Presence Of Extramedullary Disease Research Articles

Real-world outcomes of teclistamab for the treatment of relapsed/refractory multiple myeloma at UC San Diego Health: A single-institution experience.

e19504 Background: Bispecific antibodies (BsAb) are emerging as a promising class of cancer immunotherapy. Teclistamab, a BsAb targeting B-cell maturation antigen (BCMA) expressed on plasma cells, received FDA approval for the treatment of relapsed/refractory (R/R) multiple myeloma (MM) in 2022. Here we describe the real-world experience of teclistamab at a single institution. Methods: We retrospectively reviewed patients with R/R MM who received teclistamab at University of California San Diego and had at least 6 months of follow up. Baseline characteristics, efficacy outcomes, and safety outcomes were collected. Kaplan-Meier method was used to describe survival. Results: A total of 18 patients who received teclistamab between 01/01/2023 and 06/15/2023 were included in this analysis. The median age was 67 years old (range 50-83). Median prior lines of therapy was 6.5 (range 3-11). All patients had triple-refractory disease; all but one had penta-refractory disease. Approximately 44% of patients had extramedullary plasmacytomas at time of BsAb initiation; 39% had received prior BCMA therapy (2 belantamab, 5 ide-cel) before teclistamab. High-risk cytogenetics (t(4;14), t(14;16), t(14;20), Del17p, Gain1q) were characterized for 13 patients with data available. 6 had a single high-risk mutation, 4 had two, and 1 had three. Incidence of cytokine release syndrome (CRS) was 12 (67%); (4 (33%) grade 2, no grade 3-5). 6 (50%) received tocilizumab to treat CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was 2 (11%); (1 (50%) grade 2, no grade 3-5). Pain crisis occurred in 11% of patients. The incidence of infection was 67%; the majority were grade ≥ 3. The overall response rate (ORR) by IMWG criteria was 50%. All patients who responded had a very good partial response (VGPR) or better; further response data was not available due to the lack of restaging bone marrow biopsies during treatment. Median duration of response for the entire cohort was not reached. Median progression-free survival (PFS) was 12.5 months (95% CI 1.0 – not reached); median overall survival (OS) was not reached (95% CI 7.8 – not reached).Univariate analyses showed no statistically significant relationship between response and prior BCMA therapy (p=.91), response and presence of extramedullary disease (p=.31), or response and mSMART risk stratification (p=.13). Conclusions: Overall, the incidence and grades of CRS, ICANS, and infection in our cohort were similar to those observed in the phase I/II MajesTEC-1 trial. In contrast, the ORR and PFS in this study were lower compared to the MajesTEC-1 study. This difference may be due to a greater proportion of patients with high-risk cytogenetics and more aggressive disease, as depicted by the higher median prior lines of therapy and higher rates of extra-medullary plasmacytomas and triple-/penta-class refractory disease.

Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel.

7508 Background: Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy in patients with relapsed/refractory multiple myeloma (RRMM). However, outcomes in patients with extramedullary disease (EMD) remain to be better characterized. Methods: We included patients from 11 US academic centers, who were evaluated for EMD and were infused with ide-cel between May 2021 and April 2023. Patients with soft tissue or visceral lesions non-contiguous from bony lesions were classified as having true EMD, with paraskeletal disease classified as non-EMD. Disease responses were evaluated using the IMWG criteria. Time-to-event analyses were performed from the date of ide-cel infusion. Results: Among 351 patients with RRMM treated with ide-cel, 84 (24%) had EMD prior to infusion. Median follow-up for the entire cohort was 18.2 months (95% CI: 17-19.3). Baseline characteristics at ide-cel infusion for EMD and non-EMD cohorts are depicted in the table. For the EMD and non-EMD cohorts, the Day 30 objective response rates (ORR) were 58% vs. 69% (p=0.1), Day 30 ≥complete response rates were 16% vs 24% (p=0.11), the Day 90 ORR were 52% vs 82% (p<0.001), and best ORR were 58% vs 82%, respectively. The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p<0.0001) for the non-EMD cohort. The median duration of response for EMD among day 30 responders was 6.4 months (95% CI: 5.1-8.4). In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.8 (95% CI: 1.2-2.5), p<0.001] after adjusting for ECOG status, revised ISS stage, penta-drug refractoriness, elevated ferritin, prior BCMA-directed therapy and use of bridging therapy. Pattern of progression in the EMD cohort (n=68/84) included EMD site only (21%), hematologic only (22%), or both (57%), with comparable PFS for type of progression (p=0.19). The median overall survival (OS) was 14.8 months [95% CI: 9-Not reached (NR)] for EMD and 26.9 months [95% CI: 26.3 vs NR, p=0.006)] for the non-EMD group. Rates of Grade ≥2 cytokine release syndrome or neurotoxicity syndrome were comparable between the two cohorts. Conclusions: Patients with EMD demonstrate significantly inferior Day 90 ORR and presence of EMD is an independent risk factor for inferior PFS. [Table: see text]

Impact of Extraosseous Extramedullary Disease on Outcomes of Patients with Relapsed-Refractory Multiple Myeloma receiving Standard-of-Care Chimeric Antigen Receptor T-Cell Therapy

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post–ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08–3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53–4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31–0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32–0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05–4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03–7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45–34.59), post–ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09–28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23–6.17) experienced shorter OS. In contrast, post–ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17–0.79) and post–ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24–0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post–ASCT outcome prediction beyond clinical trials.

Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma.

Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

Population Pharmacokinetics (PopPK) and Exposure-Response (E-R) Analyses for Belantamab Mafodotin Monotherapy in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Enrolled in DREAMM-2 and DREAMM-3

