International Myeloma Working Group Criteria Research Articles

Outcomes Multiple Myeloma Patients Progressing after BCMA-Directed Chimeric Antigen Receptor T Cell (CART) Therapy

Background: Chimeric Antigen Receptor T Cell Therapy (CART) targeting B-cell Maturation Antigen (BCMA) has gained approval for Relapsed/Refractory Multiple Myeloma (RRMM) following a minimum of four prior lines of therapy (LOT). Despite the significant improvement in outcomes with a remarkable progression-free survival (PFS) reported in pivotal trials, a substantial proportion of patients (pts) eventually experience disease progression. The available treatment options thereafter are currently limited, and the outcomes in this specific cohort of pts have not been extensively characterized. This study aimed to investigate the clinical outcomes of pts with RRMM who failed BCMA CART therapy, either as standard of care (SOC) or as part of a clinical trial. Methods: We conducted a retrospective analysis as of 7/10/2023 of RRMM pts progressing after BCMA CART and receiving the next LOT at the University of Kansas Medical Center in collaboration with US Myeloma Research Innovations Research Collaborative (USMIRC). Those who received therapy on clinical trial as the next LOT were included. Baseline demographic data were described, and outcomes were evaluated for two subgroups: “early” relapse pts (progression ≤ 6 months) and “later relapse”, those progressing after 6 months. Baseline pt characteristics were outlined by descriptive analyses. Responses including overall response rate (ORR), and complete response or better (>CR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the use of Fisher's exact test and the Kaplan-Meier method for progression-free (PFS) and overall survival (OS) calculations. OS was calculated from relapse after CAR-T till the last office visit/death. Regression models for univariate and multivariate analysis were performed. Results: Thirty pts were included in the analysis. Baseline demographics is summarized in Table 1. The majority (57%) had extramedullary disease (EMD) and 90% had an ECOG performance status of 0-1. The mean age of the pts was 61.3 years (SD=9.6), with 73% male and 80% White. Pts had 5 median prior LOT. All pts were refractory to PI, IMid, Daratumumab, double-refractory and-triple refractory. 63% were penta-refractory. Sixteen (53%) pts relapsed ≤ 6 mo after CART infusion and 14 (47%) relapsed after 6 months, with median follow-up of 21.73 Months (25-75 IQR: 13.87-40.17 mo). Baseline demographics were similar. The presence of 1p genetic mutation was significantly associated with lower incidence of early progression (early: 0% vs later: 36%, p=0.014). Also, pts with 2 autologous stem cell transplants (ASCT) had later relapses (early: 0% vs later: 43%, p=0.009). Outcomes with next LOT: Of these 30 pts, 10 received BCMA-directed therapies (3 got belantamab mefodotin and 7 received bispecifics (BCMA on Harpoon trial and teclistamab, 2 received GPRC5D targeting bispecific, talquetamab. The rest 18 (60%) got chemo immunotherapies including 1 ASCT and 5 VD-PACE/KD-PACE. 70% of pts progressed on the next LOT. Overall response rate (ORR) was 30%. (Figure 2a). There were 14 deaths, all related to myeloma progression. The median OS was 8.53 months (4.9-NR). Figure 2b summarizes the LOT and OS outcomes. In univariate analysis (UVA), EMD was associated with a significantly higher risk of death (HR=4.15, 95% CI=1.12-15.3, p=0.019), but this was not significant after adjusting in the multivariate analysis (MVA) (HR=2.74, 95% CI=0.63-11.8, p=0.2). Male gender was associated with worse survival in UVA. However, no factors were associated with a higher risk of death in a multivariate analysis. Conclusion: This study describes outcomes for post-CART relapse in RRMM. Most pts do not respond to the first LOT post-BCMA CART relapse. The survival was less than a year, suggesting need for further studies with a longer follow-up and larger sample size to establish the best regimen for CART failure and characterize prognostic factors associated with poor outcomes for CART relapses.

A Comparative Study of Clinical Characteristics, Cytogenetic Abnormalities and Outcomes Among Multiple Myeloma, Primary Light-Chain Amyloidosis and Multiple Myeloma with Concurrent AL Amyloidosis

Introduction: Multiple myeloma (MM) and light-chain (AL) amyloidosis are both plasma cell dyscrasias and may coexist in the same patients, contributing to distinct clinical outcomes. Although they share a similar spectrum of cytogenetic abnormalities (CA), the distribution and prognostic value of these aberrations are varied. The use of fluorescence in situ hybridization (FISH) in predicting outcomes for MM is well established, while the prognostic value of CA in AL amyloidosis, notably in MM with concurrent AL amyloidosis, is still evolving. This study aimed to evaluate the outcomes of patients with MM, AL amyloidosis and coexistence of the two disorders, and address the landscape and prognostic implication of CA in patients with these 3 types of plasma cell dyscrasias. Methods: A total of 902 consecutive patients with newly diagnosed MM between January 2007 and October 2021 or AL amyloidosis between January 2007 and June 2023 were retrospectively included. Patients were classified as MM alone, MM with coexistent AL amyloidosis (MM-AL) or primary AL amyloidosis alone (pAL-alone). The presence of symptomatic MM was based on the International Myeloma Working Group (IMWG) criteria and the diagnosis of AL amyloidosis was confirmed by Congo-red-positive biopsy and immunoelectron microscopy study of the amyloid. Demographic and clinical characteristics, FISH results, along with real-world effectiveness outcomes including best hematologic response, overall survival (OS), and progression free survival (PFS) were assessed. Results: Of the 902 patients enrolled, 658 patients were in the MM-alone group, 99 in the MM-AL group and 145 in the pAL-alone group. The three groups share a similar incidence rate of CA, while the prevalence of t(11;14) was significantly higher in pAL-alone group than MM-AL and MM-alone group (41.0% vs. 24.5% vs. 16.6%, p<0.001), and the prevalence of del13q14, gain1q21 and IMWG high-risk cytogenetic abnormalities [HRCA, including t(4;14), t(14;16) and del17p] decrease in turn in MM-alone, MM-AL and pAL-alone group(del13q14, 46.4% vs. 38.1% vs. 29.7%, p=0.005; gain1q21, 52.6% vs. 46.4% vs. 27.8%, p<0.001; HRCA, 27.5 % vs. 17.2 vs. 7.6%, p<0.001) (Table). In patients with AL amyloidosis with or without coexisting MM, presence of del13q14 was associated with higher level of baseline bone marrow plasmacytosis and difference in involved and uninvolved free light chain (dFLC). Compared with the MM-alone group, a significantly lower proportion of the MM-AL group achieved hematologic response (90.4% vs. 67.7%, p<0.001) and very good partial remission (VGPR, 44.6% vs. 68.9%, p<0.001). The OS of patients with MM-AL was significantly inferior to patients with MM-alone (median, 25.2 months vs. 96.8 months, p<0.001) or pAL-alone (median, 25.2 months vs. not reached, p<0.001 )(Figure B), while patients with MM-alone has shorter PFS than AL amyloidosis irrespective of the presence or absence of MM (MM-alone vs. pAL-alone: median, 56.8 months vs. not reached, p=0.007; MM-alone vs. MM-AL: median, 56.8 months vs. not reached, p=0.515) (Figure A). Other than MM-alone group, no significant difference in PFS and OS was found between pAL patients with and without HRCA, as well as the MM-AL group, indicating the difference in prognostic implications of common HRCAs among the three groups. When stratified by the type of plasma cell disorders and status of t(11;14) (a CA that strongly related to poor outcome of pAL), patients with MM-AL and t(11;14) presented the worst OS (median, 8.2 months, p<0.001) (Figure C). Conclusion: This comparative study presented an apparent discrepancy in distribution and prognostic role of CA in different plasma cell dyscrasias. Comparing with patients with MM-alone and pAL-alone, MM-AL patients, notably with the presence of t(11;14), had the poorest survival.

