitoring after the initial 3 step up doses. There are limited real-world data on the characteristics of and risk factors for CRS and ICANS with Tec. Such data could inform management of Tec patients (pts), including patient selection for inpatient or outpatient step-up dosing. Methods: RRMM pts treated with standard-of-care Tec across 13 U.S. academic institutions were included in this analysis. The follow-up data cutoff was 30 April 2024. CRS and ICANS classification was based on the American Society for Transplantation and Cellular Therapy consensus grading criteria. Multivariable logistic regression models were fitted to estimate the effects of covariates on CRS and ICANS events, with a particular focus on grade ≥2 CRS, any-grade ICANS, and the combination of CRS grade ≥2 and/or any-grade ICANS. Results: 385 pts were included in the analysis, with a median of 6 lines of prior therapy. Median age was 68 years (range 31-92), 88 patients (25% of pts with available data) had ECOG ≥2, and 301 pts (78%) would have been ineligible for MajesTEC-1. 48 (33%) of 145 evaluable pts with a baseline bone marrow (BM) prior to Tec had >50% BM plasma cells, 139 pts (36%) had extramedullary disease (EMD) (either paraskeletal or true-EMD) and 5 pts (1%) had plasma cell leukemia prior to start of Tec. 224 pts (59%) received Tec with an accelerated step-up dosing regimen, defined as having at least one step-up dose interval of ≥ 2 days. 220 pts (57%) developed any-grade CRS [Grade 1: 46% (N=179), grade 2: 10% (N=37), grade 3: 0.8% (N=3), grade 4: 0.3% (N=1)]. Median time to CRS from start of Tec was 3 days (range, 0-15). Fifty-four pts (14%) developed any-grade ICANS [Grade 1: 7% (N=26), Grade 2: 5% (N=18), grade 3: 3% (N=10), grade 4: none]. There were no grade 5 CRS or ICANS events. Median time to onset of ICANS from start of Tec was 4 days (range, 0-25). There was one case of hemophagocytic lymphohistiocytosis in the entire cohort. 38% of pts received tocilizumab and 17% of pts received corticosteroids. In univariate analysis (UVA), baseline platelet <50, triple-class refractory, penta-refractory status, and EMD prior to start of Tec were associated with increased risk for CRS grade ≥2 (p-values <0.1) and incorporated in MVA. Baseline platelet <50, age >60, ECOG ≥2, Hgb <8 g/dL, BM plasma cells >50%, and ferritin or CRP in the upper quartile were associated with increased risk for any-grade ICANS in UVA (p-values <0.1). Baseline platelet <50, ECOG ≥2, Hgb <8 g/dL, BM plasma cells >50%, ferritin or CRP in the upper quartile, and prior BCMA exposure were associated with increased risk of CRS grade ≥2 and/or any-grade ICANS in UVA (p-values <0.1). Accelerated step-up dosing, renal impairment (CrCl < 30 mL/min) and baseline LDH in the upper quartile were not associated with an increased risk of either CRS or ICANS in UVA. Baseline BM plasma cells >50% was excluded from multivariable analysis (MVA) due to high number of missing data, since most pts (62%) did not undergo BM biopsy prior to start of Tec. In MVA, risk factors for CRS grade ≥2 included baseline platelet <50 at the start of Tec treatment (OR: 2.35, 95% CI 1.08-5.08; p=0.03) and penta-refractory disease (OR: 2.48, 95% CI 1.13-5.45; p=0.02). Risk factors for any-grade ICANS included platelet <50 (OR: 4.18, 95% CI 1.88-9.28; p=0.0004), age >60 (OR: 7.54, 95% CI 1.63-34.89; p=0.01) and CRP in the upper quartile (OR: 2.51, 95% CI 1.16-5.43; p=0.02). Risk factors for CRS grade ≥2 and/or any-grade ICANS included platelet <50 (OR: 2.65, 95% CI 1.42-4.94; p=0.002) and ECOG ≥2 (OR: 2.07, 95% CI 1.19-3.61; p=0.01). Conclusions: This real-world analysis of RRMM pts treated with Tec revealed comparable rates CRS and ICANS relative to the MajesTEC-1 study, and these were mostly limited to grade 1/2. MVA demonstrated a significantly higher risk of CRS grade ≥2 and/or any-grade ICANS in pts with baseline platelet <50 and/or ECOG ≥2, the former may reflect BM disease burden. These results may help identify pts who are at higher risk for IEC related toxicities with Tec that would warrant inpatient monitoring during initial step-up dosing. OP, AA, & LF: co-first authors. AG, HCL & JK: co-senior authors