Background: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate (ADC) with a humanized afucosylated anti-BCMA monoclonal antibody (mAb) conjugated to a cytotoxic payload (microtubule-disrupting agent monomethyl auristatin F [MMAF]) by a protease-resistant maleimidocaproyl (mc) linker. This ADC binds to BCMA and induces cell death by direct cell killing and immune-mediated mechanisms. The DREAMM-2 trial (NCT03525678) showed rapid, deep, and durable responses to single-agent belamaf in patients with RRMM. The Phase 3 DREAMM-3 trial (NCT04162210) evaluated single-agent belamaf vs. pomalidomide plus low-dose dexamethasone in patients with RRMM at second relapse or later (Weisel et al., J Clin Oncol 41, 2023 [suppl 16; abstr 8007]); DREAMM-3 did not meet its primary endpoint on superiority for progression free survival (PFS). The present analysis evaluated the PopPK of the ADC and cytotoxin cysteine-mcMMAF (cys-mcMMAF) as well as the E-R relationships for key efficacy and safety endpoints to contribute to further understanding of belamaf. Methods: Patients with RRMM were administered intravenous (IV) doses of belamaf 2.5 or 3.4 mg/kg Q3W in DREAMM-2 (n=218) and 2.5 mg/kg Q3W in DREAMM-3 (n=217). Previously built PopPK models of ADC and cys-mcMMAF were updated and used to predict individual Cycle 1 exposure measures for the E-R analyses performed on the DREAMM-3 belamaf arm only. Exposure-efficacy analyses evaluated the probability of response (PoR), PFS, and time to response (TTR). Exposure-safety analyses evaluated the probability of occurrence of adverse events of special interest such as changes in best corrected visual acuity (BCVA), grade ≥2 or ≥3 corneal events, grade ≥3 thrombocytopenia and infusion-related reactions (IRR). Logistic regression models were used to assess event probabilities, while Cox proportional-hazard models were used to assess time to event endpoints. Stepwise covariate analyses were performed. Results: The PopPK data were described well by two-compartment models with linear elimination. The ADC model included time-varying clearance and the cys-mcMMAF model included decreasing MMAF:mAb ratio after each dose. ADC clearance was reduced on average by 30% over the first 5 months on treatment. The PopPK of ADC and cys-mcMMAF were both influenced by disease-related factors (baseline concentrations of soluble BCMA [sBCMA], immunoglobulin G, and albumin), as well as body weight and to a lower extent body mass index. Mild to severe renal impairment, mild hepatic impairment, age, race (Black or Asian), or prior therapies were not found to impact the PopPK of belamaf. Cycle 1 ADC average concentrations (C avg) were inversely correlated with disease burden factors and highly correlated (r=0.97) with ADC trough concentration (C tau). In DREAMM-3, PoR and PFS were higher and longer with higher ADC exposure when evaluated independently of other covariates. In the final model, PoR and PFS were respectively lower and shorter with higher baseline sBCMA or prior anti-CD38 mAb treatment; PoR was also related to presence of extra medullary disease. TTR was not related to ADC exposure or other factors. Safety endpoints were associated with exposure. Higher ADC C avg was associated with higher probability of developing grade ≥2 or ≥3 corneal events and inversely associated with time to their onset. ADC C avg was similarly associated with changes in BCVA but with a lower intercept for BCVA-related endpoints. Baseline sBCMA was inversely associated with probability of grade ≥2 corneal events. Lower baseline platelet count (but not ADC exposure) was associated with increased probability of grade ≥3 thrombocytopenia. ADC C avg was inversely associated with probability of IRR. In addition, the observed incidence of post-treatment anti-belamaf antibodies was low (&amp;lt;1%) with no observed impact on PK, efficacy, or safety. Conclusion: PopPK and E-R analyses for DREAMM-3 demonstrated the impact of disease factors and patient characteristics on PK, efficacy, and safety endpoints following single-agent belamaf, consistent with prior results for later-line populations.

Comparative Efficacy of Ciltacabtagene Autoleucel Versus Elotuzumab, Isatuximab, and Selinexor-Based Regimens in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma with 1-3 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison

Introduction: Ciltacabtagene autoleucel (cilta-cel; Carvykti) was assessed in the phase 3 randomized controlled trial CARTITUDE-4 for adult patients with relapsed and refractory multiple myeloma (RRMM) who have received 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD), and a proteasome inhibitor (PI) and are refractory to lenalidomide. Other therapies used to treat patients with multiple myeloma who have received at least one other therapy and are lenalidomide-refractory vary by country, but broadly include doublet and triplet regimens based on daratumumab, pomalidomide, bortezomib, and carfilzomib. This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm of CARTITUDE-4 versus relevant comparators based on their target trial populations. Methods: Comparators for the matching adjusted indirect comparisons (MAICs) were identified a priori based on regimens used in the target population including; SVd, EloPd, IsaKd, DKd, DVd, Kd, Vd, Pd, and Ide-cel. PVd and DPd were not of interest given their inclusion in the CARTITUDE-4 trial. Melflufen+d, PanVd, VenVd, PCd, IxaKd, D-monotherapy, V-monotherapy, CyVd, and DVCd were not of interest for the US, EU-5, the Netherlands, and Canada. A systematic literature review identified publications of relevant clinical trials for these treatments, which were assessed for feasibility of an indirect treatment comparison. Feasibility was determined based on study design and degree of overlap with the CARTITUDE-4 population (prior LOT, lenalidomide-refractoriness, and exclusion criteria around previous therapies, i.e., prior daratumumab). We report here on comparisons vs. EloPd (ELOQUENT-3), IsaPd (ICARIA-MM), and SVd (BOSTON). Due to differences in methods for the comparisons versus ide-cel (KarMMa-3) and versus DKd, Kd, DVd, Vd, and Pd, these are reported separately. Comparison to IsaKd was not feasible due to a lack of published data in the lenalidomide-refractory subgroup (baseline characteristics and efficacy data), and key differences in exclusion criteria. Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed utilizing individual patient-level data (IPD) from patients randomized to the cilta-cel arm of CARTITUDE-4 (N=208). The eligibility criteria from each of the comparator trials were applied to the cilta-cel IPD, and outcomes for the matched population were compared against published summary data for EloPd (N=60), IsaPd (N=154), and SVd (N=195) using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted by weighting the cilta-cel data to match the reported baseline characteristics of the comparator trials in terms of refractory status, cytogenetic risk, ISS stage, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, HRs including 95% CIs were estimated using a weighted Cox proportional hazards model. Results: After adjustment, patients in the cilta-cel arm were significantly more likely to achieve an overall response than patients in EloPd or IsaPd arms, and to achieve ≥VGPR and ≥CR versus patients in all other comparators arms ( Table 1). In addition, cilta-cel was associated with a significant reduction in the risk of disease progression or death (PFS) versus all comparators, ranging from 39% (versus SVd) to 68% (versus IsaPd) ( Table 2). Conclusions: Cilta-cel demonstrated clinical benefit over EloPd, IsaPd, and SVd for response outcomes and PFS, highlighting its potential as an effective treatment option for patients with RRMM who have received at least one other therapy and are lenalidomide-refractory. These comparisons provide valuable information to contextualize the efficacy of cilta-cel in countries where treatment for these patients may be different from DPd or PVd.

Post CAR-T Peripheral Lymphocytosis and Its Kinetics Are a Potential Biomarker for Response and Immune Mediated Toxicities

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

Safety and Efficacy of a Locally Produced Novel Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) (HBI0101) for the Treatment of Relapsed and Refractory Multiple Myeloma