Real-World Utilization of Daratumumab in Front-Line Treatment of Newly Diagnosed Multiple Myeloma: A Retrospective Observational Study

Introduction: Daratumumab (DARA), a CD38 monoclonal antibody, has demonstrated remarkable efficacy among newly diagnosed (ND) and relapsed/refractory multiple myeloma (MM) patients. The introduction of a quadruplet therapy with an addition of DARA per the GRIFFIN trial has improved the treatment paradigm. However, the real-world data on treatment patterns and utilization of DARA in front-line treatment are limited. This study aimed to evaluate the real-world utilization of DARA in front-line treatment and examine factors that may impact the utilization of DARA-based regimen in NDMM. Methods: We conducted a retrospective observational study of all patients, age ≥ 18, with clinical MM who were newly diagnosed and treated within the Yale New Haven Health (YNHH) system between August 1, 2020 and August 31, 2022. We manually reviewed clinical presentation, age at diagnosis, gender, race, ethnicity, Revised International Staging System (R-ISS) stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), insurance type, practice setting, immunoglobulin (Ig) isotype, hemoglobin (Hb), creatinine (Cr), and calcium (Ca) at diagnosis, presence of bone lesion, bone marrow plasma cell (BMPC) %, cytogenetic abnormalities, transplant eligibility, and treatment response based on the International Myeloma Working Group (IMWG) criteria at 3 months after front-line therapy. Descriptive statistics were performed with Pearson's χ²-test using GraphPad PRISM version 9.0.0. Results: We identified 241 patients with NDMM during the study period within the YNHH system. Overall median age at diagnosis was 69 years (interquartile range: 61-78). 60.2% (n=145) were male, 68% (n=164) identified themselves as white and 90% (n=217) as non-Hispanic. 51.9% (n=125) had R-ISS stage II and 65.6% (n=158) had ECOG PS of 0-1. 63.1% (n=152) were treated at a community practice setting and 53.9% (n=130) had commercial insurance. 55.6% (n=134) had IgG isotype and 41.1% (n=99) had unfavorable risk cytogenetics which was defined as a 17p deletion, t(4;14), t(14;16), t(14;20), gain or amplification of 1q, 1p deletion, and chromosome 1 translocations. 28.2% (n=68) received front-line quadruplet therapy: DARA+lenalidomide (LEN)+bortezomib (BORTE)+dexamethasone (DEX) (n=54), DARA+cyclophosphamide+BORTE+DEX (n=10), or DARA+LEN+carfilzomib (CARFIL)+DEX (n=4). 58.5% (n=141) received triplet therapy, 8.3% (n=20) received doublet therapy, 0.83% (n=2) received monotherapy, and 4.1% (n=10) opted for hospice care. 41.5% (n=100) received DARA in front-line treatment: quadruplet as above (n=68), triplet of DARA+LEN+DEX, DARA+BORTE+DEX, or DARA+CARFIL+DEX (n=31), and doublet of DARA+DEX (n=1). Factors including gender (male vs. female, p=0.018), practice setting (academic vs community, p=0.014), R-ISS stage (I vs II vs III vs unknown, p=0.003), Ig isotype (IgG vs IgA vs light chain vs other, p=0.006), cytogenetic abnormalities (standard risk vs unfavorable risk, p=0.02), and transplant eligibility (transplant eligible vs transplant ineligible, p=0.001) were associated with the adoption of DARA in front-line treatment. While 51.7% (n=46) of the patients treated at an academic practice setting received DARA in front-line treatment, only 35.5% (n=54) of the patients treated at a community practice setting received such treatment. 69% (n=69) of those who received DARA-based regimen in front-line treatment achieved at least a very good partial response (VGPR) at 3 months compared to 54.6% (n=77) of those who received non-DARA-based regimen. There were no significant differences in age, race, ethnicity, ECOG PS, insurance type, laboratory data (Hb, Cr, and Ca) at diagnosis, presence of bone lesion, and BMPC % between the group treated with DARA-based regimen and the group treated with non-DARA-based regimen. Conclusion: This analysis of real-world data from patients with NDMM highlighted underutilization of DARA in front-line treatment, especially at a community practice setting. Gender, practice setting, R-ISS stage, Ig isotype, cytogenetic abnormalities, and transplant eligibility were significantly associated with the adoption of DARA in front-line treatment. Additionally, utilization of DARA in front-line treatment was associated with a better treatment response at 3 months, suggesting that interventions to promote the utilization of DARA will help improve outcomes of NDMM patients.

Impact of Prior Lines of Therapy before Autologous Hematopoietic Cell Transplant on Survival in Standard Risk Multiple Myeloma

Introduction: Patients with standard risk (SR) multiple myeloma (MM), as defined by the absence of high risk cytogenetic abnormalities including immunoglobulin heavy chain (IGH) gene translocations such as t(4;14), t(14;16), t(14;20), deletion of (17p), or gain/amplification(1q), have favorable prognosis and respond well to standard of care induction with plasma-cell directed therapy followed by AHCT consolida-tion and lenalidomide (LEN)-based maintenance. Despite this, it has been noted that a significant proportion of SRMM patients may suffer from early relapse after AHCT, and could potentially benefit form mitigation strategies. The aims of this study were to assess the impact of prior lines of therapy on post-AHCT outcomes in SR MM patients, and then evaluate the role of an augmented LEN-based maintenance regimen in those who did not achieve a complete response (CR) post transplant. Methods: All MM patients who underwent AHCT at our institutions between January 2011 and January 2021 were retrospectively reviewed. Electronic medical charts were searched to collect data on baseline demographic characteristics, disease status, fluorescent in situ hybridization (FISH) cytogenetic studies, blood and bone marrow studies, number of lines of treatments pre-AHCT, as well as maintenance therapy post-transplant. Responses were according to the International Myeloma Working Group (IMWG) criteria. Kaplan Meier method was used for event free survival (EFS) assessment. Results: A total of 293 SR MM patients were included in this analysis, of whom 188, 63, 32 and 10 received 1, 2, 3, and ≥4 lines of therapy pre-AHCT. Despite having comparable CR rates pre-AHCT (28% vs 19% vs 22% vs 10%, respectively; p=0.3), patients with ≥4 prior lines of therapy experienced significantly worse outcomes as determined by shorter mediant EFS of 8.4 months vs 54.5, 55.9 and 21.7 months (P<0.0001) for the 1, 2, and 3 pre-AHCT lines of therapy groups, respectively ( Figure 1A). We then focused on the subgroup of SR MM patients (n=100) who did not achieve a hematologic CR at day-100 post-AHCT. Among them 87 were placed on LEN-monotherapy, and 13 on LEN-based combination maintenance therapy post-AHCT. Of note, none was LEN-refractory. Both the LEN-monotherapy and combination groups had comparable baseline patients and disease characteristics including age (60.5 vs 56 years, p=0.07), time from diagnosis to transplant (≥12 months in 24% vs 30.8%, p=0.7), hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score ( ≥3 in 44% vs 30.8%, p=0.5), male representation (59% vs 69%, p=0.6), white ethnicity (82 vs 77%, p=0.7), international scoring system stages (p=0.9), pre-AHCT number of lines of therapy (p=0.8), and pre-AHCT bone marrow plasma cell percentage (≥10% in 9.5% vs 7.7%, p=0.9), respectively. Kaplan-Meier survival analysis showed a significantly shorter median estimated EFS for the LEN monotherapy group at 38.1 months vs 68.6 months (p=0.03) for the LEN combination maintenance group ( Figure 1B). Conclusion: SR MM constitute heterogenous group of patients with variable outcomes post-AHCT. Those with heavily pretreated disease, that have received four or more lines or therapy, tend to have worse outcomes post transplant, therefore, should be considered for alternative approaches such as chimeric antigen receptor T cell therapies or bispecific agents. For patients who undergo AHCT but do not achieve a CR, LEN-combination maintenance should be strongly considered especially in the setting of relapsed-refractory disease.

A Phase 2, Single-Arm, Non-Inferiority Study of Limited-Duration Teclistamab for Relapsed and Refractory Multiple Myeloma (LimiTec)

