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Background: Venetoclax (Ven), a BCL2 inhibitor, has shown promising responses in multiple myeloma (MM) patients with t(11;14) and/or BCL2 expression. However, consistent benefit in clinical trials remain elusive. This report evaluates the efficacy and safety of Ven combination therapies, including in the non-t(11;14) subgroup, and examines the impact of secondary cytogenetic abnormalities (SGA) on outcomes. Methods: This retrospective study included multiple myeloma (MM) patients without concurrent AL amyloidosis treated with Ven-based combinations at Mayo Clinic sites from January 2015 to December 2023. FISH data was collected at diagnosis and before venetoclax initiation to assess SGAs. Refractoriness was defined by progression on or within 60 days of stopping treatment. Patients refractory to at least one proteasome inhibitor (PI), immunomodulatory drug (ImiD), and anti-CD38 antibody were considered triple-class refractory (TCR). Ven combinations were grouped as: Daratumumab/CD38 antibody (Dara)-Ven based if received Dara ± other drugs, PI-Ven-based without Dara, Ven-dexamethasone (Ven-d), and other combinations (Ven-Misc). BCL2 expression in patients without t(11;14) was determined by immunohistochemistry (IHC). Progression-free survival (PFS) was calculated from treatment initiation to disease progression or last follow-up. Results: We included 232 patients in this study. The median age at diagnosis of MM was 62 years (range 32-87), and the median age at initiation was 68 years (range 35-89). The median time from diagnosis of MM to initiation of Ven was 55 months (95% CI 28, 89 months), and the median follow-up from initiation of Ven-based treatment was 17.2 months (95% CI: 14, 22). Patients had received a median of 3 lines (IQR 4-6); 65% (n=152) of patients were TCR, 71% (n=163) had received autologous stem cell transplant and 7% (n=16) patients had received prior immune effector therapy prior to initiation of Ven-based therapy. The majority (83%, n=190) of the patients harbored a t(11;14); in the patients without t(11;14), a BCL2 expression by IHC was tested in 18 patients and positive in 17 patients. The most common Ven-based combinations included: Dara-Ven-d (19%, n=44), PI-Ven-d (30.2%, n=70), Ven-d (48.3%, n=112), Ven-misc (2.6%, n=6). The overall response rate for the entire cohort was 57% [64% for t(11;14) and 26% for non t(11;14), p<0.0001]. The median PFS for the entire cohort was 9.5 months (95% CI 8.5,13), and the duration of response was 18 months (95% CI 15.2-23.3). The median PFS was 11.8 months (95% CI 9.5-16.7) for patients harboring a t(11;14) compared to 2.9 months (95% CI 1.8, 8.4) for patients without a t(11;14), p<0.0001. Among the non-t(11;14) cohort with BCL2 expression, the median PFS was 1.8 months (95% CI: 1.2-4.2). Among the 190 patients with t(11;14), 18% (34/190) harbored deletion 17p and 32% (60/193) harbored a 1q gain/amplification (referred hereforth as 1q21+) at initiation of Ven-based therapy. In the cohort of patients with t(11;14), the presence of either del17p or 1q21+ (n=85/190) was associated with a significantly inferior PFS [median PFS 8.2 months (95% CI: 5.5,13)] vs. 15.1 months (95% CI: 11.6, 22), p=0.03. At the last follow-up,42 patients had ongoing treatment with ven-based combination. Most common reasons for discontinuation were progression (77% N=140), adverse effect (12%, n=22), patient/provider preference(9%, n=17); 2% (n=4) patients died without progression (3 infection, 1 unclear). The most commonly utilized maximum dose of venetoclax was 400 mg (42%); 15% (n=35) of patients required a dose reduction, and 23% (n=54) received a ramp-up. Tumor lysis syndrome was not noted in any patient. Infectious complications were noted in 23% (n=52). The estimated median OS from initiation of ven-based Rx was 34 months (95%CI 25-47). The estimated median OS for patients without a t(11;14) was 6.2 months (95% CI: 3.3-11.3) compared to 46 months (31.4-54.1), p<0.0001. In the t(11;14) subgroup, the 18-month OS rate was 79% for patients without 1q21+/del17p vs. 50% for patients with a 1q21+/del17p (p=0.002). Conclusion: Venetoclax-based regimens represent an important treatment option for patients harboring a t(11;14). The PFS in patients with BCL2 expression without t(11;14) was poor suggesting lack of efficacy of venetoclax-based regimens for that subgroup. Presence of concurrent del17p and/or 1q21+ with t(11;14) portends an inferior PFS.