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CART) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM), with recent phase 3 studies showing clear advantage of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel)over standard-of-care. However, access to these commercial CART products is a major barrier, and it is estimated that only around a quarter of eligible R/R MM patients will receive CART nowadays. HBI0101 is a novel second generation optimized anti-BCMA CART with 4-1BB co-stimulatory domain, that was developed in an academic setting, at Hadassah Medical Center and Bar-Ilan University. The phase Ia study evaluating HBI0101 (NCT04720313) demonstrated a manageable safety profile and an initial high efficacy (Asherie, Haematologica 2022). Here, we present the updated results of 50 patients receiving 800x10^6 CART cells in the NCT04720313 phases 1a-b / 2. METHODS: The phase 1a study with HBI0101 which first evaluated 20 R/R MM patients with ≥3 prior lines of therapy, including a PI, IMiD and anti-CD38 antibody, revealed a dose of 800x10^6 CART cells to be safe and effective. The phase Ib and phase 2 of the study evaluated this dose infusion in 43 additional patients. Inclusion criteria were relatively permissive with minimum creatinine clearance of 20ml/min, platelet count of 30x10 9/ml, left ventricular ejection fraction of 40%, and ECOG performance status of ≤2. Lymphodepletion included fludarabine 25mg/m 2 and cyclophosphamide 250mg/m 2 on days -5 to -3 before infusion (bendamustine 90mg/m 2 and on days -4 and -3 for patients with creatinine clearance &amp;lt;30ml/min). Planned manufacturing time was 10 days. RESULTS: Of 51 patients who underwent lymphocyte apheresis, 50 (98%) were treated with 800x10^6 CART cells; 7 patients in the phase Ia cohort and 43 in the phases 1b / 2 cohorts. HBI0101 production success rate was 100%, with manufacturing time of 10 days for all patients. The median age was 65y (range 40-84). The median number of prior lines was 4 (range 3-13) and most patients (47/50, 94%) were triple refractory to PI, IMiD and anti-CD38 antibody. Twenty patients (40%) were penta-refractory and 10 (20%) were refractory to the anti-BCMA antibody drug conjugate belantamab mafodotin. Forty-six patients (92%) were refractory to the last line of therapy. Twelve patients (24%) had high risk cytogenetics (t(4:14), t(14:16) or deletion 17p); 31 (62%) when 1q gain included. Sixteen patients (32%) had extramedullary involvement at study entry. Grade 3-4 hematological toxicities were common (anemia- 62%, thrombocytopenia- 54%, neutropenia- 98%, lymphopenia- 100%). Cytokine release syndrome (CRS) occurred in 48/50 (96%)- grade 1/2- 17 patients (82%); grade 3- 7 patients (14%). Tocilizumab was used in 40/48 patients with CRS (median of 1 dose, range 1-4) and corticosteroids in 8/48. Two cases of immune effector cell associated neurotoxicity syndrome (ICANS) were observed (grade 1 and 2). Two patients developed CART-associated hemophagocytic lymphohistiocytosis syndrome (HLH). No irreversible organ toxicities or treatment related deaths occurred. The overall response rate (ORR) was 45/50 (90%), including 29 patients (58%) with complete response (CR)/stringent CR, 10 (20%) with very good partial response and 6 (12%) with partial response. Thirty-five patients (70%) achieved minimal residual disease (MRD) negativity at day +30. At a median follow-up of 11.9 months (range: 0.6-19), the median progression-free survival was 10.6 months, and the median overall survival was not reached (Figure 1). Although the presence of extra-medullary disease and prior anti-BCMA therapy correlated with worse outcome, high response rates were still observed (ORR of 98%/75% for patients without/with extra-medullary disease, respectively, and 95%/75% for patients without/with prior anti-BCMA therapy, respectively). Updated results will be communicated at the presentation time. CONCLUSION: Our findings demonstrate the manageable safety and high efficacy profiles of HBI0101 also in high-risk patients. Fast production time enabled the timely treatment of 98% of apheresed patients. These favorable data are encouraging and support decentralization of CART production at an academic setting, ensuring a sufficient CART supply in the light of the increasing demand.

Clinical Factors Associated with Cytokine Release Syndrome and Dosing Recommendations for Restarting Elranatamab Following an Interruption

BACKGROUND In the MagnetisMM-3 (NCT04649359) study, elranatamab (ELRA) administered at a dose of 76 mg once-weekly (QW) with 2 step-up priming doses of 12 mg on day 1 and 32 mg on day 4 had a manageable safety profile, with 56.3% of patients developing cytokine release syndrome (CRS) and 98.8% of events occurring with the first 3 doses. Here, we report clinical factors associated with CRS and dosing recommendations for restarting treatment after dose interruptions in patients with relapsed or refractory multiple myeloma (RRMM) undergoing treatment with ELRA. METHODS Eligible patients received ELRA subcutaneously in step-up priming doses of 12 and 32 mg on days 1 and 4 of cycle 1, respectively, followed by 76 mg of ELRA QW. CRS events were graded according to the criteria of the American Society for Transplantation and Cellular Therapy and managed according to published guidelines. Multivariable analyses were performed to identify clinical factors associated with CRS. Baseline factors (extramedullary disease by BICR, prior antibody-drug conjugate, prior CAR-T, number of prior lines of therapy [≤5, &amp;gt;5], sex, and age [continuous variable]) were included in the model for CRS after the initial dose, and only post-baseline factors (time to previous CRS and time to initial tocilizumab use) were included in the model for CRS after the second dose. A previously described population pharmacokinetic (PK) model was used to simulate different interruption scenarios and determine how long it takes for ELRA exposure to drop below the threshold associated with CRS events (Hibma J, et al. Poster presented at PAGE 31 2023 [abstract 10648]). The data used to develop this model was collected from the following open-label elranatamab trials: MagnetisMM-1 (NCT03269136; phase 1), MagnetisMM-2 (NCT04798586; phase 1), MagnetisMM-3 (NCT04649359; phase 2), and MagnetisMM-9 (NCT05014412; phase 1/2). Of 183 patients who were treated in MagnetisMM-3 with the 2 step-up priming dosing, 106 patients (57.9%) experienced CRS, 43.7% grade 1, 13.7% grade 2, and 0.5% grade 3. Tocilizumab was used to manage CRS. Of the 130 CRS events, 37 (28.5%; 20 grade 1 and 17 grade ≥2) were treated with tocilizumab, and 93 (71.5%; 82 grade 1 and 11 grade ≥2) were not. After the initial elranatamab dose, 79/183 patients had CRS. The presence of extramedullary disease was predictive of a decreased risk of CRS after the initial dose. Of the 180 who received a second elranatamab dose, 35 had CRS afterwards. In a multivariable model also adjusting for CRS after the initial dose, prior tocilizumab use was predictive of a decreased risk of CRS after the second dose. After receiving doses of 76 mg of ELRA, 16 instances of dose delays lasting &amp;gt;6 to ≤12 weeks were observed. In most of these instances (11/16; 68.8%), patients did not repeat the 32-mg step-up dose. In 5 instances, patients restarted treatment with 32 mg of ELRA. No patients experienced CRS after retreatment. For the 4 instances of dose delays lasting &amp;gt;12 weeks after a 76-mg dose, patients repeated the 32-mg step-up dose in 2 instances, and patients received &amp;gt;32 mg ELRA after the interruption in the other 2 instances, with none experiencing CRS after retreatment. With dose delays of 6-12 weeks, ELRA exposure decreases below the C max after a 32-mg dose but not less than that for the 12-mg dose. With dose delays &amp;gt;12 weeks, ELRA exposure decreases below the C max after a 12-mg dose. To minimize the risk of CRS events after dose interruptions, clinical and PK data and modeling were used to develop recommendations for restarting therapy (Figure). CONCLUSIONS Extramedullary disease and use of tocilizumab were associated with a decreased risk of CRS. Based on clinical and PK data and modeling, it is recommended that patients receiving 76 mg ELRA who then experience dose delays lasting 6-12 or &amp;gt;12 weeks should restart treatment at doses of 32 or 12 mg, respectively.