Background and Significance: Teclistamab, a BCMA-directed T-cell engager (anti-BCMAxCD3 bispecific antibody), is currently approved for relapsed/refractory multiple myeloma (MM) patients with ≥4 prior lines of therapy, including an IMID, proteasome inhibitor, and CD38 antibody. Teclistamab is typically dosed on a regular schedule (every 1-4 weeks) indefinitely until disease progression. Yet continuous exposure, as reported on the phase 1/2 MajesTEC-1 study, was associated with infectious complications in 78% of patients, with 52% grade 3 or 4 events (van de Donk et al, ASCO 2023) and several fatal infections (Moreau et al., NEJM 2022). Sustained off-drug responses have been observed in patients who discontinued teclistamab for reasons other than progression and have also been reported with cevostamab, an anti-FcRH5xCD3 bispecific antibody under investigation as a limited-duration regimen (17 cycles) in MM (Lesokhin et al, ASH 2022). These findings raise the possibility that limited-duration teclistamab might provide comparable efficacy with lower risk compared to continuous therapy. Therefore, we hypothesize that monitored discontinuation of teclistamab in patients with deep response after 6-9 months of continuous therapy, with option to resume upon early sign of MM growth, will be non-inferior to that of historical controls [from the MajesTec-1 trial] who were treated with continuous teclistamab dosing. Study design and methods: This is a single-arm, non-inferiority study in which patients who have achieved a very good partial response (VGPR) or better, according to International Myeloma Working Group (IMWG) response criteria, following 6-9 months of standard-of-care teclistamab, will be offered monitored drug discontinuation. Patients will be monitored monthly off-drug for up to 24 months and will be allowed to resume commercial teclistamab on-study in the event of early disease growth (defined as increase in involved free light chain >20 mg/L with ratio >5) or progression (as defined by IMWG criteria).The primary objective is to preliminarily assess whether the rate of treatment failure of limited-duration teclistamab after 6 months of drug discontinuation is non-inferior to that of historical controls who received continuous therapy, where treatment failure is defined as any of the following events: (1) disease progression after teclistamab re-initiation (for subjects who resume teclistamab for early disease growth), (2) failure to achieve at least minimal response to teclistamab re-initiation (for patients who resume teclistamab for IMWG progression), (3) initiation of non-teclistamab systemic MM therapy, or (4) death due to complications of MM, teclistamab, or infection. Secondary endpoints will evaluate time to progression, rates of re-response, the rate and severity of infections, types of clinical complications with progression, patient reported outcomes, and immune cell subset composition. Analysis of minimal residual disease (MRD), tumor features, and bone marrow microenvironment parameters, which will be pursued as exploratory correlative analyses in this study, may identify factors that predict durable response to limited-duration therapy and thereby enable more precise selection of patients likely to benefit from this approach. A subset of patients will be enrolled in an optional biomarker sub-study for analysis of these exploratory endpoints. We will enroll ~75 subjects to reach the target of 64 evaluable subjects assuming 15% will be not evaluable. The sample size was calculated based on a non-inferiority test for the primary outcome of failure-free probability at six months after the date of discontinuation of teclistamab against the null value of 0.79 that estimated from a historical cohort with 80% power, 0.05 alpha level, and a non-inferiority margin of -0.15. The power was evaluated at the value such that no difference between the historical and early discontinuation values using a one-sided one-sample continuity-corrected Z-test for testing a binomial proportion (normal approximation) with the standard deviation estimated under the null value. Conclusions: This single-arm, phase 2 study is exploring whether limited-duration teclistamab is non-inferior to continuously administered therapy in patients who have received 6 to 9 months of teclistamab and have achieved at least a very good partial response. Accrual started in July 2023.

SOR-CART-MM-001 Study: A Phase I, Open-Label, Dose-Escalation, Pharmacokinetic, and Pharmacodynamic Study of Safety and Efficacy of CAR2 Anti-CD38 A2 CAR-T Cells in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Background: B-cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR-) T cells, show high response rates in patients with highly refractory and heavily treated myeloma, and have become a standard treatment in this setting. The durability of these responses, however, has been limited with few long term remissions. One approach to potentially improve CAR T outcome is to direct these cells to alternative targets such as CD38 almost universally expressed on malignant plasma cells. In this open-label phase I multi-institutional study we explored the efficacy and safety of CAR2 anti-CD38 A2 CAR-T cells in patients with RRMM. Methods: The SOR-CART-MM-001 study was a multicenter, open-label, “3+3” dose-escalation, phase 1b trial of a single administration of a fully human antibody with lambda light chain generated by transduction of activated T cells with an anti-CD38 A2 CAR expressing retroviral vector. A single dose of CAR2 Anti-CD38 CAR-T cells was administered 2 days post lymphodepletion with single-agent cyclophosphamide 1.5 g/m 2. The primary endpoint was determination of the maximum tolerated dose (MTD) assessed by the occurrence of treatment-emergent dose-limiting toxicities during the 28-day treatment period in the dose-escalation phase of the study. Dosing was divided into three cohorts ranging from 1 × 10 5 cells/kg (Cohort 1) to 1 × 10 7 cells/kg (Cohort 3). Circulating CAR-T cells were measured at different timepoints post infusion. Key eligibility criteria included ≥3 lines of therapy with prior proteasome inhibitor, immunomodulatory IMID drug or daratumumab exposure, measurable and progressive MM per International Myeloma Working Group criteria and ECOG ≤ 2. Results: Between March 2018 and March 2022, 9 patients were enrolled and assigned to each of the three Cohorts. Patient demographics and baseline characteristics are described in Table 1. Hematologic toxicity was the most common treatment emergent adverse event experienced (6/9, 66.7%), all Grade 3 or Grade 4. All cytopenias recovered in 21 days in subjects treated with no more than MTD. Two subjects within Cohort 3 exhibited mild cytokine release syndrome (CRS) (Grade 1 and 2) with one of these two subjects also developing mild neurotoxicity (Grade 2). No CRS or neurotoxicity was observed at either of the lower dose levels. Two serious adverse events (SAEs) were reported: Klebsiella sepsis 60 days after treatment that recovered in 4 days after antibiotics and muscle weakness at 24 days after treatment that received within 1 day without treatment and neither were deemed related to the study medication. The first 2 patients in Cohort 3 met dose limiting toxicity (DLT) criteria after treatment due to grade 3 hematological toxicity and the next lower dose 1 x 10 6 cells/kg (Cohort 2) became the MTD. Pharmacokinetic data showed the percentage of the detectable circulating CAR-T cells in any subject at any time point was low with many showing no detectable cells. 4 deaths were reported after the end of the study period, and none were considered related to the investigated CAR-T cells (3 due to progression and one due to COVID-19). Overall, a total of 3 patients had a partial response (PR) and 3 patients had stable disease (SD) across 3 dose levels. PR constituted the best response in the study and the durations of objective clinical responses were each less than 3 months. These treatment responses are summarized in Table 2. Conclusion: This phase I trial demonstrated that CAR2 anti-CD38 A2 CAR-T cells were generally well tolerated at the Cohort 2 (MTD) dose and demonstrated objective though short responses even in patients progressing after daratumumab and belantamab mafodotin. More clinical studies are needed to optimize the efficacy and tolerability of CAR-T cell therapies for patients with RRMM. This study was completed, and no more patients will be enrolled. DART-RRMM-101 is a phase 1b, open-label, dose-escalation study ongoing to assess allogeneic Anti-CD38 A2 Dimeric Antigen Receptor T Cells in RRMM (ClinicalTrials: NCT05007418).

A Phase II Study of Isatuximab in Combination with Pomalidomide and Dexamethasone in Patients with Multiple Myeloma Progressing on or after One Line of Lenalidomide-Containing Therapy

Introduction Relapse in patients (pts) with multiple myeloma (MM) is a common occurrence, resulting in a continued need for novel treatment approaches. Isatuximab (Isa), a monoclonal antibody (mAb), combined with pomalidomide (Pom) and dexamethasone (Dex), is indicated for the treatment of pts with relapsed/refractory multiple myeloma who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy. The current study aims to evaluate the efficacy and safety of IsaPomDex in pts with MM relapsing for the first time after one line of treatment containing lenalidomide (Len). Methods EAE115 (NCT05298683) is an ongoing, investigator-initiated, phase II, prospective, open-label, multicenter study aiming to enroll 108 pts. Eligible pts are adults with documented MM who have evidence of progressive disease, by the International Myeloma Working Group criteria, on or after treatment with only one prior line of anti-myeloma therapy with lenalidomide (≥2 cycles, alone or in combination) and a proteasome inhibitor. Pts must also have adequate bone marrow and hepatic function and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with previous anti-myeloma therapy with any anti-CD38 mAb, pomalidomide, or stem cell transplant within 12 weeks before treatment initiation. Pts receive six 28-day cycles of Isa 10 mg/kg (once weekly [QW] by intravenous [IV] infusion on days 1, 8, 15, and 22 in cycle 1 and days 1 and 15 in subsequent cycles), Pom 4 mg (per Os on days 1-21, each cycle), and Dex 40 mg or 20 mg for pts ≥75 years old (per Os or IV on days 1, 8, 15 and 22, each cycle). Fifteen to 60 minutes before Isa infusions, patients receive pre-medications to mitigate potential infusion-related adverse reactions. Following initial 6 cycles, pts achieving at least very good partial response (VGPR) are randomized 1:1 to receive Isa (Q2W or Q4W) plus PomDex, and pts achieving <VGPR continue treatment with Isa (Q2W) plus PomDex. Treatment is given until progressive disease, death, unacceptable adverse events (AEs), lost to follow-up, or consent withdrawal. The study primarily evaluates the overall response rate (ORR; defined as partial response [PR] or better) to IsaPomDex therapy at six months. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty pts had received at least one dose by the cut-off date, of whom 16 (80.0%) were continuing with IsaPomDex treatment; four (20.0%) pts had discontinued due to physician or pt decision or progressive disease or death. At baseline (cycle 1, day 1), pts had a median age of 72.0 years (range: 60.0-85.0), 10 (50.0%) were male, and 13 (65.0%) had ECOG PS 0. Eleven (55.0%) pts were at stage II by the revised International Staging System, 9 (45.0%) pts had lytic bone lesions, 5 (25.0%) pts had high-risk cytogenetics, and 1 (5.0%) pt had soft-tissue plasmacytomas (Table 1). Regarding previous treatment outcomes, 14 (70.0%) pts had achieved ≥VGPR (stringent complete response, 2 [10.0%] pts; complete response, 2 [10.0%] pts; VGPR, 10 [50%] pts). Five (25%) and 1 (5.0%) pts achieved partial and minimal response, respectively. Six (30.0%) pts had received ASCT in the prior line. At a median follow-up of 3.4 (range: 0.6-6.1) months, the median number of IsaPomDex cycles received was 3.0 (range: 1.0-7.0); one (5.0%) pt received six treatment cycles. Of the 18 (90.0%) response evaluable pts (2 pts were ongoing without 2 efficacy assessments) VGPR and PR were achieved by 4/18 (22.2%) and 9/18 (50.0%) pts, respectively. ORR was achieved by 13/18 (72.2%) pts, and the median (range) time from IsaPomDex study dose to first response (≥PR) was 1.0 (range: 0.9-1.3) months. Thirteen (65.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these pts, 10 (50.0%) had a ≥1 grade (gr)≥3 TEAE and 4 (15.0%) had ≥1 gr ≥3 serious TEAE. The most common TEAEs were neutropenia in 9 pts (45.0%), anaemia in 3 pts (15.0%) and fatigue in 3 pts (15.0%). The most common gr ≥3 TEAE was neutropenia in 7 pts (35.0%) (Table 2). Conclusions Second-line treatment with IsaPomDex in pts with MM who have progressed on or after one Len-containing line of treatment appears to be effective, although longer follow-up is needed to assess its efficacy. No new safety signals were observed with the combination.

