Relapsed/refractory Multiple Myeloma Pts Research Articles

Abstract CT071: Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy

Abstract Introduction: Despite therapeutic advances, multiple myeloma remains incurable. BCMA targeting immunotherapies, such as bispecific T-cell engagers (TCE) and autologous CAR-T provide high response rates, but relapses are common. Autologous CAR-T are logistically challenging due to the need for apheresis, prolonged manufacturing and occasional manufacturing failures. Importantly, pts who have progressed after a prior BCMA targeting immunotherapy are an emerging area of high unmet need. Emerging data indicate that autologous CAR-T have lower clinical activity in pts ho have progressed on TCE. Methods: P-BCMA-ALLO1 is an allogeneic CAR-T therapy manufactured from healthy donor T-cells available “off-the-shelf” and being evaluated in a phase 1 clinical trial (P-BCMA-ALLO1-001) in RRMM pts. This primary objective is to determine the maximum tolerated dose of P-BCMA-ALLO1, and the key secondary objective is to investigate the anti-myeloma activity. The pts must have progressed on a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody. The study allows enrollment of pts who have received prior BCMA targeting therapy. The study is exploring escalating P-BCMA-ALLO1 doses and several different lymphodepletion chemotherapy (LD) regimens. Here we report the safety and early efficacy results for the 5 pts who were treated with P-BCMA-ALLO1 after having progressed on BCMA targeting CAR-T, TCE or both. These pts were treated in arms P1 (LD: cyclophosphamide (cy) 500 mg/m2 + fludarabine (flu) 30 mg/m2 X 3 days) or arm P2 (LD: cy 1000 mg/m2 + flu 30 mg/m2 X 3 days) at a P-BCMA-ALLO1 dose of > 2 X 106 to <6 X 106 cells/kg. Results: The median pt age was 62 years and median prior lines of therapy was 10. Three pts were treated in arm P2 and 2 in arm P1. Two pts had received prior teclistamab, 2 had received prior CAR-T and 1 had received prior teclistamab and CAR-T. P-BCMA-ALLO1 was well tolerated with no dose limiting toxicities or graft vs. host disease. Three of the five pts developed cytokine release syndrome (all grade (G) 2) and one developed G2 immune effector cell neurotoxicity syndrome. Three of the five pts (60%) achieved clinical responses with all three achieving the best response of very good partial response. The two non-responders had previously received and failed to achieve clinical response with teclistamab. One pt who had previously received both teclistamab and CAR-T achieved VGPR. Conclusion: In conclusion, P-BCMA-ALLO1 is an allogeneic CAR-T that is available “on-demand” with activity in RRMM pts who have progressed following prior BCMA targeted CAR-T and TCE. We believe this is the first such report of an allogeneic CAR-T showing clinical activity in such a pt population with high unmet need. Enrollment is continuing and updated data will be presented at the meeting. Citation Format: Bhagirathbhai Dholaria, Leyla Shune, Andrew Kin, Katherine McArthur, Jeff D. Eskew, Christopher E. Martin, Sabrina Haag, Joanne McCaigue, Hamid Namini, Sam DePrimo, Stacey Cranert, Julia Coronella, Devon Shedlock, Rajesh Belani. Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT071.

A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1. We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high-risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)-exposed (including both Len-sensitive and Len-refractory pts), and 22% were Len-refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non-hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1-2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow-up of 38 m, median PFS (mPFS) was 16 m and the 1-year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len-naïve (NR), age ≥70 (20 m). In pts exposed to Len, non-refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len-refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len-sensitive, independent of age, and cytogenetic risk.

Clinical Significance of Measurable Residual Disease (MRD) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Chimeric Antigen Receptor (CAR) T Cells and T-Cell Engagers (TCE)

Clinical Significance of Measurable Residual Disease (MRD) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Chimeric Antigen Receptor (CAR) T Cells and T-Cell Engagers (TCE)

A Phase II Multicenter Clinical Trial Assessing the Safety and Efficacy of Ixazomib, Pomalidomide and Dexamethasone Combination As Second or Third-Line Treatment for Triple-Class Exposed Patients with Relapsed and Refractory Multiple Myeloma (iPod-790 Trial)