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

Background: Tec is a BCMA-directed bispecific antibody (BsAb) approved for RRMM after ≥4 prior lines of therapy (LOT) based on the MajesTEC-1 trial. However, patients who had previously received a BCMA-DT were excluded from MajesTEC-1. Herein, we evaluated outcomes of RRMM patients with prior exposure to BCMA-DT treated with standard-of-care Tec. Methods: This was a multicenter retrospective cohort study. We compared variables between different groups using Chi-squared and Kruskal-Wallis tests, and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards model. We used the maximally selected rank statistics method to determine the optimal cut-off point for continuous variables to find the most significant difference in PFS among different groups. Results: A total of 385 patients were included in this study. 193 patients had received a prior BCMA-DT, of whom 77%, 22%, and 1% had received 1, 2, and 3 prior anti-BCMA agents, respectively. In patients who had received a prior BCMA-DT, 35% were aged ≥70 years, 24% had ECOG performance status (PS) ≥2, 61% had high-risk FISH, 32% had extramedullary disease (EMD) at Tec initiation, and 42% were penta-refractory. Compared to the cohort without prior BCMA-DT (n=192), patients who were treated with prior BCMA-DT were more likely to have high risk FISH (61% vs 49%, p=0.02), and higher median number of prior LOT (7 vs 5, p <0.001). The specific types of prior BCMA-DTs with the respective overall response rate (ORR) to the most recent prior BCMA-DT were: antibody drug conjugate only (ADC, n=47, ORR 43%), chimeric antigen receptor T-cell therapy only (CAR T, n=99, ORR 86%), BsAb only (n=6, ORR 100%), ADC + CAR T (n=36, ORR 56%), and other ADC/CAR T/BsAb combinations (n=5, ORR 60%). Median follow up was 9.9 (95% CI:9.5-10.6) months. Patients with prior receipt of BCMA-DT had a lower ORR (51.4% vs 61.5%; p=0.012) and ≥very good partial response rate (39.4% vs 52.6%, p=0.009), but similar ≥complete response rate (22.3% vs 24%; p=0.78) to Tec compared to those without prior BCMA-DT. Moreover, patients with prior BCMA-DT had worse median PFS compared to patients without prior BCMA-DT (prior BCMA-DT: 4.6 months, 95% CI: 2.7-7.5; without prior BCMA-DT: 8.2 months, 95% CI: 5.7-12.2; p=0.017). On multivariable analysis incorporating prior BCMA-DT, age, cytogenetics, EMD, and ECOG PS, receipt of prior BCMA-DT was not independently associated with PFS (HR 1.25, 95% CI 0.95-1.64, p=0.1). The estimated 1-year OS rate was 58.9% (95% CI: 51.64-67.2) for the prior BCMA-DT group vs 65.1% (95% CI: 58.1-73.1) for the group without prior BCMA-DT, p=0.16. For the prior BCMA-DT cohort, response rates to Tec were numerically higher in patients who received CAR T (ORR 51.2%) followed by ADC (ORR 45.5%), and bispecific (ORR 30%) as their most recent prior BCMA-DT (p=0.39). No significant difference in PFS was noted when stratifying patients by number of prior BCMA-DTs, types of all prior BCMA-DTs received, type of most recent prior BCMA-DT, or depth of response to most recent BCMA-DT. Patients who responded to Tec had a numerically longer median time from most recent BCMA-DT exposure to Tec initiation compared to non-responders: 10.5 vs 7.5 months, p=0.48. We found that the optimal cut-off for time from last BCMA-DT exposure to Tec initiation was 8.7 months. Patients with > 8.7 months between last exposure to prior BCMA-DT and Tec initiation had a superior median PFS with Tec (8.1 months, 95% CI: 4.6-11.7) compared to patients with < 8.7 months from last exposure to prior BCMA-DT (2.5 months, 95% CI: 1.1-5.7), p=0.001. The toxicity profile for patients with prior BCMA-DT was similar to those who had not received a prior BCMA-DT. Grade ≥2 CRS occurred in 8.7% vs 13% (p=0.18), and grade ≥2 ICANS in 7.7% vs 6.7%, (p=0.85) of patients with and without prior BCMA-DT, respectively. Patients in the prior BCMA-DT cohort were more likely to have grade 3 thrombocytopenia in the first 30 days after Tec initiation (10.7% vs 6.6%; p=0.08). Conclusion: This is the largest study to date of any BCMA-directed BsAb among BCMA-exposed patients. Receipt of prior BCMA-DT was associated with a trend toward worse PFS, although not statistically significant, and lower likelihood of attaining an overall response. Waiting >9 months between sequencing BCMA therapies may be associated with improved PFS. D.D., M.A.V.M., J.A.D: co first authors; F.A., C.F., L.S.: co senior authors