Adolescents and Young Adults with Multiple Myeloma, Kuwait Experience

Background Multiple myeloma MM is an incurable plasma cell malignancy with a median age of 65 years at diagnosis worldwide, a small number of publications were focused on young adult Multiple myeloma MM with special characteristics and clinical outcomes. Objectives To evaluate the incidence of MM among adolescent and young adults (AYA) in Kuwait aged 40 and below. Also, to describe the clinical characteristics, high risk features and treatment outcomes at the Kuwait Cancer Control Centre (KCCC). Materials &amp; Methods We collected data retrospectively from the hematological malignancy registry at KCCC and looked at AYA patients (pts) with a confirmed diagnosis of Multiple myeloma at our center from 2015 till 2022, we looked at age of onset, gender, nationality, year of myeloma diagnosis, presence of extramedullary disease, International Staging System score (ISS score), cytogenetic aberrations, induction therapy, receipts of auto-transplant and maintenance therapy. Results From 2015 till 2022, 340 patients were diagnosed with MM in Kuwait, eleven patients were found 40 years old or younger, only one was female patients, the median age was 35 years old, around a third were Kuwaiti, 73% were non-Kuwaiti of middle eastern background, 4 patients were found to have extramedullary disease at diagnosis, with advanced stage ISS III found in 3/9 pts. One patient was found with 1Q gain and the rest of the 10 patients were with negative del17p, t (4,14), t(14,16), gain1q and t(11,14). Of note, interphase FISH cytogenetic is not done with CD138 selection. Six patients were treated with RVD induction (Lenalidomide, Bortizomib, Dexamethasone), two patients treated by CTD (Cyclophosphamide, Thalidomide, Dexamethasone), one pt treated by VCD (Bortizomib,Cyclophosphamide,Dexamethasone), one patient treated by Daratumumab RVD, and one patient treated by VTD. Overall response rate (ORR) was 90.9%, (10/11) responded patients proceeded to HDCT/ASCT and all these patients went on maintenance post-transplant, two patients were lost to follow up while 9 patients still under follow up, median follow up 33 months, one pt had a relapse after transplant. Conclusion MM is an uncommon disease among AYA in Kuwait (3.2%) of all myeloma patients, with favorable durable responses in this group of patients.

Allogeneic Stem Cell Transplantation in Adolescent and Adult Patients with Acute T Cell Lymphoblastic Leukemia / Lymphoma : Single Center Experience of 143 Patients

Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/-LL) is an aggressive hematological neoplasm originates from T-cell progenitors. T-ALL and T-LL are distinguished by the presence of more or &amp;lt;20% marrow blasts, respectively. Allogeneic hematopoietic cell transplantation (SCT) is typically recommended for adults with T-ALL in second or later complete remission (CR2+), but also may be offered to patients in first CR (CR1) with high-risk features. Our center reported previously outcomes of allogeneic HCT (allo-SCT) in 53 adolescent and young adults of T-ALL ( Biol Blood Marrow Transplant. 2012;18(12):1897-1904). Patients and Methods: We analyzed the outcomes of adults (age &amp;gt;14years) with T-ALL who received allo-SCT at King Faisal Specialist Hospital and Research Center between January 1985 and September 2018. Patients eligible for allo-SCT included HR patients in CR1 and any patient in &amp;gt; CR2 or relapse. Patients in CR1 had one or more of the following HR features: WBC count at presentation &amp;gt; 100,000/mm3, residual disease in bone marrow (BM) at day 14 postinduction, central nervous system (CNS) involvement at diagnosis and the need for more than one induction regimen to achieve CR1. Full-intensity conditioning regimens were used for all patients. The majority of patients (95.1%) received cyclophosphamide 60 mg/kg once daily i.v. for 2 consecutive days (total dose, 120 mg/kg), followed by 12 Gy of fractionated total body irradiation (TBI) given in 6 fractions. Seven patients (4.9%) received busulfan 16 mg/kg (1 mg/kg per dose orally every 6 hours over 4 consecutive days) and cyclophosphamide 60 mg/kg once daily i.v. for 2 consecutive days (total dose, 120 mg/kg).Short-course methotrexate plus cyclosporine (MTX/CSA) was the GVHD prophylaxis regimen used, in all patients. Results: 143 patients underwent allo-SCT and were included in this study; some of them were referred in CR for allo- SCT after undergoing induction chemotherapy outside our institution. Median age was 20 years (range, 14-52).Majority of patients were males 116 (80.6%). Extramedullary presentation was reported in 34 patients (23.8 %) with CNS involvement in 15 patients (10.5%). For SCT outcomes, the incidence rates for relapse 27.1%, acute GVHD 45.8%, grade II-IV acute GVHD was 29.9% and that of chronic GVHD was 38.9%, extensive chronic GVHD was 21.5%. GVHD relapse free survival (GRFS) was reported in 27.1%. The majority of relapses occurred within 1 year after SCT. The cumulative incidence of relapse (CIR) at 1 year was 22.4% 95% CI (15.9 - 29.5), at 2 years was 23.8.8% 95% CI (17.2 - 31) and at 5 years was 25.9% 95% CI (19 - 33.3). Other outcomes, Hemorrhagic cystitis (HC) was noted in 9.7%, sinusoidal obstruction syndrome (SOS) 9% The mean time for overall survival (OS) was 166.77 months (95% CI = 136.54 - 197), and the median survival time was 41 months (95% CI = 15 - 266). For the CR1 group was 205.63 months (95% CI = 166.59 - 244.66). At 10 years, OS of the CR1 group was 74.44 months (95% CI = 63.67 - 85.22), and for the &amp;gt; CR2 group was 35.36 months (95% CI = 24.39 - 46.32); p= 0.0001 PFS analysis showed, the overall mean survival time for disease progression at 5 years was 33.16 months (95% CI = 28.77 - 37.54), and the median survival time was 32 months (95% CI = 12 - 55). For the CR1 group was 39.82 months (95% CI = 34.54 - 45.09), and for the &amp;gt;CR2 group was 22.83 months (95% CI = 16.02 - 29.64), p &amp;lt; 0.0001. At 10 years, PFS for the CR1 group was 74.95 months (95% CI = 63.58 - 86.31), and for the &amp;gt;CR2 group was 41.24 months (95% CI = 27.37 - 55.11) with statistically significantly difference, p &amp;lt; 0.0001. On multivariate analysis, chronic GVHD was significantly associated with a lower OS (P=0.006) and PFS (P=0.01).Disease status at SCT remained significantly associated with PFS (P=0.02),but not OS (P=0.07). The presence of extramedullary disease and CNS involvement at diagnosis had no effect on the different outcomes. Conclusions: Allo-SCT could provide better disease control for HR patients with T-ALL/LL in CR1. Dismal outcomes are reported in patients beyond CR1 with early relapses post allo-SCT are almost inevitable. Better understanding of disease's molecular background in addition to MRD applications, could help to identify more patients in CR1 status who might benefit from allo-SCT. Post SCT strategies including maintenance or pre-emptive interventions might be needed to improve SCT outcomes for T-ALL

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.