Introduction: Despite significant improvement in the outcomes of early treatment lines in myeloma, most patients (Pts) invariably relapse. As triple and quadruple regimens are being introduced at the upfront setting, many Pts are either triple-class exposed or triple-class refractory (TCE/TCR) early in their disease course. Although novel immunotherapies are emerging with impressive efficacy among TCE/TCR myeloma Pts, their use is currently limited due to potential toxicities, costs and logistic constraints. We report the outcomes of the IPoD-790 clinical trial (NCT04790474), an all-oral regimen: ixazomib (IXA), pomalidomide (POM) and dexamethasone (DEX) (IPd) combination, in Pts with relapsed refractory multiple myeloma (RRMM) who progressed after bortezomib (BTZ), lenalidomide (LEN) and daratumumab (DARA) therapies. Methods: A phase 2, investigator initiated, open-label, single-arm, prospective, multicenter study evaluating the safety, tolerability and efficacy of IPd as a second or third-line combination treatment for TCE RRMM Pts. Pts receive IXA: 3 mg days (d) 1,4,8,11 of 21-d Cycles (Cy) 1-3; 4mg d 1,8,15 of 28-d Cy 4-24. POM 4mg: d 1-14 Cy 1-3; d 1-21 Cy 4-24. DEX 20mg: d 1,2,8,9,15,16 Cy 1-3; d 1,2,8,9,15,16,22,23 Cy 4-24. Treatment continues for 24 cycles, or until disease progression (PD) or unacceptable toxicity (the earliest of the three). After completion of 24 treatment cycles, Pts continue POM DEX as standard of care. The primary endpoint is progression free survival (PFS) according to IMWG criteria. Results: Fifty-five (out of the 60 Pts planned) were enrolled; we report data on 46 Pts who had their first dose between March 2021 and April 2023, further data will be presented at the meeting. The median age was 72 (range: 53-88); 18 (39%) were ≥75 years old; 59% were male, ISS was I/II/II for 48% / 25% and 28% respectively; 59% had high risk FISH cytogenetics (t(4:14), t(14:16), +1q21, del17p) with 14% double-hit. Nine percent had extramedullary disease at study enrollment. Exposure rates to BTZ, LEN and DARA were 100%, 98% and 96%, respectively. Forty-one percent had undergone autologous bone marrow transplantation. Refractoriness rates to BTZ, LEN and DARA were 57%, 91% and 65%, respectively. Thirty-seven percent were TCR. At data cutoff date of 15-Jun-2023, the median follow-up time was 10.4 [95% CI 7.6-13.2] months. Ninety-three percent of the Pts had at least one treatment emergent adverse event (TEAE) and 65% had a TEAE grade 3 or 4. Common (≥ 10%) TEAEs include neutropenia 35% (28% Gr 3 or 4), pneumonia 24% (17% Gr 3 or 4), thrombocytopenia 22% (15% Gr 3 or 4), back pain 22% (2% Gr 3 or 4), asthenia 20% (0% Gr 3 or 4), diarrhea 20% (0% Gr 3 or 4), peripheral edema 20% (2% Gr 3 or 4), COVID19 infection 15% (2% Gr 3 or 4 ), anemia 13% (2% Gr 3 or 4), acute kidney injury (AKI) 13% (7% Gr 3 or 4), rash 13% (0% Gr 3 or 4). At data cut-off date, 31 Pts (67%) discontinued the study treatment; 20 (43%) due to PD, 7 (15%) due to adverse events (including 3 patients with pneumonia, and 1 patient each with COVID19 infection, campylobacter gastroenteritis, upper gastrointestinal bleeding and AKI) and 4 (9%) died (2 cases of pneumonia, 1 COVID 19 infection and 1 cerebro-vascular accident). Overall response rate was 59% (27/46); 8 Pts (17%) achieved complete or very good partial response (CR/VGPR), 19 Pts (41%) achieved partial response (PR) and 12 Pts (30%) had stable disease (SD). The median PFS was 6.6 [95% CI 2.9 - 10.3] months (Figure 1a). Median duration of response (DOR) was 10.8 months. Median OS was not reached; 1-year overall survival was 81.6±6.7% (Figure 1a). One-year OS was significantly better for responders (89.3±7.3%) than non-responders (72.2±10.7%), p=0.015 ( figure 1b). Conclusions: IPd combination with a twice-weekly ixazomib induction provided an all-oral safe and efficacious therapy in triple-exposed RRMM Pts, most of whom were refractory to both DARA and LEN. Response rates and PFS are encouraging, compared to parenteral PI and IMiD combination regimens in TCE/TCR MM, with a favorable safety profile and convenience, especially among an elderly and frail population with relapsed myeloma.

Initial Clinical Results and Immune Correlates of a Phase 2 Study of Daratumumab, Bortezomib, Dexamethasone Followed By a Proteasome Inhibitor in-Class Transition ( iCT) to Daratumumab, Ixazomib, Dexamethasone in Relapsed Refractory Multiple Myeloma