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Introduction: High dose chemotherapy and autologous stem cell transplantation (ASCT) is one of the most effective therapies in light chain (AL) amyloidosis. It is associated with a high hematologic response rate and leads to durable remissions. High dose melphalan is the most frequently used conditioning chemotherapy, as has been used in multiple myeloma (MM). Melphalan dose is based on renal function, age, degree of cardiac involvement and patients' frailty and is predictive of outcomes. While studies that assessed the conditioning schedule have been conducted in MM, with variable results, no such studies were done in AL amyloidosis. Methods: In this retrospective study, we explored the impact of the conditioning schedule on post-transplant outcomes in a large multicenter study. Patients with AL amyloidosis who underwent ASCT for the primary diagnosis of AL amyloidosis between January 1, 2003, and December 31, 2020, were included in this study. Results: One thousand seven hundred and eighteen (n=1718) patients from 9 centers are included. The median age was 58 years, and 61% were male. Most patients had one (43%) or two (33%) involved organs, with the most involved organs were the kidneys (69%) followed by the heart (52%). Induction therapy was given to 52% of patients. The conditioning regimen was almost exclusively melphalan (99.2%), with 65% receiving full dose melphalan (≥170 mg/m 2). Melphalan was given over two days in most patients (80%). A rest day between conditioning and stem cell infusion was provided in 53% of patients, mostly in those who received melphalan on a single day rather than over 2 days (87% vs 44%, P<0.001). Post-transplant hematologic response was available for 1569 patients (91% of patients) and were assessed from baseline. Complete response (CR) and very good partial responses (VGPR) were achieved post-ASCT in 33.7% of patients each. Low dFLC-partial response (PR) was achieved in 2.7% and PR in 18% of patients. Altogether, satisfactory post-ASCT response (CR, VGPR, or low-dFLC PR combined) was achieved in 70% of patients. Compared to no induction, less than a PR to induction was associated with a lower probability of achieving satisfactory post-ASCT response, while PR or better to induction had higher chances of satisfactory post-ASCT response (65% vs 46% vs 84%, P<0.001). A single day of melphalan conditioning was associated with a higher probability of satisfactory post-ASCT response compared to two days of conditioning (82% vs 67%, P<0.001). Omitting a day of rest between conditioning and stem cell infusion was also associated with higher satisfactory post-ASCT response compared to having a rest day (76% vs 65%, P<0.001). The Table lists other predictors for a post-ASCT satisfactory hematologic response. In a nominal multivariate logistic regression analysis, independent predictors for higher post-ASCT satisfactory hematological response rate included: PR or better to induction therapy, female gender, kappa light chain isotype, lower dFLC at baseline, and kidney and liver involvement. In addition, full dose melphalan, conditioning given over a single day and having no rest day between conditioning and stem cell infusion were also associated with a higher likelihood of satisfactory post-ASCT response. Post-ASCT hematologic CR rate was higher in those receiving full dose conditioning (36% vs 28%, P<0.001), in those having no rest day (40% vs 28%, P<0.001) but not in those who received one day of conditioning versus two days (35% vs 33%, P=0.5). The rate of ICU admission was higher in those receiving no day rest (17.7% vs 12.6%), P=0.003) and among those who received reduced dose melphalan (18.1% vs 