Long-Term Efficacy and Safety of Elranatamab Monotherapy in the Phase 2 Magnetismm-3 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)

BACKGROUND Elranatamab is a humanized, bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, with the aim of inducing T-cell-mediated cytolysis of the myeloma cells. In the MagnetisMM-3 (NCT04649359) trial, an open-label, multicenter, non-randomized, phase 2 registrational study of elranatamab monotherapy, patients with RRMM who had not received prior BCMA-directed therapy (ie, BCMA-naïve patients; n=123) achieved objective responses with an overall response rate (ORR) of 61%. Here, we report the long-term efficacy and safety of elranatamab. METHODS Eligible patients had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Patients received step-up doses of 12 and 32 mg elranatamab subcutaneously on days 1 and 4 of cycle 1, respectively, followed by 76 mg elranatamab once-weekly (QW), starting on day 8 of the first 4-week cycle. Patients who received ≥6 months of QW dosing and achieved ≥ partial response lasting at least 2 months were transitioned to a once every 2 weeks (Q2W) dosing schedule and from Q2W to once every 4 weeks after at least 6 Q2W cycles. Treatment with elranatamab continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR, assessed by blinded-central review per International Myeloma Working Group criteria. Minimal residual disease (MRD) status was assessed using next-generation sequencing, with MRD negativity defined as <1 myeloma cell in 10 5 nucleated cells. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) severity were graded by American Society for Transplantation and Cellular Therapy criteria. RESULTS After a median follow-up of 15.9 months (data cutoff, April 16, 2023), 32.5% of patients remained on treatment. The confirmed ORR was 61.0% (n=123; 95% CI, 51.8-69.6), with 35.8% of patients achieving complete responses (CR) or better. Among evaluable patients (those with ≥CR and evaluable for MRD, n=29), 89.7% achieved MRD negativity. Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) have not been reached, and the probabilities of maintaining a response, being progression-free, and being alive at 15 months were 70.8% (95% CI, 58.2-80.2), 50.2% (95% CI, 40.2-59.3), and 56.3% (95% CI, 47.0-64.6), respectively. All participants (100%) had ≥1 any grade treatment-emergent adverse events (TEAEs), and 70.7% of patients had grade 3/4 TEAEs. The most common any grade (≥25%) and grade 3/4 (≥10%) adverse events (any grade, grade 3/4) were infections (69.9%, 40.7%), CRS (57.7%, 0%), anemia (48.8%, 37.4%), neutropenia (48.8%, 48.8%), diarrhea (41.5%, 1.6%) thrombocytopenia (31.7%, 23.6%), lymphopenia (26.8%, 25.2%), fatigue (36.6%, 4.1%), nausea (26.8%, 0%), injection site reaction (26.8%, 0%), hypokalemia (26.0%, 10.6%), cough (26.0%, 0%) pyrexia (30.9%, 4.1%), decreased appetite (33.3%, 0.8%), leukopenia (15.4%, 13.0%) and COVID-19 pneumonia (14.6%, 11.4%). CONCLUSIONS Extended follow-up from the ongoing phase 2 MagnetisMM-3 trial of elranatamab in heavily pretreated participants with RRMM demonstrated sustained clinical efficacy, with median DOR, PFS, and OS not reached, and no new safety signals.

Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1)

Background and Significance Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that precedes the development of multiple myeloma (MM). Traditionally, patients with SMM have undergone observation until progression to MM, but this paradigm can result in poor outcomes for some patients. Phase 3 clinical trials have demonstrated that early treatment with lenalidomide with or without dexamethasone can delay the development of end-organ damage and improve overall survival among SMM patients with high-risk features. Linvoseltamab (REGN5458) is a fully human B-cell maturation antigen (BCMA)×CD3 bispecific antibody that targets BCMA on plasma cells and CD3 on T cells, resulting in targeted T-cell-mediated cytotoxicity. In the Phase 1/2 LINKER-MM1 study, linvoseltamab alone induced deep and durable responses with a generally manageable safety profile in patients with relapsed/refractory MM (Lee et al. EHA. 2023). These data highlight the potential of novel immunotherapies with promising single-agent activity to be attractive therapeutics for early intervention to prevent progression to MM. Study Design and Methods LINKER-SMM1 is an open-label, Phase 2 study (NCT05955508) designed to evaluate the safety and efficacy of linvoseltamab monotherapy in adult participants with SMM who are at a high risk of progression to MM. High-risk criteria include having both ≥95% clonal plasma cells in the bone marrow (BM) and immunoparesis and/or ≥2 of the following: serum M-protein >2 g/dL, free light chain ratio >20, and BM plasma cells >20%. Participants must have a confirmed diagnosis of SMM within 5 years of enrollment, Eastern Cooperative Oncology Group performance status ≤1, and adequate organ function to be eligible. Participants will be excluded from enrollment if they have myeloma-defining events, uncontrolled infection, history of allogeneic stem cell transplantation, or received prior treatment for SMM. The study will take place at approximately 15 sites in Spain and will include two parts: Part 1 (safety run-in) to evaluate the preliminary safety and tolerability of linvoseltamab and Part 2 (expansion) to evaluate the clinical activity of the selected dosing regimen. In Part 1, at least 6 participants will receive linvoseltamab starting with a step-up schedule before reaching the full dose. All subsequent treatment with full-dose linvoseltamab will be given over 28-day cycles until completion of 24 cycles or occurrence of a protocol-defined reason for discontinuation. Assuming that initial safety is shown to be acceptable, an additional 34 participants will be enrolled in Part 2 according to the dosing regimen established in Part 1. Post-treatment safety monitoring will continue for up to 90 days after the last dose of linvoseltamab, and participants with an ongoing response will continue routine efficacy assessments until confirmed biochemical progression, start of non-protocol cancer therapy, or death. Long-term follow-up will continue for up to 5 years after the last dose of linvoseltamab. The primary endpoints in Part 1 are frequency of adverse events (AEs) of special interest, including grade ≥2 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and frequency and severity of treatment-emergent AEs. In Part 2, the primary endpoints are complete response (assessed by International Myeloma Working Group criteria) and minimal residual disease (MRD) negativity (10 -5 sensitivity) after 12 and 24 months of treatment. Secondary endpoints include cumulative safety, overall response rate, duration of response, sustained MRD negativity, biochemical and clinical progression-free survival (PFS), time to myeloma-defining event, time to initiation of first-line treatment for MM, and overall survival as well as immunogenicity and serum concentration of linvoseltamab over time. Exploratory endpoints include PFS after the start of first-line treatment for MM, adequacy of stem cell collection, patient-reported outcomes, and various biomarker changes. As this is a proof-of-concept study, results will be analyzed using descriptive statistics and no formal hypothesis testing is planned. Study accrual is planned to begin in Q4 2023.