Background: The regimen of daratumumab, bortezomib, and dexamethasone (DVd) was approved in relapsed refractory multiple myeloma (RRMM) patients (pts) with >1 line of therapy based on the pivotal phase 3 CASTOR study. Notably in CASTOR, bortezomib was administered for a fixed duration of 8 cycles, and both the parenteral administration route and treatment-related peripheral neuropathy (PN) may limit continuous bortezomib exposure in clinical practice. As an alternative, we conducted a phase 2 study of DVd, followed by daratumumab, ixazomib, dexamethasone (DId) utilizing a proteasome inhibitor (PI) in-class transition ( iCT) with the hypothesis that oral ixazomib may provide a more tolerable and convenient way to deliver continuous PI- and anti-CD38-based therapy to improve efficacy (NCT03763162). Methods: This phase 2 single-center study enrolled RRMM pts with 1-3 lines of prior therapy with disease progression on or following the last line of therapy. Key exclusion criteria included prior ixazomib exposure, refractoriness to anti-CD38 therapy, and refractoriness to bortezomib or carfilzomib therapy at last exposure. Enrolled pts received DVd for 3 cycles on a 21-day (D) cycle with daratumumab on D1, D8, and D15 and subcutaneous (SC) bortezomib 1.3 mg/m 2 on D1, D4, D8, and D11. Starting cycle (C) 4, pts transitioned to DId on a 28-day cycle, with daratumumab on D1 and D15 for C3-C7 and on D1 starting C8 and oral ixazomib 4 mg on D1, D8 and D15. Daratumumab was initially administered intravenously (16 mg/kg) but later changed to SC injection (1800 mg) with a protocol amendment. Bone marrow (BM) aspirates were performed pre-treatment, post-C3, post-C6 (optional), and at progression to evaluate immune correlates of therapeutic response and resistance using 4 16-color multiparameter flow cytometry panels (2 T-cell, 1 NK/myeloid, and 1 B-cell). The primary endpoint of the study was progression free survival (PFS) with planned enrollment of 40 pts. Results: As of 15 May 2023, 36 pts have enrolled with a median of 1 prior line of therapy. Median age was 66, 67% were male, 28% were Black, 97% were lenalidomide-refractory, and 42% had high-risk cytogenetics (Cg; del 17p, t(4;14), t(14;16), and/or +1q21 gain/amplification). Overall response rate was 83%, ≥very good partial response (VGPR) rate was 53%, and ≥complete response rate was 19%. At a median follow-up of 24.8 months, median PFS was 21.1 months and median response duration was 26.2 months. Median PFS among pts with high-risk Cg, 1 line of prior therapy, and 2-3 lines of prior therapy was 21.1 months, 22.8 months, and 14.3 months, respectively. The most common treatment emergent adverse events (TEAEs) of any grade were diarrhea (69%), thrombocytopenia (69%), fatigue (67%), and lymphopenia (67%). The most common ≥grade 3 TEAEs were lymphopenia (42%), thrombocytopenia (42%), and hypertension (31%). Treatment emergent PN occurred in 61% pts (11% ≥ grade 3). The most common reason for treatment discontinuation was disease progression (42%), and 16 (44%) pts remain on study with ongoing responses. Efficacy and safety stopping rules for the study have not been met. Multiparameter flow cytometry immune correlates from BM aspirates demonstrated significantly lower Ki67 + cell frequency and significantly higher PD-1 + cell frequency within the CD8 + T-cell population at baseline in pts with no response versus those with optimal responses (≥VGPR). Among pts with short PFS (<12 months), CD4 +/CD8 + ratio and CD4 + non-T-reg naïve T-cells were significantly higher post-C3 and post-C6 compared to pts with longer PFS (>12 months). Among initial responders who later progressed on therapy, T-regulatory cells were significant increased at progression compared to pre-C4, and NK cell CD16 expression was significantly reduced at progression compared to baseline. Finally, distinct patterns of CD4 + T effector memory (EM) cell subsets were observed with significantly decreased EM1 and increased EM3 subsets at progression compared to baseline. Conclusion: Treatment with DVd followed by DId with a PI iCT from bortezomib to ixazomib is a feasible approach for continuous PI and anti-CD38 therapy, leading to durable responses in RRMM pts, among whom nearly all (97%) were lenalidomide refractory. Immune correlates revealed distinct patterns of T-cell and NK-cell phenotypes when profiled serially in responding and non-responding pts. Additional correlative analyses are ongoing.

Efficacy Outcomes and Characteristics of Patients with Multiple Myeloma (MM) Who Achieved Sustained Minimal Residual Disease Negativity after Treatment with Equecabtagene Autoleucel (Eque-cel, CT103A) in Fumanba-1