BACKGROUND Several studies have highlighted the poor clinical outcomes observed among patients with relapsed/refractory multiple myeloma (MM), particularly those with triple-class refractory (TCR; refractory to at least one protease inhibitor [PI], one immunomodulatory drug [IMiD], and one anti-CD38 monoclonal antibody [mAb]) disease. The aim of this study was to describe the longitudinal changes in quality of life (QOL) and other patient-reported outcomes (PROs) among TCR MM patients who initiated a new line of therapy in real-world clinical practice. METHODS A prospective, multi-site observational study was conducted through the Mayo Clinic system. Patients with TCR MM initiating a new line of therapy (defined as the index date) were followed for a 12-month observation period. For patients initiating a CAR-T therapy, PRO survey assessments were conducted at apheresis, lymphodepletion chemotherapy, and every month after T-cell infusion until Month 6. All other patients received a survey assessment before index and every month thereafter until Month 6. PRO measures included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30; including the Global Health Score [GHS]), the EORTC Multiple Myeloma Questionnaire (QLQ-MY20; including the Disease Symptoms [DS] domain score), the EORTC QLQ for Chemotherapy-Induced Peripheral Neuropathy (CIPN20), the EuroQoL-5 Dimensions (EQ-5D), the Patient Global Impression of Severity (PGIS), and the Patient Global Impression of Change (PGIC). PRO surveys were supplemented with retrospective chart reviews conducted at 3 months and 12 months following the index date to obtain clinical information. Descriptive data were reported at each timepoint separately for patients who received CAR-T and non-CAR-T index therapies. The study is ongoing and this abstract reflects all patient data collected as of May 2024. RESULTS This interim analysis included 77 patients (58% male, 95% White, mean age 66 years). The median time interval between becoming TCR and the index date was 5.6 months (interquartile range [IQR]: 1.8, 18.2). Most patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 (48% and 45%, respectively) and were Revised International Staging System (R-ISS) I or II (27% and 36%, respectively); 42% of patients had high-risk cytogenetics and 14% had extramedullary disease. The median (IQR) number of prior treatment lines was 4 (4, 5). Forty-two patients initiated a CAR-T therapy as their index therapy (12 and 30 treated with ide-cel and cilta-cel, respectively); the remaining 35 patients predominantly initiated a treatment regimen containing an IMiD (51%), a PI (54%), an anti-CD38 antibody (40%), or an alkylating agent (37%). Among these non-CAR-T patients, common regimens used were pomalidomide + elotuzumab + corticosteroids (26%), carfilzomib + cyclophosphamide + corticosteroids (20%), and pomalidomide + carfilzomib + corticosteroids (17%). Among CAR-T patients, QOL generally remained stable from apheresis (mean GHS and EQ-5D VAS were 62.3 and 66.4, respectively) to lymphodepletion (61.2 and 65.9) to Month 6 (64.2 and 68.9). Disease symptoms improved (mean DS domain scores at apheresis, lymphodepletion, and Month 6 were 25.7, 24.1, and 20.1, respectively) though pain, specifically, plateaued/worsened (mean pain domain scores were 24.5, 32.1, and 32.6). Based on the PGIC, 76% of patients reported being “a little better” or “much better” as early as Month 1, which stabilized over time (75% at Month 6). Among non-CAR-T patients, QOL largely remained stable (GHS and EQ-5D VAS was 62.9 and 68.4, respectively, at baseline and 64.9 and 67.7 at Month 6), though disease symptoms, including pain, improved over time (DS was 28.0 at baseline and 22.8 at Month 6; pain was 40.8 at baseline and 28.1 at Month 6). Based on the PGIC, 30.7% of patients reported being “a little better” or “much better” at Month 1, which improved to 52.7% by Month 6. CONCLUSIONS In this interim analysis of an ongoing prospective observational study, baseline values suggest a significant QOL burden among TCR patients. QOL generally remained stable for both CAR-T and non-CAR-T patients over the first several months post-therapy with some select improvements in disease symptoms. However, the patients (particularly CAR-T patients) directly reported some holistic improvement based on the PGIC as early as Month 1.

Introduction: Teclistamab (Tec) is the first approved BCMA x CD3 bispecific antibody for the treatment of triple-class-exposed patients with relapsed/refractory multiple myeloma (RRMM) based on the pivotal MajesTEC-1 study. Tec was associated with high overall response rate (ORR) of 63% in heavily pretreated patients. After a longer follow-up of 30.4 months, CR rate was 46.1%, median duration of response (DOR) was 24 months (95% CI, 17.0 - not estimable), and median progression-free survival (PFS) was 11.4 months (95% CI, 8.8 - 16.4). Herein, we present updated analysis of real-world outcomes and safety with tec in RRMM with extended follow-up of more than 12 months. Methods: This is an international multicenter retrospective study of patients with RRMM treated with tec on-label at 9 academic centers from 5 countries (United States, United Kingdom, Greece, Spain, and Canada) through the International Myeloma Working Group (IMWG) Immunotherapy Committee. Patients with RRMM treated with commercial tec at the respective institutions between May 24, 2022 to January 4, 2024 were included. Median follow-up was 14 months with data collected until July 15, 2024. High-risk cytogenetic abnormalities (HRCA) was defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using the IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (interquartile range [IQR] or range). PFS, overall survival (OS), DOR were evaluated using the Kaplan-Meier method. Results: There were 223 patients included in this analysis with the following characteristics: median age of 67 (range 33-91) with 24% ≥75 years; 45% female; 74% White, 10% Black, 9% Asian, and 7% other/unknown; 86 of 176 (49%) with high risk cytogenetics, including del(17p), t(4;14), t(14;16), t(14;20), and gain/amp 1q; 29.4% (37/126) with known extramedullary disease; 14% with creatinine clearance ≤30 ml/min. Patients received a median of 6 (IQR, 4-8) prior lines of therapy with 52% (107/206) being penta-drug refractory. Among 212 patients with available data, 161 (75.9%) patients would have been ineligible for MajesTEC-1. There were 94 (42%) patients who received prior BCMA-directed therapy (29.8% antibody-drug conjugate [ADC] alone; 45.7% CART alone; 6.3% bispecific antibody alone; 17.0% ADC and CART). Median time from diagnosis to tec initiation was 6.1 (range 0.6-29.2) years. For the 206 response-evaluable patients, ORR was 66%, including 25.2% ≥CR, 33.5% VGPR, and 7.3% PR. ORR for the 90 response-evaluable patients with prior BCMA-directed therapy was 54.5% (21.1% ≥CR, 26.7% VGPR, 6.7% PR). After a median follow-up of 14 (95%CI, 13-14) months, median PFS and OS were 8.8 (95% CI, 5.5-14) and 20 (95% CI, 18-not reached [NR]) months, respectively. 12-month PFS estimate was 46% (95% CI, 40%-54%), and 12-month OS rate was 65% (95% CI, 59%-72%). Median DOR was 17 (95% CI, 17-NR) months with 12-month estimate of 68% (95% CI, 60%-77%). Tec step-up dosing occurred in the outpatient setting for 57 (25.6%) patients. CRS occurred in 119 out of 222 (53.6%) patients with almost all being grade 1-2, except for 1 grade 4 event. ICANS occurred in 18 out of 216 (8.3%) patients (grade 1-2: 5.1%; grade 3-4: 2.8%). Any grade infection occurred in 130 (58.3%) patients; 25.1% of patients had grade ≥3 infection, including 10 patients with grade 5 infection. While receiving teclistamab, 79 (35.4%) patients had ≥2 infections. IVIG was given in 114 out of 164 (69.5%) patients. Conclusion: In this multicenter international real-world analysis of outcomes and safety associated with tec, ORR was high at 66% with 25.2% of patients achieving ≥CR. CR rates may be underestimated due to infrequent bone marrow confirmation in the real-world datasets. Encouragingly, ORR was 54.5% in BCMA exposed RRMM patients, including 21.1% with ≥CR. After a median follow-up of 14 months, heavily pretreated patients including patients with prior BCMA therapy had durable responses with median PFS of 8.8 months and median DOR of 17 months. There were no new safety signals noted in this real-world study. This is the largest real-world study to date of teclistamab with long-term follow-up of more than 12 months. Additional data including more patients, longer follow-up and results from difficult to treat subgroups will be presented at the meeting.

Background Emerging evidence has demonstrated rare subacute to late neurological toxicities (NTs) after BCMA CAR T-cell therapy (CAR-T) in multiple myeloma (MM). These adverse events can be categorized as: 1) Parkinsonism (PD), 2) cranial nerve (CN) palsies, and 3) peripheral neuropathies/Guillan Barré syndrome (GBS). These toxicities can cause significant morbidity, but given their relative rarity in clinical trials, there is limited data regarding evaluation and treatment. To our knowledge, this is the largest and only global registry of delayed NTs after BCMA CAR-T. Methods We retrospectively established a registry of NTs via the Immune Therapy Working Committee of the International Myeloma Working Group (IMWG). We gathered data pertaining to demographics, MM characteristics, MM response, NT signs/symptoms, diagnostic workup, and treatment. Result A total of 52 patients with delayed neurotoxicity were included from 14 institutions and 6 countries; 92% received ciltacel, 4% idecel, and 4% investigational CAR-T. Median age at CAR-T infusion was 65 years; 69% were male and 88% were Caucasian. Median bone marrow plasma cell (PC) burden was 15% prior to CAR-T (range 0-95%). Patients received a median of 4 prior lines of therapy (LOT), with 67% progressing on last LOT. Seventeen percent had pre-existing neurological diagnoses (including stroke, epilepsy, migraines). We identified sixteen cases of PD (94% with movement disorder, 69% with cognitive impairment, 75% with personality changes), occurring at a median of 26 days (range: 15-87) after CAR-T. Ninety four percent had CRS (grade (G)1 50%, G2 38%, G3 6%, G4 0%), while 19% had ICANS (G1 13%, G2 6%, G3-G4 0%). Median peak absolute lymphocyte count (ALC) was 9.5 x 109/L, peak C-reactive protein (CRP) 60.9 mg/L, and peak ferritin 1893.5 ug/L within the first 30 days. Concurrently, 3 upper respiratory infections (URIs) and 2 low-level HHV7 in the cerebrospinal fluid (CSF) were detected. A median of 73% of T-cells in the CSF were CAR-T, based on a flow cytometry assay. Ten patients received steroids (median 19 days after symptoms, 70% partial response, 20% no response, 10% unknown), 2 received intrathecal (IT) methotrexate-based therapy (median 32 days after symptoms, 1 with no response, 1 unknown), 5 received intravenous (IV) cyclophosphamide (median 31 days after symptoms, 40% full response, 20% partial response, 40% no response), 4 received high-dose IVIG ≥1g/kg for one or more dose (50% partial response, 50% no response), and 6 received dopamine agonists. There were 37 CN palsies (76% CN7, 15% CN6, 7% CN5, 2% CN3), occurring at a median of 37.5 days (range: 7-482) after CAR-T. Eighty one