Outcomes of BCMA-Directed Chimeric Antigen Receptor T-Cell (CART) Therapy in Patients with Relapse-Refractory Multiple Myeloma with Extramedullary Disease

Background: Presence of extramedullary disease (EMD) is associated with poor outcomes for patients with relapsed-refractory multiple myeloma (RRMM) and has been identified as a major risk factor for early progression (≤ 3 months) after CAR T-cell therapy. Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are B-cell maturation antigen (BCMA) targeting CAR T-cell therapies approved for patients with RRMM who have received ≥4 prior lines of therapy (LOT). This is a multicenter retrospective study on the real-world safety and efficacy of commercially available ide-cel and cilta-cel in heavily pretreated RRMM patients with EMD. Methods: Three U.S. academic centers, part of the U.S. Myeloma Innovations Research Collaborative (USMIRC), contributed data to this analysis, which included patients with RRMM who had received an ide-cel or cilta-cel infusion ≥30 days prior to data-cut off (7/1/2023). Baseline patient characteristics were outlined by descriptive analyses. Responses including overall response (ORR), and complete response or better (≥CR) rates were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the Fisher's exact test and Kaplan Meier method for progression free (PFS) and overall survival (OS) calculations. Results: A total of 132 patients who received commercial (standard of care) BCMA-directed CAR T-cell therapy between 5/1/2021 and 5/30/2023 were included in this study. Out of these, 64 (48%) patients had a previous history or existing EMD prior to CART infusion. Table 1 summarizes the main patient characteristics and outcomes stratified as EMD and non-EMD groups. Both groups had comparable baseline patient and disease characteristics including median age, ECOG performance status, median bone marrow plasma cell percentage, high-risk cytogenetics, number of prior LOT, refractoriness status prior to CART and type of CAR T-cell product received. CART-related toxicities were comparable between the EMD and the non EMD groups. Cytokine release syndrome (CRS) was seen in 73% (≥ grade 3: 5%) of EMD patients vs 79% (≥ grade 3: 4%) of non-EMD patients (p=0.79). Likewise, immune effector cell-associated neurotoxicity syndrome (ICANS) was noted in 28% (≥ grade 3: 5%) of EMD patients vs 32% (≥ grade 3: 9%) of non-EMD patients (p=0.72). Infections were seen in 39% of the EMD group vs 28% of the non-EMD group (p=0.38). Response rates were also similar between the EMD vs non EMD cohorts: ORR 78% vs 96% (p=0.44); and ≥CR rate 42% vs 51% (p=0.54), respectively. With a median follow up of 7.2 (range 0.5-22.8) months for the entire patient cohort, the estimated median PFS was inferior for the EMD group (6.5 months [95% CI, 5.1-9.6]) compared to the non-EMD group (9.8 months [95% CI, 8.2-16.4]) (p=0.017) (Figure 1). At the time of data cut-off, 43 patients had died, 77% from disease progression, 11.5% from CART-related complications and 11.5% from unrelated causes. The estimated median OS was significantly worse for the EMD group (12.9 months [95% CI, 9.5-NA]) compared to the non-EMD group (19.4 months [95% CI, 1.2-NA]) (p=0.031). Conclusions: This is the largest multicenter retrospective study delineating the real-world outcomes of ide-cel and cilta-cel CAR T-cell therapies in RRMM patients with the high-risk disease feature of EMD. Based on our results, patients with prior history or presence of existing EMD at the time of CART infusion did not have any excessive treatment-related toxicities. However, these patients did experience shorter PFS and OS compared to patients without EMD highlighting the presence of EMD as a risk factor for poor outcomes after CART. Therefore, this group of patients should be considered for pre- and post-CART risk mitigation strategies aiming to prevent disease progression and improve survival outcomes.

A Prospective, Multinational Study of Clinical and Biological Factors Associated with Short Overall Survival in Multiple Myeloma

Introduction: Multiple myeloma (MM) is an incurable cancer, but a subset of patients can achieve long-term remission and overall survival (OS). We aimed to study the clinical and biological factors associated with short OS defined as less than 3 years. Methods: A prospective, observational, multinational study was conducted by Australian and New Zealand (ANZ) and Asia-Pacific (APAC) Myeloma and Related Disease Registry (MRDR) from January 2013 to January 2023, across 5 countries (Australia, New Zealand, Korea, Singapore, Malaysia). Eligible patients were ≥18 years old, diagnosed with MM per International Myeloma Working Group (IMWG) criteria, received a bortezomib-containing triplet, and had at least 3 years of follow-up or had deceased within 3 years. Descriptive analysis was completed using chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables. The Kaplan-Meier method was used for analysing OS and follow-up data. The ‘stepwise’ function in Stata was used for the forward stepwise logistic regression, with the p-value set to 0.1. All analyses were completed using Stata 16. Results: Of the 1539 patients enrolled, majority were from ANZ (1071 and 359, respectively), with male preponderance (61.0%). Half were above 65 years old. High risk cytogenetic abnormalities, a criterion of the Revised International Staging System (R-ISS), was unknown for half of the patients (49.4%). 45.3% patients presented as ISS stage 1, 21.9% stage II, and 32.8% stage III, respectively at study entry . The most frequent front-line agent used in combination with bortezomib-based triplet was cyclophosphamide [VCd, 1380 (89.7%)], followed by thalidomide [VTd, 92(6.0%)], lenalidomide [VRd, 63 (4.1%)] and daratumumab [DVd, 4 (0.3%)]. The median follow-up was 29.9 months (95%CI: 28.3-31.8) and the median OS was 87.7 months (95%CI: 80.9-93.2). Thirty percent patients had OS<3 years. Clinical and biological factors associated with long OS (≥3 years) were compared with those <3 years (Table 1). Baseline factors associated with higher odds of short OS included age≥65, Eastern Cooperative Oncology Group performance status (ECOG PS)≥2, ISS III, lower creatinine clearance and platelet count, high LDH and poor cytogenetic abnormalities (Table 1). In a multivariate analysis, age≥65 (OR:2.50; p<0.001), ECOG≥2 (OR:2.08; p<0.001), ISS III (OR:2.48; p<0.001), t(4;14)[OR:2.04; p=0.004], t(14;16)[OR:6.33; p=0.004] and 17p deletion (OR:2.77; p =0.001) were associated with a significantly shorter OS. Conclusion: From clinician perspective, identifying patients with an increased likelihood of shorter OS through the determination of patient- and disease-specific risk factors might be clinically relevant to facilitate better treatment decisions.

Dose Escalation of ISB 1342, a Novel CD38xCD3 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1342 is a humanized CD38xCD3 bispecific T-cell engager using Ichnos proprietary Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform, designed to simultaneously bind CD38 on multiple myeloma (MM) cells and CD3ε on T cells, to induce tumor killing. This mechanism of action is different from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. ISB 1342 exhibits potent killing of the primary MM cells and MM cell lines with low sensitivity to daratumumab ( Pouleau B. et al. Blood 2023; 142 (3): 260-273). We report here, the updated findings from the weekly dose-escalations of intravenous (IV) and subcutaneous (SC) injections of an ongoing, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM. Methods: Adult patients with RRMM that relapsed after or were refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received ISB 1342 on a weekly (QW) schedule by IV or SC injection with a priming dose on the first day in 2 parallel dose-escalation schemas. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation in the QW schedule began at 0.2/0.3 mg/kg priming/treatment dose and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and select a recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives includ evaluation of anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ISB 1342. Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory. Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed. After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower C max and delayed T max relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting. Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.

Toxicity and Efficacy Outcomes of Teclistamab in Patients with Relapsed-Refractory Multiple Myeloma (RRMM) Above the Age of 70 Years: A Multicenter Study