Background: Equecabtagene autoleucel (eque-cel, CT103A), which is designed with a fully human BCMA-specific CAR structure, was recently granted NMPA approval for the treatment of adult patients (pts) with relapsed/refractory multiple myeloma (RRMM) after ≥3 prior lines of therapy (LOT). The pivotal phase 2 FUMANBA-1 study (NCT05066646) demonstrated deep and durable responses with eque-cel in heavily pretreated patients with RRMM. Recent studies have demonstrated the utility of minimal residual disease (MRD) as a prognostic biomarker for long-term outcomes of RRMM, wherein achievement of sustained MRD-negative status was associated with an improvement in PFS of pts treated by eque-cel in FUMANBA-1 study. We sought to characterize the baseline and disease characteristics of pts with sustained MRD negativity (pts who continued to remain MRD negative ≥6 mo and ≥12 mo). Methods: FUMANBA-1 study enrolled RRMM pts who received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. All pts received a single infusion of eque-cel at the dose of 1.0 x 10 6 CAR-T cells/Kg. Pts who had progressed on previous BCMA CAR-T cell therapy were not included in this analysis. The primary endpoint was ORR. Additional endpoints included ≥CR rate (key secondary), DOR, PFS, and safety. ORR and CR were assessed per IMWG criteria; DOR and PFS were analyzed via Kaplan-Meier methods. MRD negativity was a secondary objective and was assessed on bone marrow samples at baseline; day 14, 28; and 2, 3, 6, 9, 12, 15, 18, 21 and 24 mo using EuroFlow next-generation flow, regardless of disease status. Evaluable samples passed calibration and quality control and included sufficient cells for evaluation at 10 -5 testing threshold. Characteristics were analyzed in pts who had MRD negativity <6 mo, or sustained ≥6 mo and ≥12 mo. Pts who did not achieve MRD negativity at any time point were considered to be MRD positive. Results: Of the 88 pts who achieved MRD negativity in FUMANBA-1, 74 had at least 6 mo follow up without progression after initial MRD-negativity and 43 had at least 12 mo follow up without progression after initial MRD-negativity. MRD negativity was sustained for ≥6 mo in 78.4% (58 of 74 with at least 6 mo follow-up without progression after initial MRD-negativity) and ≥12 mo in 74.4% (32 of 43 with at least 12 mo follow-up without progression after initial MRD-negativity; 7 pts evaluable for sustained MRD at ≥6 mo but not ≥12 mo had PD). Pts with sustained MRD negativity (≥6 mo, and ≥12 mo) had longer progression free survival (PFS; Figure 1A) compared with pts who did not (MRD negative <6 mo). Key pt and disease characteristics in these different groups (Figure 1B), and potential associations with sustained MRD negativity were analyzed descriptively. Baseline R-ISS disease stage III was more common in pts with MRD sustained for ≥6 mo (8.6%) and ≥12 mo (9.4%) compared with pts who had MRD negativity <6 mo (3.3%). Baseline high tumor burden diseases were less common in pts with MRD sustained for ≥6 mo (70.7%) and ≥12 mo (65.6%) compared with pts who had MRD negativity <6 mo (90%). Triple-class exposure was also less common in pts with MRD sustained for ≥6 mo (12.1%) and ≥12 mo (12.5%) compared with pts who had MRD negativity <6 mo (30%). Pts with sustained MRD negativity had trends toward shorter median time since diagnosis (38.6 mo and 40.2 mo for pts with MRD negativity sustained ≥6 and ≥12 mo, respectively versus 43.5 mo for those with MRD negativity <6 mo). Other baseline characteristics, including presence of high-risk cytogenetics, ECOG performance status, extramedullary disease and number of prior LOT did not differ across MRD subgroups, and were similar to the overall FUMANBA-1 population. Conclusions: Based on our descriptive analysis, pts receiving eque-cel achieved MRD negativity irrespective of their high-risk cytogenetics, extramedullary disease, number of prior LOT and performance status. Presence of high tumor burden at baseline, and prior triple-class exposure might be factors that impact achievement of sustained MRD negativity. These data suggest that while eque-cel is effective for a broad range of pts, specific pt and disease characteristics may be associated with sustained MRD negativity and better long-term outcomes. Sustained MRD negativity might be a promising prognostic indicator for RRMM pts treated by eque-cel.

Balancing Monitoring and Access: Optimal Duration of Monitoring for CD19 and BCMA CART Recipients for Lymphoma and Myeloma