percent had CRS (G1 68%, G2 14%, G3-G4 0%); 11% had G1 ICANS (G2-G4 0%). Median peak ALC was 4.1 x 109/L, CRP 25.4 mg/L, and ferritin 543 ug/L within the first 30 days. We identified 2 concurrent URIs, 4 CMV viremia (50% with viral load >1500 IU/mL), 1 HHV6 viremia, and 1 HSV in the CSF. Thirty-two (86%) received steroids for a median duration of 12 days, 50% with full response, 3% with no response, and 47% with partial response (of which 43% had later full recovery without further intervention). One received IT methotrexate and another received IV cyclophosphamide without response. Thirteen (41%) received IVIG, of which 38% was high-dose IVIG. Four patients with CN palsies developed peripheral neuropathy/GBS. Eight patients (15%) in this cohort were not heavily pre-treated (≤1 prior LOT); 7 developed CN palsies (6 after ciltacel, 1 after investigational CAR-T) and 1 PD (after idecel). These patients had median <5% PC; none had extramedullary disease. Median ALC was 4.14 x 109/L, CRP 33 mg/L, and ferritin 448.5 ug/L within the first 30 days. Conclusions Delayed NT requires prompt recognition, evaluation for alternative causes, and treatment. In our cohort, the majority of patients were male and Caucasian, suggesting that sex and race may impact the likelihood of developing NT. Individuals with PDs had greater inflammatory response (CRS, ALC, CRP, ferritin) compared to those with CN palsies. CN palsies responded to steroids and/or IVIG, whereas PD had at best partial response to steroids, prompting additional therapy. These toxicities notably did occur in less heavily pre-treated patients, perhaps driven by immune fitness and greater circulating T-cells rather than MM burden. At the time of the annual meeting, data will be updated with additional NTs from less heavily pre-treated patients.

Introduction: Ven is a BCL2 inhibitor that has shown clinical efficacy in RRMM patients (pts) particularly those that harbor t(11;14). Ven has been evaluated in clinical trials as a single agent, in combination with dexamethasone (dex), immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and anti-CD38 monoclonal antibodies (MAb) yet its place in the therapeutic landscape remains in question. In this retrospective analysis, we aim to evaluate the real-world efficacy of Ven-based regimens in RRMM pts treated outside of a clinical trial across the 3-site MCCC. Methods: We retrospectively analyzed the medical records of pts with RRMM treated with Ven-based regimens between January 2015 and October 2023 at the MCCC. Refractoriness was defined by progression on or within 60 days of stopping treatment. Categorical variables were compared with Chi-square tests and continuous variables were compared with t-tests. Outcomes were estimated using the Kaplan-Meier method and curves were compared between the groups using log-rank tests. Results: 83 pts were included in the analysis. The median age was 71 (39-93), 63% were male, 93% were white, 27% had ISS III, 18% had high risk cytogenetics (HRCyto), 76% had t(11;14), the median prior lines of therapy (LOT) was 4 (1-15), 68% received ≥ 4 prior LOT, 87% received prior autologous transplant, 58% were triple-class refractory (TCR), 64%/23% were penta-drug exposed/refractory (PDE/R), 8% received prior BCMA-directed therapies (BDT), 58% received Ven+dex, 25% received Ven+PI +/-dex, 6 % received Ven+anti-CD38 MAb+/-dex and 11% received Ven+other. The median follow-up time from start of a Ven-based regimen was 29 months (mo). The median Ven dose was 800mg (20-1600) with 25% of pts receiving Ven ramp-up dosing. The overall response rate (ORR) to a Ven-based regimen was 58% and was 64% for pts with t(11;14) and 40% for pts without t(11;14); p=0.06. Ven-treated pts with HRCyto had inferior PFS (3mo) and OS (8mo) compared to patients who did not have HRCyto who had a PFS of 9mo (p=0.020) and OS of 80mo (p<0.001). The ORR for TCR and PDR pts were 52% and 42%, respectively. No significant ORR differences were noted across the different Ven-based regimens (p=0.32). The median PFS for pts with t(11;14) was 10mo compared to 2mo for pts w/o t(11;14); p=<0.001. The median OS for pts with t(11;14) was 80mo compared to 10mo for pts without t(11;14); p=0.001. Ven-treated pts who received 1-3 prior LOT has superior ORR, median PFS, and median OS; 89%, 25mo, and 99mo, respectively, compared to pts who received ≥4 prior LOT who achieved an ORR of 43% (p<0.001), median PFS of 5mo (p<0.001) and median OS of 25mo (p<0.001). Ven-treated pts that were TCR had inferior PFS (5mo) and OS (26mo) compared to pts who were not TCR who achieved a PFS of 12mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts that were PDR had inferior PFS (4mo) and OS (22mo) compared to pts who were not PDR who achieved a PFS of 9mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts who received prior BDT (n=7) achieved an ORR of 29% and had a median PFS and OS of 2mo and 6mo, respectively on a Ven-based therapy. 59 pts received additional therapy in the post Ven-progression setting. The ORR to post-Ven progression therapies was 53% (n=31/59), the median PFS was 9mo and median OS was 35mo. The most common post-Ven progression regimens used were PI-based (n=16; ORR=56%), anti-CD38 MAb-based (n=14; ORR=50%), BDT (n=12; ORR=83%), selinexor-based (n=3; ORR=0%) with BDT resulting in highest ORR (p=0.048) and PFS (p=0.005). Conclusions: Ven-based regimens are effective in heavily pre-treated pts with RRMM however they are more effective when used within 1-3 prior LOT, in pts with t(11;14), and in pts without HRCyto, TCR or PDR MM. BDT appear to be the most efficacious therapies in the post-Ven progression setting.