Efficacy of Carvykti in CARTITUDE-4 Versus Other Conventional Treatment Regimens for Lenalidomide-Refractory Multiple Myeloma Patients Using Inverse Probability of Treatment Weighting

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) who have received one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. CARTITUDE-4 demonstrated superiority of cilta-cel over PVd and DPd on progression-free survival (PFS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or stringent CR]). Other available therapies for the treatment of this patient population where individual patient data was available for analysis include: daratumumab in combination with bortezomib and dexamethasone (DVd), bortezomib in combination with dexamethasone (Vd), carfilzomib in combination with daratumumab and dexamethasone (DKd) or dexamethasone alone (Kd), and pomalidomide in combination with dexamethasone (Pd). This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm (i.e., patients apheresed or infused with cilta-cel) in CARTITUDE-4 vs each of these regimens in the same target population. Methods: Individual patient data were collected from the CARTITUDE-4 (cilta-cel), CASTOR (DVd and Vd), CANDOR (DKd and Kd), and APOLLO (Pd) RCTs. Patients who met CARTITUDE-4 eligibility criteria were identified from the above mentioned RCTs. As no patients in the comparative trials had prior treatment with anti-CD38, patients with prior exposure to anti-CD38 therapies in the cilta-cel cohort were excluded. Key prognostic baseline covariates including refractory status, ISS stage, presence of extramedullary disease, and time to progression on prior line, were adjusted for using inverse probability of treatment weighting (IPTW), with average treatment effect in the treated weights. Differences in baseline characteristics were assessed using standardized mean differences. PFS, ORR, VGPR or better, and CR or better were compared between patients in the cilta-cel arm and the comparator regimens. Relative efficacy of cilta-cel vs comparator regimens were estimated with hazard ratios (HRs) and 95% confidence intervals (CIs) from weighted Cox proportional hazards models for PFS, and response rate ratios (RRs) and 95% CIs from weighted logistic regression models for ORR, VGPR or better, and CR or better. Sensitivity analyses using alternative statistical approaches and including additional covariates were explored. Results: After the exclusion of 53 patients with prior exposure to an anti-CD38 therapy, 155 patients in the cilta-cel arm remained. Across the comparative trials, 44 patients treated with DVd, 46 patients treated with Vd, 98 patients treated with DKd, 46 patients treated with Kd, and 92 patients treated with Pd met the inclusion criteria of CARTITUDE-4. Baseline covariates were similar across the cohorts after IPTW. Patients randomized to the cilta-cel arm showed significant improvements in PFS (adjusted HRs from 0.11 vs Vd to 0.51 vs DKd), VGPR or better (adjusted RRs from 1.51 vs DKd to 5.13 vs Vd), and CR or better rate (adjusted RRs from 2.90 vs DKd to 35.24 vs Pd) (Table). Improvements in ORR were also observed against all comparator regimens (adjusted RRs from 1.22 vs DKd to 1.90 vs Pd), though were marginally not statistically significant vs DVd and Kd. Treatment with DKd consistently yielded the best results out of all comparator regimens, but results were still in favor of cilta-cel. Results of cilta-cel benefit were consistent across sensitivity analyses, yielding adjusted HRs below 1.00 and RRs above 1.00 in all cases against other comparator regimens. Conclusions: Data from CARTITUDE-4 and these analyses demonstrate the benefit of cilta-cel over additional regimens commonly used in clinical practice, highlighting its potential to become a new standard of care option for patients with RRMM, who have received one to three prior lines(s) of therapy, including an IMiD and a PI, and who are refractory to lenalidomide. These comparisons provide valuable information to contextualize the efficacy of CARVYKTI in countries where standard of care may be different from DPd/PVd.

Teclistamab in Relapsed Refractory Multiple Myeloma: Multi-Institutional Real-World Study

Introduction: Teclistamab is the first BCMA-targeting bispecific antibody (bsAb) that has received FDA approval in RRMM based on the MajesTEC-1 study, which showed a single-agent ORR of 63%. In this report, we present the safety and efficacy of teclistamab since its approval in a real-world multi-institutional cohort. Methods: All consecutive patients with RRMM treated with at least one dose of standard-of-care teclistamab at 5 academic centers in the US were included in this study. Data including patient demographics, disease, and treatment characteristics at the most recent assessment before starting treatment were retrospectively collected. Results: A total of 89 patients were treated across 5 academic institutions. The median age was 68 years (range: 37-89), with 48% (n=43) females. Among the patients, 30% (n=27) were Black, 2.2% (n=2) Asian and 12% (n=11) were other minorities. High-risk cytogenetic profile was observed in 65% (n=49/75) of the patients. About 48% (n=39) of the patients exhibited EMD on PET-CT. Four patients had CNS involvement, 1 had pPCL, and 3 had concomitant AL amyloidosis. Furthermore, 98% (n=87) of the patients had triple-class refractory MM, while 85% (n=76) had penta-refractory MM. The median prior lines of therapy were 6 ( range: 3-13) and 80% (n=71) of patients received a prior ASCT. About 37% (n=33) had received prior BCMA-directed therapy, which included BCMA CAR-T in 17, BCMA BsAb in 5, and Belantamab mafadotin in 11 patients . Table 1 compares this patient cohort with the MajesTEC-1 study population. Grade 1/2 CRS was observed in 48% (n=43) of patients, while 3% (n=3) experienced grade 4 CRS. Grade 1/2 ICANS was noted in 7% (n=6) of patients, grade 3/4 in 4.4% (n=4), and grade 5 in 1 patient. Steroids were utilized in 22% (n=16) of patients, while tocilizumab was administered in 44% (n=32) of patients. Notably, step-up dosing of teclistamab was administered entirely in the outpatient setting in 9% (n=8) of patients. For the remaining, inpatient step-up dosing was administered, and the median hospitalization duration was 10 days. At a median follow-up of 1.35 months (range: 0.16-4.38), the ORR among the evaluable patients was 55%, with rates of ≥ VGPR and PR at 37% (n=28) and 18% (n=13), respectively. The 3-month PFS rate was 54% (95% CI: 43%, 69%), while the 3-month OS rate was 80% (95% CI: 71%, 90%). Multivariate analysis did not reveal any significant associations between disease response and the following factors: number of prior lines of therapy (HR 1.03, 95% CI 0.76-1.42), baseline lymphocyte counts (HR 0.98, 95% CI 0.47-2.02), high-risk cytogenetics (HR 0.38, 95% CI 0.09-1.39) and the presence of extramedullary disease (HR 0.56, 95% CI 0.15-1.93). There was a trend towards worse ORR in patients with prior exposure to BCMA targeting agents, albeit not quite significant (HR 0.28, 95% CI 0.07-1.04, p=0.065). There were 61 infectious events with 50%, 45% and 5% of these being viral, bacterial, and fungal infections, respectively. The most common sources of infections were upper respiratory tract infections/pneumonias (33%), blood borne infections including bacteremia and viremia (27%) and urinary tract infections (11%). The cumulative incidence of any infection at 3 months was 55% and grade 3/4 infections were seen in 55% (n= 54) of cases. There was one grade 5 infection noted in this study due to COVID 19 pneumonia. Primary IVIG and PJP prophylaxis were used in 40% (n=34) and 51% (n=43) of patients, respectively and the use of such was associated with a significant reduction of infectious events (26/51 [51%] of any infectious event for no IVIG use vs 13/34 [38%] for IVIG use, p= 0.015). The results will be updated with longer follow-up at the meeting. Conclusion : In this large real-world, multi-institutional study including a diverse cohort of heavily pretreated patients with triple-class and penta-refractory MM, including approximately 40% with prior BCMA exposure, teclistamab demonstrated a respectable ORR of 55% with ≥ VGPR in 37% of cases. The incidence of Grade 3 or higher infections at 3 months remained high at 56%, however the use of prophylactic measures, including primary IVIG prophylaxis was associated with a significant reduction of all infections and should be strongly considered in patients receiving teclistamab.

Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Therapy in High-Risk Newly Diagnosed Multiple Myeloma

Background: Carfilzomib, lenalidomide and dexamethasone (KRd) has been shown to be an effective induction regimen for newly diagnosed myeloma (NDMM), particularly in myeloma with high-risk (HR) features in the FORTE trial (Mina et al, Lancet Onc 2023). Here, we present a retrospective analysis in patients with HR NDMM in a real-world population from two high-volume centers, highlighting efficacy and survival outcomes in high-risk subgroups to gain a better understanding of the utility of this regimen in clinical practice. Methods: We conducted a retrospective study of patients with HR NDMM treated with KRd at Memorial Sloan Kettering (MSK) and Winship Cancer Institute from 1/1/2015 to 9/30/22. Cutoff date for analysis was 12/31/2022. HR was defined as the presence of high-risk cytogenetic abnormalities (HRCA) including +1q, del(1p), t(4;14), t(14;16), t(14;20), and/or del(17p), circulating plasma cells (cPC) ≥5%, extramedullary disease (EMD), and/or complex cytogenetics by conventional cytogenetics. Patients who received ≤1 prior cycle of a different MM regimen were included. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. Discrete patient characteristics were summarized by frequency (percentage) and continuous characteristics were summarized by median (Interquartile Range, IQR). Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier method. Association between time to event outcomes and patient's characteristics were determined by log-rank test. Univariate Cox proportional hazard model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: We identified 179 consecutive NDMM patients with HR features treated with KRd at MSK (N=106) and Winship Cancer Institute (N=73). Baseline patient characteristics are listed in Table 1. The median age was 62 (IQR, 55-68) and 28% of patients were Black. There were 45 (25%), 76 (42%), 47 (26%), and 11 (6%) patients with 0, 1, 2, 3+ HRCA, respectively. A median of 5 (IQR 4-6) cycles were administered. At data cutoff, 70% of patients received upfront autologous stem cell transplant (ASCT). Best overall response rate (ORR) by the end of KRd induction was 94% for 178 response-evaluable patients, including 39% with ≥complete response (CR) and 78% with ≥very good partial response (VGPR). After a median follow-up of 41.9 (95% CI 39-45.6) months, the median PFS (mPFS) was 78.2 months (95% CI 52.5-not reached [NR]), and 2-year estimated PFS was 79% (73%-85%). Median OS (mOS) was not reached, and 2-year OS was 92% (95%CI 89%-97%). For HR subgroups based on the number of HRCA present, mPFS was 78.2 (95% CI 40.1-NR), 65.2 (43.4-NR), 55.9 (44.9-NR), and 17.5 (8.78-NR) months for patients with 0, 1, 2, 3+ HRCA, respectively, with 2-year PFS of 83% (95% CI, 73%-95%), 82% (74%-92%), 78% (67%-91%), and 46% (24%-87%), respectively (P=0.35). Median OS was NR for patients with 0, 1, and 2 HRCA and was 58.2 months (95% CI 38.8-NR) for patients with 3+ HRCA with 2-year OS of 93% (95% CI, 86%-100%), 96% (91%-100%), 89% (81%-99%), and 81% (60%-100%), respectively (P=0.13). In univariable analysis, lack of t(14;16) (HR 0.32, 95%CI 0.11-0.95; P=0.03), White race (HR 0.38, 95%CI 0.17-0.84; P=0.02), presence of ≤2 HRCA (HR 0.31, 95%CI 0.11-0.92; P=0.04) were associated with longer OS in this cohort of HR-NDMM patients treated with KRd induction. Multivariable analysis for clinical variables, including specific HRCA, number of HRCA present, age, gender, race, R-ISS stage, presence of EMD, presence of cPCs, cardiac history, and upfront ASCT did not demonstrate any single variable was a significant predictor of progression or death. Conclusion: For this real-world patient population, KRd induction was associated with high response rates and promising outcomes with best ORR of 94% and mPFS of 6.5 years for patients with high-risk newly diagnosed multiple myeloma consistent with FORTE trial data. PFS did not significantly differ among HR patients with 0, 1, 2, 3+ HRCA although mPFS for patients with 3+ HRCA was only 17.5 months. Data with maintenance therapy and longer follow-up outcomes will be presented at the meeting.