Background: Due to the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndromes (ICANS), a four-week monitoring period near the authorized treating center (ATC) is a requirement for all currently approved chimeric antigen receptor T cell (CART) therapies, as part of the required Risk Evaluation and Mitigation Strategy (REMS) programs. The purpose of the REMS program is to facilitate prompt administration of tocilizumab within 2 hours in the event of life-threatening adverse events . Most ATCs require patients to stay within a 30-60-minute radius of the ATC and require a dedicated caregiver. While monitoring is essential for safety, the optimal duration of monitoring post-CART has not been studied. It is an area of need as there is a known financial burden of relocation, which may increase gaps in access to care, especially for underserved populations. We evaluated real-world safety outcomes of patients receiving CD19 and BCMA CART for non-Hodgkin lymphoma (NHL) and relapsed refractory multiple myeloma (RRMM). Methods: Patients (pts) with NHL and RRMM who received commercial CD19-directed (axi-cel, tisa-cel, liso-cel, brexu-cel) and BCMA-directed CART (ide-cel, cilta-cel) respectively, from 1/2017 to 1/2023, at the University of Kansas Health System and Medical University of South Carolina were included. Based on each patient's 5-digit zip code, travel distance to the ATC, median household income, and rural or urban residence were estimated. Patients were divided into two groups: those who had either first or recurrent CRS or ICANS occurring at Day 7 or later (Events≥ D7) and the group with no CRS/ICANS ≥ Day 7 (No Events ≥ D7). Chi-square test and proportion tests were calculated. Results: 185 patients (pts) including 127 NHL pts (59% axi-cel, 19% tisa-cel, 13% liso-cel, 8% brexu-cel) and 58 RRMM pts (75% ide-cel and 25% cilta-cel) were included. Most patients (65%) lived beyond 30 minutes of the ATC, and only 23.2% were from rural neighborhoods. (Table 1) 150 pts were in the “No Events ≥ D7” while 35 pts were in the Events≥ D7 group. There were no differences in baseline characteristics of these groups (Table 1). 151 pts (81.6%) and 70 (39%) pts developed new-onset CRS and ICANS respectively on D0-28. Median time to onset for CRS vs ICANS: 2 (IQR 25-75%:1-4) vs 5 (IQR 25-75%:3-8). Median time to CRS vs ICANS resolution relative to infusion was 6 days (IQR 25-75%: 3-7) vs 11 days (IQR 25-75%: 8-15). 137 (91%) had onset of CRS D0-6, 12 (26% of at-risk at D7) developed CRS D7-14. There was no new onset CRS D15 onwards, although one pt (axi-cel recipient) developed CRS recurrence D15-28, and another axi-cel recipient developed CRS recurrence D43. Only these 2 pts had ongoing CRS beyond D14. 45 (64%) had onset of ICANS D0-6, 20 (14% of at-risk at D7) developed ICANS D7-14. Of the 119 at risk, 4 pts (1 axi-cel, 1 tisa-cel, 2 ide-cel) developed ICANS D15-28 and one pt (cilta-cel recipient) experienced new ICANS onset beyond D28. 30 pts had ongoing ICANS beyond D14 and 5 beyond D28. There was no significant association with disease, early vs no early event, product, co-stimulatory domain (CD28 vs 4-1BB), year of infusion (2021 onwards vs prior), or SDOH with CRS or ICANS on multivariate analysis. Resource Utilization: Tocilizumab (toci) was administered in 67% pts, median 2 doses (1-4). Median time to first dose toci was 3 days (0-11) and median time to last dose was 4 days (0-43). 44% pts received steroids, and all had first dose prior to D15. 14 pts had infections requiring admission D15-28. Other outcomes and resource utilization are shown in Table 2. Mortality:There were 15 deaths D0-90, mostly due to progression (9), 4 due to infection, and 1 “other” cause. No deaths were attributable to CRS or ICANS. Of these, one death occurred D0-28 (in an axi-cel recipient) due to progression. Conclusions: Despite differences in patterns of CRS and ICANS with CART products, there is a low incidence of CRS and ICANS onset beyond 2 weeks, but persistent risk of other fatal complications, mostly infectious, even beyond the mandated monitoring period. Our study suggests a flexible monitoring period proximal to the ATC for CRS/ICANS may be safe for select patients and will likely be more feasible especially for disadvantaged populations with limited support. Exploring hybrid models and earlier partnership of referring centers and ATCs for monitoring, may allow personalized continuum of care and improve outcomes.

30-Minute Infusion of Isatuximab in Newly Diagnosed Multiple Myeloma (NDMM) Patients: Results of a Phase 1b Study