Introduction: Frailty is known to be an important risk factor for adverse outcomes in multiple myeloma (MM) and is often under-represented in clinical trials. Frail patients are known to have increased toxicity, high rates of treatment discontinuation rates and decreased efficacy including worse overall survival in MM. Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb) that was approved based upon the pivotal MajesTEC-1 study showing high overall response rates in patients with R/R MM. In MajesTEC-1, the median age was 63, and patients with ECOG ≥ 2 were excluded, suggesting that the vast majority of patients in the trial were fit. There is a paucity of data both in clinical trials as well as in the real-world regarding the outcomes of patients, particularly frail patients, with BsAb. This data is needed to both understand current outcomes of frail patients as well as devise strategies for future optimization with BsAb treatment. We performed a retrospective analysis utilizing the International Myeloma Foundation (IMF) immunotherapy database with the objective of understanding the outcomes of older adults (age ≥ 70) including frail patients treated in the real-world with teclistamab. Methods: Data was collected from 7 individual academic sites for patients aged ≥ 70 years treated with teclistamab in the real-world. Data collected include patient demographics, disease characteristics, as well as efficacy and toxicity associated with teclistamab. Frailty score was retrospectively calculated using the simplified/IFM frailty index which includes chronological age, ECOG PS and Charlson Comorbidity Index categorizing the patients into fit (score 0-1) or frail (≥ score 2). Fisher's exact tests were performed to evaluate differences in outcomes between fit and frail patients. Results: A total of 81 pts were included in our total cohort. The median age was 76 year (range 70-91). Among them, 44 (54%) were > age 75 and 23 (28%) > age 80. Twenty-eight (35%) patients had an ECOG performance status of ≥2. Using the simplified/IFM frailty index, 22 (27%) were classified as fit and 59 (73%) were frail. In the frail subgroup, a high proportion of patients (42%) would be classified as ultra frail (frailty score of ≥3). Selected baseline patient and disease characteristics are as follows: high risk cytogenetics including 1q gain/amp (fit 67% vs frail 43%), median prior lines (fit 7 vs frail 5), triple class refractory (fit 81% vs frail 88%), CrCl <30 (fit 5% vs frail 15%). For patients hospitalized for step-up dosing, median number of hospital days was 8 both in the fit and frail group. All grade CRS was noted in 12 (55%) fit and 28 (47%) frail patients. Among the fit patients, only 1 of the 12 patients (8%) had grade 2 CRS, whereas 8 of 28 (29%) frail patients had grade 2 (p-value=0.23). ICANS was reported in 2 (9%) fit patients and 8 (14%) frail patients (p=0.72). The majority of ICANS was grade 1 in both groups, but among the frail group, there was one grade 3 and two grade 4 ICANS cases reported. Infections were reported in 10 (45%) fit patients and 35 (59%) frail patients (p=0.32), with 2 (9%) and 14 (23%) being grade≥3 (p-value=0.21). IVIG was administered in most patients (fit 50% vs frail 58%, p=0.62). Grade 3/4 neutropenia was reported in 10 (45%) fit patients and 19 (32%) frail patients (p=0.30). The overall dosing interval was changed in 32% of fit patient and 34% of frail patients (p=1.00). The overall response rate was 50% for fit patients versus 66% for frail patient (p=0.61). The type of responses noted in the fit patient were as follows: sCR/CR 18%, VGPR 27%, PR/MR 5%, SD 18%, PD/NE 32% and for frail patients : sCR/CR 18%, VGPR 43%, PR/MR 9%, SD 5%, PD/NE 25%. The median follow-up time was 13.1 months. 12-month PFS for fit pts was 47.6% (95% CI 25.7% - 66.7%) and for frail pts 42.4% (29.0% - 55.3%). 12-months OS for fit pts was 64.9% (95% CI 39.9% - 81.6%) and for frail 61.5% (47.0% -73.1%). Conclusions: This is the first real-world study to evaluate the outcomes of teclistamab in frail older adults. With regards to toxicity, frail older adults showed a trend towards higher rates of ≥ grade 2 CRS, ≥ grade 2 ICANS as well as ≥3 grade infections. Efficacy was maintained in both fit and frail older adults similar to the MajesTEC-1 study. Our study highlights that BCMA BsAb can be safely utilized in older adults including frail older adults; however, additional proactive supportive care may be required to further optimize outcomes.