Real-World Analysis of Teclistamab in 115 RRMM Patients from Germany

Background Bispecific antibodies and CAR-T cells are currently changing the treatment landscape of relapsed and refractory multiple myeloma (RRMM), having shown high response rates and durable remissions of more than a year in clinical trials. However, some discrepancies to these results have been observed lately, with lower median progression free survival (PFS) and overall survival (OS) in the real-world setting for idecabtagene vicleucel (ide-cel), possibly related to strict entry criteria of the study and known general benefits for patients participating in clinical trials regardless of study arm allocation. Whether this also holds true for Teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody approved for treatment of RRMM in 2022 in several countries, has yet to be determined. Therefore, we thought to assess Teclistamab efficacy and tolerability in the real-world setting. Methods Data of 115 patients with RRMM treated with Teclistamab at 18 different German centers from July 2022 to July 2023 were retrospectively collected and analyzed. The patients had received at least one full treatment dose of Teclistamab. Responses were evaluated in accordance with the IMWG response criteria; in addition, near complete response was defined as serological complete remission lacking bone marrow assessment, as this was not always part of clinical routine. In non-secretory disease, response evaluation was based on radiological criteria. Kaplan-Meier methods were applied for time-to-event-analyses. For comparison of survival among groups, the log-rank test and Cox regression analysis were used. For comparison of response rates among groups, the Chi square test was applied. Results The included 115 patients (49 female, 66 male with a median age of 66.0 years) had a median history of MM diagnosis of 6.5 years and were heavily pretreated with a median of 6 (range 3-14) prior lines of therapy. The majority of patients had triple-class (91.3%) or even penta-drug (58.3%) refractory disease. 35.6% (41/115) had received BCMA-directed pretreatment, among them 20 with ide-cel, 21 with belantamab mafodotin and single patients with both or a BCMA-directed study medication. Cytogenetic high-risk features defined as del(17p), t(4;14) and/or t(14;16) and extramedullary disease (EMD) were present in 38.0% and 37.2% of patients, respectively. Around one third of patients had high disease burden with bone marrow infiltration ≥60% (37.0%) or ISS 3 (35.2%) in the latest assessment before initiation of Teclistamab. Overall, a substantial proportion of 40.9% of the treated patients would not have met selected inclusion criteria of the MAJESTEC-1 trial like measurable disease, stable hematopoiesis and kidney function. With median times to response and best response of 4.3 weeks and 8.0 weeks, we observed an ORR, defined as partial remission or better, of 56.8%. 20.9% of all patients reached a near complete or complete response. With a median follow-up of 3.9 months, median PFS was 8.7 months. Median duration of response and median OS were not reached. In the group of patients with BCMA-directed pretreatment, the ORR of belantamab-pretreated patients (70%) was comparable to that in anti-BCMA naïve patients (60.0%), whereas ide-cel pretreated patients showed a significantly lower ORR of 27.8%. Interestingly, PFS did not differ significantly between ide-cel pretreated and ide-cel naïve patients. In further subgroup analyses, the presence of EMD and an ISS of 3 were associated with inferior ORR and PFS in univariable and multivariable analysis. Safety was similar to the experience in MAJESTEC-1. 60.0% of patients developed CRS and 6.9% neurotoxicity with grade 3 or 4 events in 1.7% and 0.9% of patients, respectively. Tocilizumab was administered in 25.2% and dexamethasone in 15.7% of patients. Infections occurred in 49.6% of patients, nearly half of them requiring hospitalization. 53.9% experienced grade 3 or 4 cytopenia according to CTCAE during treatment. Conclusions With an ORR of 56.8% in all patients and 60.0% in anti-BCMA naive patients, Teclistamab showed a similar ORR in the real-world setting to that observed in the MAJESTEC-1 trial. PFS was slightly lower, but our patient collective comprised higher proportions of patients with high risk disease, extramedullary disease, high disease burden, hematopoietic or renal impairment.

Comparative Efficacy of Ciltacabtagene Autoleucel Versus Idecabtagene Vicleucel in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma Previously Treated with 2-4 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison

Introduction: Two novel B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) therapies, ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma), were recently developed and approved in 2022 and 2021, respectively, for heavily pre-treated relapsed/refractory multiple myeloma (RRMM) based on the CARTITUDE-1 and KarMMa studies. A previous comparison of these therapies in triple-class exposed patients demonstrated improved efficacy with cilta-cel versus ide-cel (Martin T, et al. Curr Med Res Opin. 2023;39(1):81-89). More recently, the efficacy and safety of these CAR-Ts were demonstrated earlier in the treatment pathway in lenalidomide-refractory, proteasome inhibitor (PI)-exposed patients with 1-3 prior line(s) of treatment (LOT; cilta-cel; CARTITUDE-4), and in triple-class exposed patients with 2-4 prior LOT (ide-cel; KarMMa-3). In the absence of a head-to-head comparison of these two therapies, an unanchored matching-adjusted indirect comparison (MAIC) was used to estimate their relative efficacy using data from CARTITUDE-4, CARTITUDE-1, and KarMMa-3. Methods: While KarMMa-3 and CARTITUDE-4 both included DPd in the physician's choice control arm, there is no published data on this subgroup from KarMMa-3. As such, an unanchored MAIC was performed utilizing individual patient-level data (IPD) from 245 patients who received cilta-cel; 208 patients from CARTITUDE-4 who had received 1-3 prior LOT and 37 patients from CARTITUDE-1 who had received 3-4 prior LOT. From these data, cilta-cel patients who fulfilled the inclusion criteria from KarMMa-3 (2-4 prior LOT and triple-class exposed) were selected, and their outcomes were compared against published summary data for ide-cel (N=254) from KarMMa-3 using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted for by weighting the cilta-cel IPD to match the reported baseline characteristics of KarMMa-3 in terms of refractory status, ISS stage, time to progression on prior LOT, cytogenetic risk, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, the hazard ratio (HR) with 95% CIs for cilta-cel versus ide-cel was estimated using a weighted Cox proportional hazards model. Results: After applying the KarMMa-3 inclusion and exclusion criteria to the CARTITUDE-1 and CARTITUDE-4 IPD (excluding patients with only 1 prior LOT or no prior daratumumab), 36 patients and 49 patients were included from the cilta-cel trials, respectively. After adjustment, patients in the cilta-cel group (effective sample size [ESS]=46) were significantly more likely to achieve an overall response (RR: 1.18 [95% CI: 1.04, 1.33]; p=0.0404), and to reach deeper levels of response as demonstrated by ≥VGPR (RR: 1.34 [95% CI: 1.16, 1.56]; p=0.0027), and ≥CR (RR: 1.91 [95% CI: 1.56, 2.34]; p&amp;lt;0.0001) compared to patients in the ide-cel group ( Table). In addition, a statistically significant reduction of 49% in the risk of disease progression or death was observed with cilta-cel versus ide-cel (HR: 0.51 [95% CI: 0.31, 0.84]; p=0.0078; Figure). Conclusions: This unanchored MAIC showed that cilta-cel provides clinical benefit over ide-cel across response outcomes and PFS for patients with triple-class exposed RRMM treated with 2-4 prior LOT. These results are consistent with the previous comparison in later line, triple-class exposed patients, continuing to highlight the value of cilta-cel for these patients. Furthermore, these comparisons provide valuable information to contextualize the efficacy of cilta-cel compared to other available CAR-Ts for multiple myeloma.

A Novel Composite Endpoint of Toxicity- and Progression-Free Survival after B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma

Introduction: BCMA-directed chimeric antigen receptor T-cell therapy (CAR T), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), are approved for patients with relapsed and/or refractory (R/R) multiple myeloma (MM). Pivotal KaRMMA and CARTITUDE-1 trials as well as real-world data demonstrated heterogeneity in toxicity and efficacy between ide-cel and cilta-cel. To account for such differences, we have established a novel composite endpoint of toxicity-free, progression-free survival within 3 months (TPFS3) after anti-BCMA CAR T therapy. We also studied factors associated with TPFS3 across ide-cel and cilta-cel and the impact of TPFS3 on overall survival (OS) after CAR T. Methods: We analyzed a retrospective cohort of 133 consecutive recipients of ide-cel or cilta-cel at Moffitt Cancer Center (05/2021-03/2023). TPFS3 was defined as absence of severe (Grade≥3) cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenia(s), myeloma progression/stable disease (PD/SD), and non-relapse mortality (NRM) within 3 months after CAR-T infusion. CRS and ICANS were graded according to ASTCT Consensus grading. Cytopenias were graded according to CTCAE v5.0 and defined as two (or more) timepoint uni- or multilineage cytopenia, including any Grade≥2 cytopenia at post-CAR T Day 30 deepening to at least Grade≥3 at Day 60 and/or Day 90. Factors associated with TPFS3 were assessed via multivariate logistic regression analysis (MVA). Landmark Cox survival analysis at the 3-month timepoint examined the impact of TPFS3 on subsequent overall survival (OS). All analyses were performed using SAS and R. Results: In total, 48.1% (N= 64; median age=66 years [range, 45-82]; male=44%) of the patients were alive, toxicity- and progression-free by 3 months after CAR T infusion. TPFS3 components included PD/SD (N=30, 43.5%), severe cytopenias (N=26, 37.7%), ICANS (N=8, 11.6%), CRS (N=3, 4.3%), and NRM (N=2, 2.9%) (Figure 1A). In the univariate analysis, TPFS3 patients differed from the rest of the cohort according to lower marrow burden ( p=0.025), revised international staging system (R-ISS) (I/II vs III; p=0.015), CRP ( p=0.019) and ferritin ( p=0.002) levels at lymphodepletion (LD). The use of ide-cel (N=109) vs cilta-cel (N=24) was not significantly associated with TPFS3 ( p=0.119). In the MVA logistic regression, lower ferritin level (median cut off=228 ng/mL) at LD was associated with TPFS3 (odds ratio [OR]=0.37 [95%CI, 0.18-0.78], p=0.008] after adjusting for age, myeloma marrow burden, presence of extramedullary disease, R-ISS, CAR T product (all p&amp;gt;0.1), and CRP (median cut off=0.41mg/dL) at LD (OR=0.51 for lower vs higher, [95%CI, 0.25-1.05], p=0.069) included in the final model together with ferritin. In the landmark Cox survival analysis at 3 months, TPFS3 was associated with 6.54-fold superior OS (hazard ratio [HR]=0.15, 95%CI 0.05-0.52, p=0.003) (Figure 1B) after adjustment for potential confounders (age, gender, CRP, CAR-T product, marrow burden, R-ISS, extramedullary disease; all p&amp;gt;0.1). Other prognostic risks associated with inferior OS in the final model of the landmark analysis included the use of bridging therapy (HR=3.98 [95%CI, 1.30-12.20], p=0.016), ECOG≥2 at LD (HR=4.53 [95%CI, 1.57-13.07], p=0.005) and higher ferritin level at LD (HR=2.60 [95%CI, 0.95-7.13], p=0.063). Conclusions: We found that 48.1% of anti-BCMA CAR T recipients with R/R MM were alive and free of TPFS3-defining events. Myeloma response failure, cytopenias and severe ICANS were the top leading components of TPFS3 which was best predicted by ferritin level at LD. TPFS3 independently predicted long-term OS. Thus, TPFS3 may serve as an ideal composite safety and efficacy endpoint in future myeloma trials with BCMA-directed CAR T.

Real World Outcomes with Idecabtagene Vicleucel (Ide-Cel) CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma

Introduction: Idecabtagene vicleucel (ide-cel) was the first FDA approved BCMA targeted CAR-T cell therapy for the treatment of relapsed/refractory multiple myeloma (RRMM). However, clinical trials are highly selective with stringent eligibility criteria. The objective of this study was to evaluate the safety and efficacy of standard of care ide-cel. Methods: Patients treated with ide-cel were reported to the CIBMTR registry for long-term follow up of safety and efficacy outcomes. The current analysis includes the first 603 adult patients who received infusion with commercial ide-cel for the treatment of RRMM, with at least one follow-up form reported. Patients treated on investigational clinical trials or who received non-conforming products were excluded. Multivariate analysis was done using Cox regression. Results: Median follow-up of the 603 patients is 6.6 months, with updated follow up to be presented at the meeting. As shown in Table 1a median age of patients was 65 years, 26% (n=157) were ≥70 years old and 59% (n=354) were male. Black and Hispanic patients comprised 13% (n=77) and 7% (n=42) of the cohort, respectively; 23% (n=137) had Karnofsky performance status &amp;lt;80%, 75% (n=451) had ≥ 1 significant comorbidity and 13% (n=77) had platelets &amp;lt;50,000/µL. Patients for whom data on prior lines of therapy (LoT) were documented (n=470), the median prior LoT was 7 (4-21), 36% (n=217) had penta-refractory disease and 5% (n=28) had received prior-BCMA directed CAR T cell therapy. Data on the use of other BCMA targeting agents are being gathered. 17% (56/331 with PET-CT data) of patients had extramedullary disease (EMD) and 1.5% (n=9) had plasma cell leukemia. High risk cytogenetics [del17p, t(4;14), t(14;16) and/or t(14;20)] were present in 23% (n=141/523) and 45% (n=269/523) when including abnormalities of 1q (ab1q). 36% (n=101/283) of patients had ISS II and 16% (n=46/283) had ISS stage III disease. Lymphodepletion regimen was fludarabine + cyclophosphamide in 95% (n=574) of patients. All patients received ide-cel dose of 300-460 million CAR-T cells, with dose of &amp;gt; 400 million in 56% of patients. Cytokine release syndrome (CRS) was seen in 81% (n=490) of patients (grade ≥3: 3%), with median time to onset being 2 days. Neurotoxicity was seen in 27% (n=164) of patients (grade ≥3: 4%), with median time to onset being 2 days. Prolonged neutropenia (defined as non-recovery of ANC ≥ 500/uL by day 30) and thrombocytopenia (non-recovery of platelets ≥ 20,000/uL by day 30) was seen in 13% (n=81) and 25% (n=148) of patients, respectively. Hemophagocytic Lymphohistiocytosis-like syndrome was seen in 1% (n=6) and tumor lysis syndrome in 1.5% (n=9) of patients. Clinically significant infections were seen in 42% (n=252) of patients (bacterial: 22%, viral: 23%, fungal: 2%). Second malignancies were seen in 4.5% (n=27) of patients, including AML/MDS in 5 patients. Table 1b shows multivariate analysis for CRS and neurotoxicity. Risk factors associated with higher likelihood of grade &amp;gt;2 CRS were age ≥ 70, female sex and baseline platelets &amp;lt; 50,000/uL. Similarly, higher risk of neurotoxicity was seen with older age, high-risk cytogenetics, lower performance status and platelets &amp;lt; 50,000/uL. Overall response rate was 71% (n=421), ≥ very good partial response rate was 53% (n=319) and ≥ complete response (CR) rate was 27% (n=162). On multivariate analysis for response, presence of EMD, CAR-T cell dose ≤ 400 million, penta-refractory disease and lower performance status were associated with lower likelihood of CR. Estimated progression free survival (PFS) at 6 months was 62% (95% CI: 58-66%) and overall survival (OS) at 6 months was 82% (95% CI, 79-85%). At last follow-up, 26% of patients have died, majority due to disease progression (70%, n=108); causes of death in the remaining 47 patients were infection (n=15), CRS (n=1), neurotoxicity (n=2), tumor lysis (n=1), organ failure (n=7), second cancer (n=5), intracranial hemorrhage (n=3) and other (n=13). Conclusion: This is the largest real-world study of ide-cel CAR-T cell therapy in patients with RRMM. We observed a favorable safety and efficacy profile in this real-world population, despite a very heavily pre-treated population and large proportion of patients having co-morbidities that would have made them ineligible for the KarMMa clinical trial. These results further support ide-cel as a therapeutic option for a broad, real-world population of patients with RRMM.