Introduction: The anti-CD38 antibody isatuximab (Isa) is approved in various countries with pomalidomide-dexamethasone for relapsed/refractory multiple myeloma (RRMM) patients (pts) with ≥2 prior therapies including lenalidomide and a proteasome inhibitor, based on the ICARIA-MM study, and with carfilzomib-dexamethasone for RRMM pts with ≥1 prior therapy, based on the IKEMA study. To enhance convenience of intravenous (IV) Isa administration, a shorter IV infusion over 30 minutes (30-min) was assessed in pts with NDMM not eligible/with no immediate intent for autologous stem cell transplantation (ASCT) still on maintenance therapy in a Phase 1b trial (NCT02513186). Results previously reported from this study showed efficacy of treatment with Isa in combination with bortezomib-cyclophosphamide-dexamethasone (VCd) or bortezomib-lenalidomide-dexamethasone (VRd), with manageable safety profiles. The rates of very good partial response or better and of minimal residual disease negativity (at 10 -5 sensitivity) were 80% and 53.3% with Isa-VCd, and 92.9% and 50.7%, respectively, with Isa-VRd [Ocio EM et al. HemaSphere 2023;7(2):e829; Ocio EM et al. Leukemia 2023;37(7):1521-1529]. Preliminary results with the new 30-min Isa administration method are presented here. Methods: Pts still receiving maintenance treatment were to be switched to the 30-min infusion with Isa at 10 mg/kg diluted in a 250 mL infusion bag of 0.9% sodium chloride. The infusion rate of the first infusion was 250 mL/hr; in the absence of infusion reactions (IRs), subsequent infusions were to be administered at an infusion rate of 500 mL/hr. The objective was to evaluate safety in terms of incidence and severity of IRs during the first 2 full 30-min infusions. The initial, recommended premedication to be given at the time of the switch consisted of dexamethasone 20 mg orally (PO) (or equivalent [eq.]), acetaminophen (paracetamol) 650 to 1000 mg PO; ranitidine 50 mg IV (or eq.), diphenhydramine 25 to 50 mg IV (or eq.), and montelukast 10 mg PO (or eq.). Prior to switching, pts received weight-based Isa infusion in the VCd cohorts and initially in the VRd Part A cohort, followed by fixed-volume Isa infusion in both VRd Parts A and B (in Part B, at 200 mL/hr from 3 rd infusion, ~75 min with no IRs/interruptions). Results: As of 19 May 2023, 29.4% of pts in Isa-VCd, 48.1% in Isa-VRd Part A, and 60.9% in Isa-VRd Part B were still on treatment. The median follow-up for all pts was 71.1, 55.1, and 38.1 months for the Isa-VCd, Isa-VRd Part A, and Isa-VRd Part B cohorts, with a median duration of exposure of 63.5, 54.1, and 40.8 months, respectively. A total of 45 pts received 142 infusions between Jan 2023 and May 2023: 45 first infusions with intermediate rate and 97 30-min infusions across cohorts, with a median of 3 cycles started by pts (range, 1-5) (44 pts received at least 2 infusions) and a median relative Isa dose intensity of 99.4% (range, 73.7-105.5%). Switching occurred at a median of 46 cycles (range, 38-88) for all treated pts. The median duration of Isa infusion in all treated pts was 32 min, 33 min, and 33 min at the 2 nd, 3 rd, and subsequent infusions, respectively ( Table). 30-min infusion of Isa was well tolerated, with no IRs and no infusion interruptions across cohorts. Conclusions: These preliminary results show that 30-min infusion of Isa is a feasible, well-tolerated, and convenient administration method for pts with multiple myeloma on Isa treatment for several months. The 30-min Isa infusion is currently being assessed from day 1 of cycle 2 in the ongoing Phase 1-2 UMBRELLA trial of Isa with or without dexamethasone in combination with novel agents, conducted in pts with RRMM (NCT04643002). Clinical trial registration: NCT02513186. Funding: Sanofi.

Carfilzomib, Daratumumab, and Dexamethasone (KdD) Vs Carfilzomib and Dexamethasone (Kd) for Relapsed/Refractory Multiple Myeloma (RRMM) in the Phase 3 Candor Study: Subgroup Analysis According to Renal Functioning

Renal impairment frequently occurs in patients (pts) with multiple myeloma (MM) and is associated with poor survival outcomes. In the phase 3 CANDOR trial, carfilzomib, dexamethasone, and daratumumab (KdD) met its primary endpoint of prolonged progression-free survival (PFS) vs carfilzomib and dexamethasone (Kd) (28.4 vs 15.2 mo; hazard ratio [HR]: 0.64; 95% CI: 0.49-0.83) after 50 months (mo) follow-up (Usmani Blood Adv 2023). The study aim was to perform a prespecified subgroup analysis of efficacy and safety by baseline renal function in pts with relapsed/refractory MM (RRMM) receiving KdD vs Kd in the CANDOR trial. Adult pts with RRMM were randomized 2:1 to KdD or Kd in the open-label, phase 3 CANDOR trial (NCT03158688) (Dimopoulos Lancet 2020). RRMM pts with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Dialysis was an exclusion criterion. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m 2 on days 1 and 2 during cycle 1 and 56 mg/m 2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks (wks) for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts >75 years). Pts were grouped according to baseline renal function (creatinine clearance [CrCl] ≥15-<60 mL/min, ≥60-<90 mL/min, and ≥90 mL/min (Dimopoulous J Clin Onc 2016). The Cockcroft-Gault formula was used to calculate baseline and on study renal function. PFS and overall response rates (ORRs) were protocol-derived/investigator-assessed. Median PFS was estimated using the Kaplan-Meier method, with HRs and corresponding 95% CIs estimated using a stratified Cox proportional hazards model. Response rates were summarized descriptively, with odds ratios (ORs) and corresponding 95% CIs estimated by Mantel-Haenszel methods using stratified randomization. Renal response was defined as pt CrCl improvement to ≥60 mL/min in any 2 consecutive study visits in pts with baseline CrCl of <50 mL/min. A total of 466 pts were randomized; renal subgroups were CrCl ≥15-<60 mL/min (renal impairment), n=67 and n=36; ≥60-<90 mL/min, n=112 and n=57; and ≥90 mL/min, n=132 and n=61 for KdD and Kd, respectively. One pt in the KdD arm with missing baseline CrCl was excluded. Baseline characteristics were generally balanced between treatment arms and renal subgroups ( Table 1). After a median follow-up of ~50 mo (data cutoff: April 15, 2022), pts treated with KdD vs Kd had improved median PFS across all renal subgroups; median PFS was 24.9 mo vs 8.4 mo (HR, 0.61; 95% CI, 0.35-1.06), 31.6 mo vs 19.9 mo (0.63; 0.41-0.96), and 27.4 mo vs 15.3 mo (0.64; 0.43-0.95) for pts with CrCl ≥15-<60 mL/min, ≥60-<90 mL/min, and ≥90 mL/min, respectively ( Table 2). Median overall survival (OS) for KdD vs Kd was 44.6 mo vs 25.2 mo (HR, 0.58; 95% CI, 0.32-1.03), 48.0 mo vs 43.7 mo (0.91; 0.58-1.43), and NE vs NE (0.74; 0.46-1.20), respectively. ORRs were 87% vs 50% (OR, 8.02; 95% CI, 2.84-22.65); 85% vs 82% (1.26; 0.49-3.27); and 86% vs 80% (1.59; 0.69-3.68), respectively. Complete response rates were 36% vs 8% (7.43; 1.85-29.74); 44% vs 21% (3.17; 1.47-6.87); and 38% vs 21% (2.20; 1.08-4.49), respectively. Among 38 KdD pts and 27 Kd pts with baseline CrCl <50 mL/min, the renal response rate was 21% vs 11% (OR, 2.65; 95% CI, 0.63-11.11), respectively. In pts with renal impairment, most common grade ≥3 TEAEs were thrombocytopenia (38% [25/66] vs 23% [8/35]), hypertension (24% [16/66] vs 20% [7/35]), anemia (24% [16/66] vs 29% [10/35]), and pneumonia (23% [15/66] vs 9% [3/35]) in the KdD arm vs Kd arm. Most common grade ≥3 TEAEs of interest in pts with renal impairment were respiratory tract infections (32% vs 14%), hypertension (26% vs 20%), and infusion reaction on the same date of any carfilzomib dosing (14% vs 11%), respectively. Grade ≥3 acute renal failure occurred in 6% vs 11%, 4% vs 7%, and 2% vs 3% of pts with baseline CrCl ≥15-<60 mL/min, ≥60-<90 mL/min, and ≥90 mL/min, respectively. Overall, the safety profile in each subgroups was consistent with the established carfilzomib safety profile (Usmani Blood Adv 2023). KdD showed consistent clinical benefit vs Kd in median PFS, ORR and OS irrespective of the baseline renal function. Safety findings were consistent with the overall study population.