Introduction: Older patients (>70 years old) are often considered ineligible for intensive treatments including autologous stem cell transplant (ASCT) and chimeric antigen receptor T-cell (CAR-T) therapies, having a relatively poor performance status and concomitant comorbidities. Therefore, the interest in this age group has been shifted in utilization of novel therapies with a less toxic side effect profile and less risk for serious complications. Teclistamab is a novel B-cell maturation antigen (BCMA)-directed bispecific antibody that received approval for the treatment of patients with RRMM after ≥4 prior lines of therapy (LOT) based on the results of the MajesTEC-1 trial. In this retrospective study, we aimed to analyze real-world data on the efficacy and toxicity profile of teclistamab in a population of older RRMM patients, and compare them with younger individuals. Methods: Five US academic centers, part of the US Myeloma Innovations Research Collaborative (USMIRC) contributed data to this analysis. One hundred and two patients with RRMM who received teclistamab as of 7/1/2023 were included in this study. Baseline characteristics were outlined by descriptive analysis. Responses, including overall response rate (ORR) and compete response rate or better (≥CR) were assessed using the International Myeloma Working Group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. Statistical analysis was done with Chi-squared test and Kaplan-Meier method for progression-free survival (PFS) calculation. Results: Of the 102 patients included in this study, 33 (32%) were above the age of 70 years (older) with a median age of 75 (range 71-87) years. Disease characteristics of the older patient population were notable for 58% with high-risk cytogenetics as defined by presence of del(17p), t(4;14), t(14;16) and/or t(14;20), and 39% with extramedullary disease (EMD) prior to teclistamab initiation. Patients were heavily pretreated with a median of 6 (range 4-17) prior LOT; 58% had undergone prior ASCT and 97%, 58%, and 58% were triple, penta, and BCMA-directed therapy (BDT) refractory, respectively. Compared to patients with age <70 years (n=69), older patients were more likely to have a worse performance status (ECOG ≥2) (45% vs 26%, p=0.05); other baseline characteristics including high-risk cytogenetics, stage III (per revised international staging system) disease, extramedullary disease, triple, penta- and BDT-refractoriness status were comparable between the two groups (Table 1). Median follow-up time for the entire cohort was 3.2 months. Patients with age >70 years had a comparable ORR (70% vs 61%, p=0.37), and ≥CR (30% vs 28%, p=0.8) rates to those with younger age. In addition, the two subgroups had comparable median estimated PFS (5.4 vs 3.8 months, p=0.61) (Figure 1). Cytokine release syndrome (CRS) in most cases was grade 1-2, and CRS rates were similar between the older and younger patient groups (67% vs 64%, p=0.7). Likewise, most immune effector cell-associated neurotoxicity syndrome (ICANS) events were grade 1-2, and rates were comparable between the two groups (21% vs 11%, p=0.17, Table 1). Patients older than 70 years were more likely to have grade 3-4 thrombocytopenia within the first 90 days from teclistamab initiation (27% vs 12%, p=0.05), while the rest of grade 3-4 cytopenias were not different between the two cohorts. Infection rates (33% vs 26%, p=0.46) and hospital readmission rates (36% vs 23%, p=0.16) were comparable between the older and younger patients, respectively. Conclusions: This is the first and largest multicenter retrospective analysis characterizing a real-world cohort of patients who received teclistamab. Based on our results, older age (>70 years) does not appear to affect response outcomes or PFS. For the most part, the safety profile appears similar, however patients older than 70 years were more likely to develop grade 3-4 thrombocytopenia. Importantly, the infection rates were not significantly different between the two groups, further supporting the broad use of teclistamab in older patients with RRMM.

Hyposecretory Progression Pattern Indicates Inferior Survival of Multiple Myeloma

Introduction: The application of novel drugs has significantly enhanced the prognosis of patients with MM. However, most patients will inevitably experience disease progression and relapse. At progressive disease (PD), patients always exhibit distinct features characterized by varying levels of M protein and plasma cells in the bone marrow (BMPC), even in the presence of end-organ damage. Notably, a subgroup of patients initially diagnosed with secretory MM exhibits a higher proportion of BMPC but a lower level of M protein when PD, rendering identification of this subgroup challenging without conducting bone marrow evaluations, leading to many patients experiencing PD but without timely treatment. The identification and comprehension of the hyposecretion at progression remain unclear and require further investigation. Thus, in this study, we aimed to assess the impact of different patterns of disease progression according to M protein and BMPC percentage on the survival and describe the features of the subgroup. Methods: We retrospectively analyzed the baseline and progression clinical features of 268 patients in our hospital between January 1, 2013 to July 1, 2023. We classified the PD patterns into three categories based on the elevated level of M protein and clonal plasma cells in bone marrow at progression: a. hyposecretory progression (HypoP) means >10% increase of the absolute percentage of BMPCs but serum M-protein increase <5g/L (or urine M protein increase < 200 mg/24h) and patients with the non-secretory subtype at diagnosis were excluded.; b. extramedullary progression (EMP) means appearance of a new extramedullary lesion; c. classic progression (ClaP) means any one or more of the other PD criteria according to International Myeloma Working Group (IMWG) criteria. High burden refers to the percentage of BMPC > 50%. Time from the first relapse to death as overall survival (OS) after the first progression (pro-OS). Results: There were 268 patients included in the study, and according to their features of M protein and BMPC at progression, 206 (76.8%) patients were classified in the ClaP group, 39 (14.6%) patients in EMP group and 23 (8.6%) patients in HypoP group. The percentage of female in HypoP group was 52.2%, which was much higher than that in other two groups (36.5% in ClaP and 30.8% in EMP). In general, the patients with MM are predominantly of the IgG subtype. Interestingly, for patients featured by hyposecretion in progression, the M protein types were mainly IgA (47.9%) and light chain type (43.5%) ( P<0.001). Compared to the ClaP and EMP group, there were more patients in HypoP presenting t(11;14) (36.8% vs 16.7% vs 11.8%) and 1q21+ (70% vs 53.8% vs 53.8%) both at diagnosis and progression. And at disease progression, the proportion of patients with t(4;14) in the HypoP group was as high as 50%. Besides, in terms of clinical manifestations, HypoP patients were more likely to suffer from hypercalcemia, renal dysfunction, and lower serum M protein level and EMP experienced high level of lactate dehydrogenase (LDH) both at diagnosis and progression. The median follow-up was 67.0m (7.6-123.0m). Figure 1 demonstrates the progression-free survival (PFS), OS and pro-OS of patients with different progression patterns. Patients in ClaP and EMP groups experienced similar PFS whereas HypoP patients had significantly shorter median PFS ( P=0.003, 23.9m vs. 22.6m vs. 14.1m). We also found that patients with ClaP and HypoP feature had inferior median OS ( P=0.007, 71.4m vs. 48.0m vs. 53.9m for ClaP vs. EMP vs, HypoP) and pro-OS ( P=0.012, 34.2m vs. 17.3m vs. 23.4m for ClaP vs, EMP vs. HypoP). Then we refer to these two as non-ClaP. In the Cox-regression, multivariate analysis showed ISS-III, ASCT and non-ClaP were associated with shorter pro-OS and OS ( Figure 1). Conclusions: In conclusion, our results indicate that the hyposecretory progression pattern is a valuable indicator of inferior survival. In such cases, bone marrow testing plays a crucial role in identifying and detecting this special group. Patients presenting with EMP or HypoP features tend to have a poorer prognosis, representing unmet clinical need. Therefore, it is important to recognize these particular patients as early as possible and to intensify treatment strategies.

A Phase 2 Study of Isatuximab in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone, Followed By Isatuximab and Lenalidomide Maintenance in Newly Diagnosed Patients with Multiple Myeloma and Severe Renal Impairment

Introduction Renal impairment (RI), a common complication of multiple myeloma (MM), is associated with increased risk of early death. Reversal of MM-associated RI is a key predictor of improved survival. Regimens containing bortezomib and dexamethasone are the treatment backbone for newly diagnosed (ND) patients (pts) with MM and severe RI, even those requiring dialysis. In the ICARIA-MM study, the addition of isatuximab (Isa) to pomalidomide and dexamethasone improved the renal response rate (RRR) in pts with relapsed/refractory MM and RI. We investigated the effect of induction treatment with Isa plus bortezomib, cyclophosphamide, and dexamethasone (VCd) on the renal function of pts with NDMM and severe RI. Additionally, we evaluate the efficacy and safety of IsaVCd induction, followed by Isa and lenalidomide (Len) maintenance. Methods EAE116 (NCT05147493) is an ongoing, investigator-initiated, phase II, prospective, open-label study aiming to enroll ~51 pts in six Greek hospitals. Eligible pts are adults with documented NDMM by International Myeloma Working Group (IMWG) criteria and severe RI (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73m 2) or in need of dialysis. Pts must also have adequate bone marrow and hepatic function and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with prior/current systemic therapy or stem cell transplantation for any plasma cell dyscrasia, history of malignancy other than MM, meningeal involvement of MM, cardiac disease, hepatitis, ongoing grade (gr) ≥2 peripheral neuropathy, or those with major surgery within two weeks before cycle (Cyc)1, day (D)1. In induction (six 28-day cycles), pts receive: Isa 10 mg/kg IV (Cyc 1: D1, 8, 15, 22; Cyc 2-6: D1, 15); bortezomib 1.3 mg/m 2 SC (Cyc 1: D1, 4, 8, 11; Cyc 2-6: D1, 8, 15, 22); cyclophosphamide 300 mg/m 2 IV (Cyc 1: D1, 8, 15; Cyc 2-6: D1, 8, 15, 22); and dexamethasone 40 mg PO or IV (Cyc 1: D1, 2, 3, 4, 9, 10, 11, 12; Cyc 2-6: D1, 8, 15, 22). In maintenance (Cyc 7 onwards), pts receive Isa 10 mg/kg IV (D1 of each Cyc) and Len 10 mg PO (or adjusted according to renal function) daily (D1-28 of each Cyc). Fifteen to 60 minutes before Isa infusions, pts receive pre-medications to mitigate potential infusion-related reactions. Treatment continues until disease progression, unacceptable toxicity, or consent withdrawal. The study primarily assesses the RRR (proportion of pts with partial renal response or better, using the eGFR cutoff values of the IMWG response criteria) at six months of treatment with IsaVCd. Other study objectives assess the pts' overall response rate (ORR; defined as partial response [PR] or better) and the safety of IsaVCd. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty-five pts have been enrolled and have received ≥1 study treatment dose; of these, 20 (80.0%) are continuing with treatment and five (20.0%) have died. At baseline, pts had a median age of 70.0 years (range 46.0-87.0), 18 (72.0%) were male, and 22 (88.0%) had ECOG PS ≤1. Thirteen (52.0%) pts were at stage II and 12 (48.0%) pts at stage III by the revised International Staging System, 6 (24.0%) pts had lytic bone lesions, 5 (20.0%) pts had high-risk cytogenetics, and 5 (20.0%) pts had soft-tissue plasmacytomas. Seven (28.0%) pts were in need of dialysis (Table 1). At a median follow-up of 3.9 months (range 0.1-8.3), pts have received a median of 4.0 treatment cycles (range 1.0-9.0). Eight (32.0%) pts have completed ≥ 6 treatment cycles. RRR was achieved by 5/11 (45.5%) pts who had initiated treatment 6 months before the cutoff date. The median time to RR was 2.8 months (range 0.9-7.0). Of the 19 (76.0%) response evaluable pts, 11 (57.9%) achieved ORR (very good partial response: 6 [31.6%]; PR: 5 [26.3%]). The median time to first response was 1.0 months (range 0.9-1.9). Twenty (80.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these, 10 (50.0%) pts had ≥1 gr ≥3 TEAE and 7 (43.8%) pts had ≥1 gr ≥3 serious TEAE. The most common gr ≥3 TEAE was peripheral neuropathy in 5 pts (20.0%) (Table 2). Conclusions Pts with NDMM and severe RI treated with upfront IsaVCd achieve RR consistent with those reported in the literature for pts receiving bortezomib-based therapy, although longer follow-up is needed to assess the regimen's impact on RI. No new safety signals were observed with IsaVCd.