Introduction: Recent efforts have shed light on the clinical and laboratory factors associated with toxicity and response to BCMA-directed CAR-T therapy in patients with relapsed/refractory multiple myeloma (RRMM). However, a major limitation of current scoring systems lies in their assessment at time of lymphodepletion. Because they are not determined before apheresis, they are ill-equipped to guide patient selection, anticipate level-of-care, or plan pre-emptive toxicity management strategies. We therefore aimed to characterize early predictors of CAR-T toxicity and response. Study Design: In this multicenter observational study, we examined demographic, clinical, and laboratory data across three distinct timepoints: indication (e.g., treatment decision), apheresis, and pre-lymphodepletion (LD). CRS and ICANS were graded according to ASTCT criteria. Hematotoxicity (ICAHT) was graded using EHA/EBMT criteria. Early infections (day 0-100) were defined based on microbiologic data or as a clinical infection syndrome, and graded per Hill et al, Blood 2018. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared by log-rank test. Cox proportional hazard models were applied to explore associations between pre-apheresis risk factors and key toxicity and survival outcomes. The CAR-HEMATOTOX (HT) score - encompassing markers of inflammation (e.g., CRP, ferritin) and marrow reserve (e.g., hemoglobin, ANC, platelet count) - was determined at each timepoint (Rejeski et al, Blood 2021). Results: We included 530 RRMM patients treated with standard-of-care cilta-cel (n=184) or ide-cel (n=346) across nine centers. Median age was 65 (range 31-88), median ECOG was 1 (IQR 0-1), and patients received a median of 5 prior lines of therapy (IQR 4-7). The median time from indication to apheresis was 16 days (IQR 7-52), while the median time from apheresis to infusion was 56 days (IQR 46-69). The proportion of high-risk patients by HT score did not change between the pre-apheresis and LD timepoints (19% vs. 20%, p=0.82). Most patients stayed either low-risk (n=388, 73.2%) or high-risk (n=68, 12.8%). However, 35 patients (6.6%) shifted from high-to-low risk, while 39 patients (7.4%) progressed from low-to-high risk - reflecting their response to bridging therapies. We noted considerable differences in morbidity and mortality based on the pre-apheresis HT score. Compared to their low-risk counterparts (score 0-2, n=427), high-risk patients (score ≥3, n=103) were hospitalized longer (12 vs. 15 days, p=0.009) and required more frequent ICU admissions (6% vs. 12%, p=0.05). They exhibited more severe early cytopenias (G3+: 8% vs. 25%, p<0.001) and late cytopenias (G3+: 7% vs. 21%, p<0.001), resulting in increased use of TPO agonists and stem cell boosts. Grade 3 or higher ICANS was also more common in HThigh patients (3% vs. 11%, p=0.006), as were severe infections (14% vs. 27%, p=0.007). We found increased non-relapsed mortality in HThigh patients (1-yr NRM 4.6% vs. 16.1%, p<0.001), but no significant difference in the occurrence of secondary malignancies (p>0.9). With a median follow-up of 12.4 months, HThigh patients showed inferior PFS (1-yr PFS 29% vs. 63%, p<0.0001) and OS (1-yr OS 49% vs. 83%, p<0.0001). Transitioning from a low-to-high score was linked to poor survival (1-yr PFS 26%), while the shift from high-to-low risk was associated with favorable outcomes (1-yr PFS 51%). In a multivariable Cox regression model of pre-apheresis features, a high HT score (aHR 2.52, p<0.0001), prior anti-BCMA therapy (aHR 1.55, p=0.04), history of extramedullary disease (aHR 1.42, p=0.02), and penta-refractoriness (aHR 1.45, p=0.02) were independently associated with PFS. Notably, the presence of more than 3 of these high-risk features defined an ultra-high-risk cohort of 28 patients (5.3%) with particularly dismal survival (1-year PFS 15%). Conclusions: Leveraging granular pre-apheresis data from a large international cohort, we identify early markers of toxicity and response in CAR-T-treated RRMM patients. The HT score - reflecting baseline inflammation and hematopoietic reserve - identified high-risk patients likely to benefit from pre-emptive toxicity mitigation strategies such as prophylactic stem cell collection. Most importantly, we characterize a small yet ultra-high-risk group of RRMM patients in need of more effective bridging and therapeutic options.