Cellular Dynamics Following CAR T Cell Therapy Are Associated with Response, Resistance and Cytokine Release Syndrome in Relapsed/Refractory Multiple Myeloma

Introduction The introduction of B cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). While long-term follow-up of CD19 CAR T cells demonstrated a connection between CAR T cell expansion and persistence with outcome, very little is known about persistence and effects on bystander cells of BCMA-targeting CAR T cells. Methods We analyzed 27 RRMM patients (pts) treated with Idecabtagene vicleucel (Ide-cel) at our center. Pts were grouped based on their remission evaluated 100 days after infusion into responders (partial response or better, n=16) or non-responders (progressive disease, n=11). Peripheral blood (pb) was drawn at day of leukapheresis, at day of infusion/after lymphodepletion (LD, d0) and at several time points following Ide-cel infusion (d7, d14, d30 and d100). In order to reflect a comprehensive picture of the longitudinal dynamics of CAR and non-CAR T cells, we subjected pb mononuclear cells to advanced flow cytometry. Additionally, we assessed the impact of cellular dynamics on the occurrence of cytokine release syndrome (CRS), tocilizumab application and the incidence of cytopenia. Results The median number of infused CAR T cells was 430x10 6 (range: 248.8 - 489.1x10 6) with one exception (25.7x10 6). There was no correlation between the median number of infused cells and in vivo expansion of CAR T cells after infusion as well as response or the development of CRS or cytopenia. Significant differences between responders and non-responders were already detected on day of leukapheresis: While non-responders showed similar numbers of CD4+ and CD8+ T cells, responders had significantly higher CD8+ T cell counts as compared to CD4+ T cells (p<0.05, Figure 1). Additionally, significantly reduced percentages of effector memory CD8+ T cells were detected in responders as compared to non-responders. The latter group showed significantly increased numbers of CD3+CD8+ T cells at the day of infusion indicating a less effective LD in non-responders. Following CAR T cell infusion, peak expansion occurred two weeks after infusion and was significantly higher in responders as compared to non-responders (p<0.001, Figure 2). CD3+ CAR T cell compartment predominantly comprised of CD8+ T cells regardless of response (median: 85%). Analysis of the distribution of CAR and non-CAR T cells after infusion revealed that the majority of CD4+ T cells in responders and non-responders were untransfected. Similar results were detected for CD8+ T cells in non-responders. However, in responders CD8+ CAR T cells approximated CD8+ non-CAR T cells with no significant differences on d7 and d14. With regard to T cell differentiation, almost the entire CD4+ T cells exhibited either a central memory or effector memory phenotype after CAR T cell infusion. Shortly after CAR T cell infusion, effector memory CD8+ T cells outbalanced all other CD8+ T cell subtypes. Most pts had no detectable CAR T cells 100 days after infusion, regardless of remission. Overall, 22 pts (81%) developed CRS shortly after CAR T cell infusion and 7 of these (32%) required tocilizumab treatment. Whereas percentages of CD3+ CAR T cells were significantly elevated in both CRS positive groups (p<0.05) shortly after infusion, absolute numbers were significantly increased only in CRS positive pts without tocilizumab. Analysis of blood counts following CAR T cell infusion revealed that cytopenias persisted longer in CRS pts treated with tocilizumab, which was also reflected by significantly increased numbers of days below thresholds for all cell lines (anemia, thrombocytopenia and leukopenia, p<0.01). Even though the occurrence of CRS and especially the treatment with tocilizumab affected blood cell composition, it did not correlate to response. Conclusion We demonstrate that BCMA-targeting CAR T cells only transiently persist in pb after infusion. Still, initial CAR T cell expansion, predominantly caused by effector memory CD8+ CAR T cells, was linked to response and CRS in RRMM pts. A correlation between CRS and tocilizumab administration with prolonged cytopenias following CAR T cell infusion was also observed. Our data provide first evidence that responders and non-responders can early be distinguished by differential cellular composition in CAR and non-CAR T cell compartments with distinct features already present at day of apheresis.