Outcomes of Patients with Relapsed/Refractory Multiple Myeloma Who Received at Least 2 BCMA-Directed Therapies

Introduction:In recent years, many B-cell maturation antigen (BCMA) directed therapies (BDT) have demonstrated clinical response in heavily treated relapsed/refractory multiple myeloma (RRMM). These therapies include antibody-drug conjugates (ADC), chimeric antigen receptors (CAR-T), T-cell engaging bispecific antibodies (BsAb), and BCMA monoclonal antibodies (MoAb). BDT represents a breakthrough in the treatment of heavily treated RRMM. While these agents have led to deep responses and remissions, they have not been curative and many patients are exposed to more than one BDT. Optimal sequencing of BDT and outcomes in patients who received 2 or more BDT is not well understood. Our study aims to address these questions in this population. Methods: A retrospective review of 39 patients with RRMM that received 2 or more types of BDTs at the University of Kansas Medical Center, in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC), as of 7/10/2023 was completed. Responses to therapy including overall response rate (ORR), complete response or better (>CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. The Kaplan-Meier method was used for progression free survival (PFS) and overall survival (OS) assessments. OS was calculated from exposure of 1 st BDT till the last office visit/death. Regression models for univariate and multivariate analysis were performed. Results: Patients were previously treated with a median of 7 (4-12) prior lines of therapy before 2 nd BDT; 75% were Caucasians, 69% had IgG isotype, 74% had high-risk cytogenetics, and 51% had extramedullary disease (EMD). All patients were triple-class exposed, 95% were triple-class refractory, 82% were penta-class exposed and 74% were penta-class refractory, only 15% received 3 different types of BDTs. Median time between relapse after 1 st BDT to initiation of 2 nd BDT was 4 (0.5-33) months. Baseline characteristics are summarized in Table 1. Median follow-up was 19.4 (11.5-NR) months for the entire cohort. The most common first BDT were CAR-T and ADC (n=15, 38% and n=12, 31%), respectively. Whilethe most common second BDT were BsAb and CAR-T (n=17, 44% and n=13, 33%), respectively. The ORR after 1 st BDT and 2 nd BDT was 54% and 54%, respectively. The responses after 1 st BDT and 2 nd BDT were found to be deep (41% ≥VGPR, 36% ≥CR) and (44% ≥VGPR; 23% ≥CR), respectively. Detailed responses for the groups of interest are reported separately in Figure 1. The estimated median PFS for 1 st BDT was 5.8 months (95% CI 2.8-9.5) while for 2 nd BDT it was 5.2 months (95% CI 1.77-NA). Median OS from exposure to 1 st BDT was 19.5 months (95% CI 16.7-NA). At the time of data cut-off, 51% of patients had died with 90% of deaths were due to disease progression. Conclusions: This is one of the first reports on outcomes with second BDT in RRMM. Despite a heavily pre-treated patient population, 2 nd treatment with a BDT resulted in deep and durable responses, similar to treatment with 1 st BDT. Progression free survival was similar with 1 st and 2 nd BDT exposure. While our study is limited by a small population, our results support the use of a different type of BDT at progression even if previously exposed to a BCMA targeting agent. Further studies are needed to provide more guidance on appropriate sequencing of BDTs.

Outcomes of Vdpace for Relapsed/Refractory Multiple Myeloma in the Era of Daratumumab Based Therapy

Background: Although the number of therapeutic options for patients with relapsed/refractory multiple myeloma (RRMM) has increased substantially, it still remains incurable and there remains a significant unmet need for treatment options for highly refractory patients. In this single-center real-world retrospective analysis, we evaluated the efficacy and safety of VDPACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) as a salvage therapy in the era of daratumumab. Methods: We retrospectively analyzed 88 patients with RRMM who received at least 1 cycle of VDPACE, between 1/2016 till 6/2023 at the University of Kansas Health System in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC). VDPACE consists of Bortezomib 1 mg/m2 subcutaneous on days 1, 4, 8 and, 11, doxorubicin 10 mg/m2 continuous infusion (CI) x 4 days, cisplatin 10 mg/m2 CI x 4 days, cyclophosphamide 400 mg/m2 CI x 4 days and etoposide 40 mg/m2 CI x 4 days. In this patient population, we identified two groups - 28 patients who were naïve to daratumumab (DN) and 60 patients who were refractory to daratumumab (DR). Descriptive analysis was performed on available data for patient characteristics, disease course and outcomes differentiating these two groups. Adverse events were graded based on the CTCAE v5.0 criteria. Responses to therapy including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. The Kaplan-Meier method was used for progression free survival (PFS) and overall survival (OS) assessment. Results: The median age for the entire patient population was 63 years (41-77). Median lines of therapies (LOT) in DN vs DR groups were 2 (1-10) vs 5 (1-10), respectively (Table 1). The ORR and ≥VGPR in DR vs DN was 53% vs 50% and 15% vs 29%, respectively. With a median follow-of 11.3 months (95% CI, 4.03-27), the median PFS for the entire patient population was 4 months (95% CI, 2.97-5.43) while the median OS was 11.1 months (95% CI, 6.97-14.9). However, the median OS for DN was 15.9 months (95% CI, 8.73-29.5) compared to 7.03 months ((95% CI, 6.27-13.57) p=0.06) for the DR group. See Figure 1. Treatment related toxicities were similar in both groups. The most common grade III/IV hematological toxicities were neutropenia (96% vs 93%, p=0.99), thrombocytopenia (93% vs 80% p=0.2), lymphopenia (89% vs 95%, p=0.3), and anemia (79% vs 73%, p=0.79). Transfusion of packed red blood cells (64% in DN vs 68% in DR group) and platelet (61% vs 80%) were common in both groups. Rates of neutropenic fever were similar in both groups; 46% in the DN vs 35% in the DR group, p=0.62, with pneumonia being the most common infection seen in 11% vs 5% of the patients, respectively. Sixty-day Rehospitalization rates in the two groups were 21% vs 50%. There was no treatment-related mortality reported with this regimen. The difference in OS after VD-PACE in DR and DN patients could be explained by higher no of prior LOT, presence of high risk cytogenetics, double refractory status, and limited options available for salvage. Conclusions: Our study shows that while the response rates with VDPACE were comparable in the two groups, there was a higher median OS in the DN. Hematologic adverse events were common in both groups, but the rate of re-hospitalization was higher in the DR group. Based on these results, VDPACE remains a safe and effective salvage therapy for patients with RRMM. For DR patients receiving VD-PACE, strong consideration should be given to clinical trials given poor long-term outcomes.

Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody that targets CD38 and CD47, generated using Ichnos' Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform. ISB 1442 is designed to kill CD38-expressing tumor cells through multiple mechanisms of action including blocking CD47-signal regulatory protein alpha (SIRPα) axis to increase several antibody effector functions: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. ISB 1442 is expected to have optimized tolerability with low potential for adverse effects on red blood cells (RBC) such as hemagglutination, platelet aggregation and RBC depletion (Sammicheli at al., ASH 2021, Blood (2021) 138 (Supplement 1): 73). We report here initial findings from the early dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1/2 study (NCT05427812) of ISB 1442 in patients with RRMM. Methods: Adult patients with relapsed refractory multiple myeloma (RRMM) to prior therapies, including a proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies received subcutaneous (SC) doses of ISB 1442 weekly (QW) in 28-day cycles. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation began at 6 mg dose with single patient accelerated titration phase for the first 3 cohorts, followed by a standard titration phase with a “3 + 3” design. The primary study objective for phase 1 is to assess the safety and tolerability to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of ISB 1442. For phase 2 the primary study objective is to evaluate efficacy of ISB 1442. Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity of ISB 1442. Exploratory objectives include assessment of minimal residual disease (MRD), assessment of cellular biomarkers in blood and bone marrow, and soluble factors in blood, and their correlation with efficacy, safety and other clinical endpoints of interest. Results: As of July 18, 2023, based on preliminary data from ongoing clinical database, 10 subjects had received once weekly SC injections of ISB 1442 in 4 dose-escalation groups from 6 mg to 150 mg. The majority were male (60%) and white (90%). The median age was 67 years (range 57-79). The median number of prior anti-myeloma lines of therapy was 6 (range 3-7); 70% were exposed to 5 drugs (2PIs, 2IMiDs, and CD38). The median number of ISB 1442 cycles was 1(range 1-2). Eight subjects (80%) experienced treatment-related adverse events (TRAEs), all were grade 1 or 2: cytokine release syndrome (CRS) (50%), injection site reactions (injection site erythema 20%, injection site bruising 10%), anemia (10%, 1 subject, grade 2) (Table 1). No grade 5 TRAE was observed. Following QW SC injection, ISB 1442 was slowly absorbed into the systemic circulation with T max generally occurring on day 2 of dosing. The ISB 1442 serum concentrations generally remained quantifiable over the entire dosing duration from 20 mg and above. The available PK data suggest an approximately dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a supra-proportional increase in serum levels in subjects treated at DL 4 (150 mg). To date, 5 subjects treated at DL4 (150 mg) have experienced clinical symptoms of CRS (Grade 1-2) following the first dose of ISB 1442. Assessment of a panel of 63 soluble factors (including multiple cytokines, chemokines and growth factors) in the peripheral blood revealed that several subjects at DL3-4 exhibited transient increases (>10-fold) in macrophage inflammatory protein-1b (MIP-1b/CCL4) within 24h after treatment with ISB 1442, consistent with a macrophage-associated mechanism of action. Conclusions: Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study.

Sequential Administration of Selinexor and CAR-T Therapy in Relapsed/ Refractory Multiple Myeloma

Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) that binds to exportin 1 and exhibits anti-tumor activity by impairing nuclear export of proteins including oncogenes and tumor suppressor proteins and is approved for use in patients with relapsed refractory multiple myeloma(RRMM). Anti-BCMA directed CAR-T therapy for patients with relapsed/refractory multiple myeloma (RRMM) is a promising new class of therapy, which has shown a high level of efficacy. Sequential administration of selinexor followed by CD19 CAR-T has shown enhanced efficacy in human phase II trials and animal models of human non-hodgkin lymphoma(Stadel et al., 2022). In this retrospective single institutional study, we report outcomes of patients with RRMM who were treated with Selinexor based regimen prior to apheresis for CAR-T therapy. Methods: We conducted a retrospective study on an IRB-approved protocol for all patients who were treated with Selinexor based regimen immediately prior to apheresis as a prior line of therapy at Hackensack University Medical Center between June 2015 and July 2022. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Response to CAR-T was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). Results: Between September 9, 2021, and April 3, 2023, 7 patients received CAR-T who were treated with Selinexor immediately prior to apheresis. The median age was 65.7 years (range: 55.1-77.1 years). Patients had a median of 6 (range: 4-10) lines of therapy (LOT) prior to CAR-T. 5 out of the 7 patients had double hit myeloma (all 5 with 17p and one other high risk). Four patients were treated with selinexor, carfilzomib and dexamethasone; two patients were treated with selinexor, daratumumab and dexamethasone and one patient was treated with selinexor, pomalidomide and dexamethasone. Four patients received Idecabtagene vicleucel (ide-cel) and three patients received ciltacabtagene autoleucel (cilta-cel). ORR was 100% with all 7 pts achieving very good partial response or better (>=VGPR). 2 patients had bone marrow biopsies that confirmed MRD -ve sCR in both patients. None of the patients have progressed so far, although median follow-up is short at 5.6 months. All patients had hematologic toxicities, 4/7 with grade III anemia (57.1%), 3/7 (42.8%) with grade or higher thrombocytopenia and 4/7 (57.1%) had grade 3 neutropenia. 2 of 7 patients had prolonged cytopenia for >6 months because of pre-existing underlying diagnoses of CCUS and MDS. 5 out of 7 patients had grade 1 Cytokine release syndrome (CRS). The other two patients did not experience CRS. Time of CRS onset was variable 2-10 days. No ICANS or infectious complications were observed. Conclusions: These results suggest that sequential use of Selinexor and CART in high risk RRMM may be an effective treatment strategy to provide deep and durable responses. The findings of our study are promising although it is limited by a small sample size and short follow-up. Further investigation in a larger study and longer follow up would be important to confirm our findings.

Real-World Safety and Efficacy of Teclistamab for Patients with Heavily Pretreated Relapsed-Refractory Multiple Myeloma

Background: Teclistamab is a B-cell maturation antigen (BCMA) targeting bispecific T-cell engager approved in October of 2022 for patients with relapsed-refractory multiple myeloma (RRMM) who have received at least 4 prior lines of therapy (LOT) based on the results of the pivotal MajesTEC-1 trial. In this multicenter retrospective study, we evaluated the real-world safety and efficacy of teclistamab, highlighting patterns of utilization and outcomes, including patients who would have been considered ineligible for MajesTEC-1 trial. Methods: Five U.S. academic centers, part of the US Myeloma Innovations Research Collaborative (USMIRC), contributed data to this retrospective analysis, which included 102 patients with RRMM who received teclistamab as of 7/1/2023. Baseline characteristics were outlined by descriptive analysis. Teclistamab was administered in a step-up dosing manner as per the package insert. All patients had received at least the two step up doses and the first full dose of teclistamab. Patients received antimicrobial prophylaxis, supportive care, and toxicity management per institutional protocols. Responses to therapy including overall response rate (ORR), very good partial response (VGPR), and complete response or better (≥CR) were evaluated using the International Myeloma Working group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. The Kaplan-Meier method was used for progression free survival (PFS), duration of response (DOR), and overall survival (OS) calculation. Results: Of the 102 patients included in this analysis, 25% were non-Hispanic Black and 44% had extramedullary disease (EMD); the median number of prior LOT was 6 (range 4-17). More than 80% (83/102) of the patients would not have met the MajesTEC-1 eligibility criteria; main reasons for ineligibility included: prior BCMA-directed therapy (BDT) (55%), ECOG performance status ≥2 (28%), and baseline cytopenias: grade 3-4 anemia (26%), and grade 3-4 thrombocytopenia (20%). All patients were triple class exposed and 92% were triple class refractory, 78% were penta-class exposed and 67% were penta-class refractory. More than half of the patients (55%) were refractory to prior BDT. Baseline characteristics are summarized in Table 1. Cytokine release syndrome (CRS) was observed in 65% of patients, all of which, except one, were grade 1-2 events, while immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 15% of the patients, with three patients having grade 3-4 events. The most common grade 3-4 hematological toxicities were neutropenia (23%), leukopenia (18%), thrombocytopenia (17%), and anemia (17%). Infections occurred in 28% of the patients, half of which were characterized as severe. The vast majority (80%) of infections involved the respiratory tract and 7% of patients discontinued teclistamab permanently due to recurrent or severe infections. After a median follow up of 3.2 months, the ORR was 64% for the entire cohort; ORR was 57%, 66% and 45% for patients who were BDT-refractory, penta-refractory, or had EMD, respectively. Of those who did respond, responses were found to be deep (72% ≥VGPR; 45% ≥CR). Patients that would have been ineligible for the MajesTEC-1 trial had an ORR of 59%. Detailed responses for the groups of interest are reported separately in Table 1. The estimated 6-month PFS, DOR, and OS of the entire cohort were 38% (95% CI, 26-56), 54% (95% CI, 34-85) and 68% (95% CI, 58-80), respectively (Figure 1). No treatment-related mortality was observed, although 26% of the patients had died at the time of data cut-off, with 89% of the deaths attributed to disease progression. Conclusion: This is the largest real-world experience of the safety and efficacy of teclistamab for RRMM. Overall, teclistamab was well tolerated with no major safety concerns, despite worse performance status and cytopenias than the MajestTEC-1 trial population. Moreover, despite the increased incidence of high-risk features, including penta-refractoriness, BDT refractoriness, and presence of EMD in this heavily pre-treated RRMM patient population, early efficacy assessment of teclistamab in a real-world setting was encouraging.