13.3%, P=0.008) but not based on number of conditioning days (P=0.56). Day 100 mortality was significantly higher in the no rest day group (5.6% vs 3.2%, P=0.01) and among those receiving reduced dose melphalan (6.8% vs 3.1%, P=0.004) compared to their counterparts, but not based on the number of days of conditioning (P=0.89). The median follow-up in the entire cohort was 104 months (95% CI 98-110). In a multivariate analysis for overall survival (OS), the conditioning dose but not the conditioning schedule was independently associated with OS. Conclusions: This study is the first to demonstrate the effect of melphalan conditioning schedule on post-transplant response. This study supports a single day melphalan conditioning in AL amyloidosis to improve post-ASCT response.

Introduction: With rapid treatment advances in multiple myeloma (MM), more patients receive the 3 main classes of MM treatments (immunomodulatory imide drug [IMiD] agents, proteasome inhibitors [PIs], and anti-CD38 monoclonal antibodies [mAbs]) in earlier lines of therapy and become TCE. This is a prerequisite for subsequent treatment with some novel therapies eg, anti-B-cell maturation antigen (BCMA) agents. Published evidence of RW clinical outcomes in patients with TCE MM is scarce in the evolving RRMM treatment landscape. The objective of this study was to assess RW clinical outcomes in patients with TCE RRMM who received treatment post-TCE. Methods: In this observational study, we analyzed de-identified patient data derived from electronic health records (EHRs) from 2 key United States (US) MM longitudinal databases (Flatiron Health MM [FHMM] and COTA Vantage MM [CVMM]). We identified patients who became TCE between November 2015 and March 2021 and received a subsequent treatment post-TCE; the earliest available end date of the 3rd treatment class was considered the date patients became TCE. The start date of the 1st treatment post-TCE (index treatment) was defined as the index date. We analyzed patient demographics, disease characteristics, prior treatment exposure, refractory status, and index treatments patterns/classes. Clinical endpoints assessed were response rates (overall and complete), overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Results: The FHMM and CVMM databases included 1,319 and 1,118 TCE patients, respectively, of whom 897 and 795 received an index treatment post-TCE. Median (range) follow-up for patients who received an index treatment was 18.1 (0.1-82.0) and 15.5 (0.03-72.3) months for FHMM and CVMM cohorts, respectively. Median age for both RW cohorts was 68 years, more than half of patients were men and the majority were White. Patients received a median of 3 lines of prior treatment (range, 1-14 and 1-12 for FHMM and CVMM cohorts, respectively). In both RW cohorts, >75% of patients who received an index treatment were triple-class refractory and approximately 10% were penta-refractory, having received treatment with 2 IMiD agents, 2 PIs, and an anti-CD38 mAb. Approximately 67% and 79% of patients in the FHMM and CVMM cohorts, respectively, had ECOG performance status 0 or 1. Approximately 54% and 61% had received prior stem cell transplantation. IMiD agents either alone or in combination with a PI and/or anti-CD38 mAb constituted the main regimens for index-treated patients. In the CVMM cohort, the overall and complete response rates were 15.2% and 1.7%, respectively; response data were not available in the FHMM cohort. Median OS (22.3 and 20.4 months), median PFS (4.8 and 4.9 months), and median TTP (5.9 and 5.9 months) were comparable for both FHMM and CVMM cohorts. Conclusions: In this observational cohort study of 2 US RW EHR databases, patients became TCE with a median of 3 prior lines of therapy. Post-TCE, most patients with RRMM still received the same 3 treatment classes with poor response and survival outcomes on their treatments. Despite advances in MM management, this study highlights the need for more efficacious novel treatments for patients with TCE MM and serves as a RW benchmark in the literature for appraising emerging data from novel agents in patients with RRMM.