Introduction: Bruton tyrosine kinase (BTK) inhibitors are highly effective against Waldenström macroglobulinemia (WM). Their effectiveness can be limited by resistance caused by BTK mutations and intolerance. BGB-16673 is a bivalent small molecule that induces BTK degradation by binding specifically to BTK and the E3 ligase. The E3 ligase catalyzes the transfer of ubiquitin molecules to BTK, which marks BTK for destruction by the proteasome. Preclinically, BGB-16673 degraded wild-type and mutant BTK associated with covalentand noncovalent BTK inhibitors (ncBTKis), leading to tumor suppression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing, open-label, first-in-human, phase 1/2 study evaluating BGB-16673 monotherapy in patients with a range of B-cell malignancies. Here, early results in patients with WM enrolled in the phase 1 portion are presented. Methods: Eligiblepatients must have confirmed R/R WM (≥2 prior therapies), an ECOG performance status of 0-2, and adequate organ function. Patients must have previously received an anti-CD20 antibody and, in the US and EU, a covalent BTK inhibitor (cBTKi). BGB-16673 was orally dosed once daily in 28-day cycles. Dose escalation used a Bayesian optimal interval design (6 planned dose levels, 50-600 mg once daily). Primary objectives were to evaluate safety/tolerability (CTCAE v5.0) and to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks (cycle 1). A secondary objective was to evaluate the overall response rate (ORR, IWWM-6 consensus criteria), with the first assessment occurring after 4 weeks of treatment. Results: As of May 24, 2024, 22 patients with WM were enrolled and treated (100 mg, n=4; 200 mg, n=10; 350 mg, n=8). The median age was 73.0 (range, 56-81) years, and the median number of prior therapies was 3.5 (range, 2-11), including prior cBTKis (n=22 [100%]), BCL2 inhibitors (n=4 [18%]), and ncBTKis (n=3 [14%]). Twenty patients (91%) had previously received chemotherapy. According to the International Prognostic Scoring System for WM, 6 patients (27%) had low-risk disease, 7 (32%) had intermediate-risk disease, and 8 (36%) had high-risk disease (missing/unknown data, n=1). Five patients (23%) had BTK mutations, 20 (91%) had MYD88 mutations, and 8 (36%) had CXCR4 mutations. The median follow-up was 4.3 (range, 0.3-21.3) months. Ninety-five percent of patients reported any-grade treatment-emergent adverse events (TEAEs; grade ≥3, 45%; serious, 23%), the most common (≥20%) of which were neutropenia/neutrophil count decreased (32%; grade ≥3, 23%), contusion (23%; no grade ≥3), and diarrhea (23%; no grade ≥3). The most common grade ≥3 TEAE (≥20%) was neutropenia/neutrophil count decreased. No atrial fibrillation, hypertension, febrile neutropenia, or major hemorrhage occurred. Three patients (14%) had a grade ≥3 infection (bronchopulmonary/cerebral aspergillosis, septic shock, and pseudomonal bacteremia/sinusitis). No patients had a TEAE that led to treatment discontinuation or dose reduction. No DLTs occurred, and the MTD was not reached. One patient (5%) died due to a TEAE (septic shock, considered related to disease progression). One patient died due to disease progression. In 21 response-evaluable patients (1 too early), the ORR (minor response or better) was 90%, the major response rate (partial response [PR] or better) was 81%, and the very good PR or better rate was 14%. Median time to first response was 0.95 (range, 0.9-3.7) months, with responses deepening over time. Seventeen patients remain on treatment and have ongoing responses. Responses were seen at the lowest dose (100 mg, 4/4), in patients previously treated with a cBTKi (19/21) and an ncBTKi (3/3), and in patients discontinued from prior BTKi due to disease progression (15/17). In addition, responses were observed in patients with and without mutations in BTK (with, 5/5; without, 6/8; unknown, 8/8), MYD88 (with, 18/20; without, 1/1), and CXCR4 (with, 8/8; without, 11/13). One patient had IgM flare at initial response assessment and went on to develop PR. Conclusions: Early data from this ongoing, first-in-human study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows promising antitumor activity in heavily pretreated patients with BTK inhibitor-exposed R/R WM, including those with BTK and CXCR4 mutations.

Introduction: Overall outcomes have improved significantly for MM with a 5-year relative survival rate currently of >60%. With effective treatments, patients from all clinical strata and age groups are expected to have meaningful benefit, but despite excellent therapeutic advancements, some patients continue to have early mortality. We conducted this study to investigate factors associated with early mortality. Methods: The National Cancer Database (NCDB) was queried for adult patients with NDMM between 2004 and 2021. We excluded patients with multiple primary malignancies or lost to follow-up (unknown vital status or last contact). Early mortality was defined as death within 6 months from MM diagnosis. Patient demographics and socioeconomic factors available in NCDB were collected. Kaplan-Meier and multivariate Cox regression were used to evaluate the likelihood of early mortality in this large cohort of MM patients using multi-variate analysis. Results: Out of 255,579 eligible patients with MM, 35,302 (13.8%) died within the first 6 months of diagnosis and 108,534 (42.5%) died after the first 6 months of MM diagnosis. The early mortality cohort had significantly higher mean age at MM diagnosis (73.9 vs. 68.5 years, p<0.001) but no significant differences were noted for gender distribution. There was a statistically significant difference for racial/ethnic distribution (p=0.019), but the percentages were very similar among non-Hispanic White (69% vs 68.1%), non-Hispanic African American (18% vs 18.7%) and Hispanic patients (4.7% vs 4.8%). Patients in the early mortality cohort were less likely to be treated at academic institutions (28.4% vs 37.8%, p<0.001) and have significantly different distribution by insurance type (less likely to have private insurance; 17.3% vs. 30%, more likely to have Medicare; 72.1% vs. 58.7%, p<0.001) although overall insurance access was similar between the two groups (95.3% vs 95.2%, p=0.283). Early mortality was associated with higher morbidity scores as per the Charlson-Comorbidity Index (CCI) (p<0.001) and were more likely to have not received any treatment for MM (53.2% in early mortality group vs. 28.4% in late mortality, p<0.001). Early mortality was also associated with a lower literacy rate (high school graduation rate 21.2% vs. 19.7%, p<0.001) and lower household income (<$46,277; 19.1% vs. 17.7%, p<0.001). Conclusion: This large real-world analysis shows that despite therapeutic advances in recent years, there is a significant percentage of patients with NDMM in the U.S. who suffer from early mortality. There are several sociodemographic and economic factors that were found to be associated with early mortality, with some showing clear trends (older age, treatment facility type, insurance type, income, education, CCI), while others like racial differences were significant but somewhat ambiguous. Identifying and addressing these factors at diagnosis will help provide personalized care plans and minimize early mortality.

Introduction Venetoclax + rituximab resulted in a 2-year progression-free survival estimate of 85% in the mostly 2nd-line, post-chemotherapy setting of the MURANO clinical trial (Seymour NEJM 2018). Short remissions with venetoclax in patients (pts) with prior cBTKi treatment (tx) for CLL are reported. However, these cohorts have included heavily pre-treated pts. Here, we report outcomes with venetoclax-based regimens in a contemporary cohort with cBTKi-exposed CLL and no prior chemotherapy. Methods We conducted a retrospective study of pts who received venetoclax for relapsed CLL after prior cBTKi tx at Mayo Clinic and across 8 centers in France. Pts with any prior chemotherapy tx were excluded. Pts were grouped as cBTKi-resistant (CLL disease progression on cBTKi) and cBTKi-exposed (any prior cBTKi tx but without disease progression). Overall survival (OS) was analyzed as the time from initiation of venetoclax until date of death or last known to be alive. Time to next therapy or death (TTNTD) after venetoclax was defined as the time from venetoclax initiation until the earliest date of next tx or death. Cox proportional hazards regression models were used to estimate associations of factors with OS and TTNTD. Results A total of 85 pts received venetoclax, including: venetoclax monotherapy (n=13, 15%), venetoclax + rituximab (n=45, 53%), and venetoclax + obinutuzumab (n=27, 32%). Patient characteristics at the time of venetoclax start were as follows: median age 69 years (interquartile range [IQR] 62-77), 59 (69%) male, 45% (33/73 evaluated) with TP53 disruption (del(17p) or TP53 mutation), 82% (46/56 evaluated) with unmutated IGHV, and 41% (15/37 evaluated) with complex karyotype (CK; ≥3 clonal structural or numerical abnormalities on karyotype). The median prior lines of therapy was 1 (IQR 1, 2); 32 (38%) pts had received prior anti-CD20 monoclonal antibody and 8 (9%) pts had received 2 prior cBTKi. Prior cBTKi tx was stopped for a reason other than disease progression in 46 (54%) pts (cBTKi-exposed) and due to CLL progression in 39 (46%) pts (cBTKi-resistant). TP53 disruption, unmutated IGHV, and CK were more common in the cBTKi-resistant subgroup. Among pts with cBTKi-resistant CLL, 60% (12/20 evaluated) had a BTK and/or PLCG2 mutation. Median follow-up from start of venetoclax-based therapy was 20 months. The median TTNTD and OS for the entire cohort was 36 (95% CI 29-not evaluable [NE]) and 68 (95% CI 39-NE) months, respectively. Among the 46 pts with cBTKi-exposed CLL, the median duration of prior cBTKi tx was 6.7 months (IQR 1.8, 23.7). The median TTNTD and OS from venetoclax start were both 78 months in pts with cBTKi-exposed CLL. The 24-month TTNTD and OS estimates were 73% and 81%, respectively. Among the 39 pts with cBTKi-resistant CLL, the median duration of prior cBTKi tx was 42.3 months (IQR 23.4, 60.1). The median TTNTD from venetoclax start in pts with cBTKi-resistant CLL was 30 months. The 24-month TTNTD estimate was 65% in the cBTKi-resistant subgroup, 53% with venetoclax monotherapy (n=5), 62% with venetoclax + rituximab (n=30), and 100% venetoclax + obinutuzumab (n=4). The median OS from venetoclax initiation was 39 months overall in pts with cBTKi-resistant CLL. The 24-month OS estimate was 84% in the cBTKi-resistant subgroup overall, 53% with venetoclax monotherapy, 87% with venetoclax + rituximab, and 100% with venetoclax + obinutuzumab. On a univariate analysis in the whole cohort, only TP53 disruption was associated with shorter TTNTD (HR 2.23; 95% CI 1.02-4.87; P=0.04) and only older age was associated with shorter OS (HR 1.05; 95% CI 1.007-1.095, P=0.02). On a univariate analysis in the cBTKi-resistant subgroup, only TP53 disruption was associated with shorter TTNTD (HR 6.68; 95% CI 1.51-29.46; P=0.01) and OS (HR 7.95; 95% CI 1.02-61.97; P=0.04). Duration of prior cBTKi exposure (as a continuous variable) was not associated with survival outcomes in the cBTKi-resistant subgroup. Conclusions Pts with chemotherapy-naïve, cBTKi-treated CLL had worse than expected outcomes with venetoclax-based tx in a mostly 2nd-line tx cohort, particularly pts with cBTKi-resistant CLL. The frequency of high-risk disease features, shorter duration of disease control with their initial cBTKi tx, and small cohort size warrant caution in generalizing these results to all pts with cBTKi-resistant disease. Novel tx trial strategies in 1st- and 2nd-line settings remain a high priority for high-risk pts.