Abstract Background: MM remains incurable and new tx options are needed, especially in heavily pre-treated R/R pts. REGN5459, a BCMAxCD3 bispecific Ab, binds to BCMA on MM cells and with low affinity to CD3 on T cells, triggering T-cell activation and plasma cell depletion with low cytokine release preclinically. This first-in-human study aimed to assess the safety, tolerability, and preliminary anti-tumor activity of REGN5459 monotherapy in pts with R/R MM. Methods: Eligible pts had received ≥3 prior lines of tx including an anti-CD38 Ab, proteasome inhibitor, and immunomodulatory drug, and had exhausted all available tx options. Pts could receive REGN5459 until progression/intolerable toxicity. Primary objectives were to assess safety, tolerability, dose limiting toxicities (DLTs), and determine the recommended Ph 2 dose (RP2D) of REGN5459 (Ph 1) and assess efficacy of REGN5459 (Ph 2) per ORR. Results: As of June 9, 2022, 43 pts were enrolled (Ph 1, 33; Ph 2, 10): median age 67 yrs (range, 26-85), 51% female, 16% high cytogenetic risk, 14% extramedullary plasmacytoma, 37% R-ISS Stage III disease, 61% triple-class refractory, and median of 5 (range, 2-9) prior lines of tx. In Ph 1, one DLT was reported in a pt receiving the highest dose (900 mg; Gr 3 hypoxia, pt later found to have primary lung cancer). RP2D was identified as 480 mg. All pts enrolled had ≥1 TEAE, 74% had Gr ≥3 TEAEs. TEAEs all-Gr in ≥30% of pts were CRS (54%), fatigue (44%), neutropenia (37%), anemia (35%), cough (30%), and diarrhea (30%). Gr ≥3 TEAEs in ≥15% of pts were neutropenia (37%), anemia (26%), lymphopenia (23%), thrombocytopenia (19%), and hypertension (16%). CRS Gr 1, 2, and 3 were reported in 47%, 2%, and 5%, respectively; there was no Gr 4 or 5 CRS. No Gr 3 CRS with RP2D. Tocilizumab was used in 19% and steroids in 9% of pts. One pt developed ICANS (2%, Gr 2). Incidence of serious TEAEs and TEAEs leading to tx discontinuation was 63% and 16%. Infections occurred in 61% (37% Gr ≥3). After data-cutoff, two deaths due to COVID pneumonia and COVID infection have been reported. ORR was 67% (58% ≥VGPR) for the entire cohort and 100% (85% ≥VGPR; 15% sCR; 39% CR) among pts receiving the RP2D (n=13). Median follow-up was 7 mos (range, 1-26) with longest response ongoing for 22+ mos. Median time to response was 0.8 mos. Median DOR was NR (95% CI, 12-NE); 12-mo DOR for RP2D was 66.7% (95% CI, 5.4-94.5). Of pts in ≥CR with available MRD results (n=8), 50% were MRD negative at the 10−5 threshold. Conclusion: These initial data show that REGN5459 has acceptable safety/tolerability in R/R MM with most CRS of low grade and low incidence of ICANS. Modulation of CD3 affinity on bispecific Abs to maximize tumor killing, and mitigate CRS and T-cell exhaustion, warrants further research. Efficacy in this heavily pre-treated cohort was encouraging, with 100% ORR with the RP2D. Updated data will be presented at the meeting. Citation Format: Attaya Suvannasankha, Prashant Kapoor, Matthew J. Pianko, Joshua Richter, Anita D'Souza, Larry D. Anderson, Andrew Magyar, Oluwaseun Aina, Anita Boyapati, Damien Cronier, Nikhil Singh, Karen Rodriguez-Lorenc, Glenn S. Kroog, Hans C. Lee. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT013.