Increased Bone Turnover and Decreased BCMA Levels in Patients with Response to Anti-BCMA CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma

Introduction For most patients (pts), multiple myeloma (MM) remains an incurable disease. Osteolytic lesions (OL) are present in 80% of pts at diagnosis and skeletal-related events are the most common cause for symptomatic relapse. Hence, myeloma bone disease (MBD) is a major cause of morbidity and mortality especially among pts with relapsed/refractory MM (RRMM). B cell maturation antigen (BCMA) targeted chimeric antigen receptor (CAR) T cells have revolutionized treatment of patients with RRMM. While remission rates are high and pts experience long-standing treatment free intervals after CAR T cell treatment, little is known about its effects on MBD and bone turnover. The latter can be determined in plasma by measuring markers of bone formation and resorption. We aimed to analyze the longitudinal development of bone turnover during and after anti-BCMA CAR T cell treatment in RRMM pts. Methods We analyzed 28 consecutive pts with RRMM who underwent treatment with either Idecabtagene-Vicleucel (n=27) or Ciltacabtagen-Autoleucel (n=1) at our center between December 2021 and February 2023. Median age at infusion was 63 (range 39-75) years. 57% of pts were male. All pts were triple-class exposed, 21% had penta-class refractory disease. Status prior to CAR T cell infusion was complete remission (CR, 11%), partial remission (PR, 21%), very good PR (14%), stable disease (4%), or progressive disease (PD, 50%). The impact of CAR T cell treatment on bone turnover was assessed by collecting plasma samples on the day of T cell apheresis, as well as days (d) 30 and 100 after CAR T cell infusion. Samples were analyzed by ELISA to evaluate plasma levels of bone formation marker Osteocalcin (OCN), bone resorption markers Tartrate-resistant acid phosphatase 5b (TRAcP5b) and fibroblast growth factor 23 (FGF23) as well as BCMA as a marker for the targeted myeloma cells. Median levels were compared between subgroups by Wilcoxon tests. Remission status after CAR T cell therapy was first evaluated at d 30 according to International Myeloma Working Group consensus criteria. Median follow-up was 6 months. Results Of the 28 pts treated with anti-BCMA CAR T cells, 64% achieved at least a PR (responders), while 36% had PD shortly (30 d) after. Within 14 d after infusion, 82% developed a cytokine release syndrome (CRS, °I or II), in 30% of which Tocilizumab was applied. Only 1 pt developed immune effector cell-associated neurotoxicity syndrome. In responders, BCMA levels in plasma decreased significantly between apheresis and d 30 ( P<.01) and between apheresis and d 100 ( P<.01), while pts with PD showed no significant change in BCMA levels at the same timepoints ( P=.6 and P=.8). Furthermore, BCMA levels were significantly higher in pts with PD at d 30 ( P<.01) and d 100 ( P=.02), compared to responders (Figure 1). Regarding bone resorption markers, TRAcP5b levels were significantly increased in responders ( P=.01) but not pts with PD ( P=.56) on d 30 after apheresis. Furthermore, we determined a significant increase of intact FGF23 between apheresis and d 30 ( P<.01) and a subsequent significant decrease of intact FGF23 ( P=.02) between d 30 and d 100 in responders. Since FGF23 and interleukin-6 (IL-6) are physiologically dependent, the observed FGF23 dynamics are likely to be an effect of increasing IL-6 in the context of CRS. Aptly, pts who received Tocilizumab because of full-blown CRS had higher intact FGF23 levels at d 30 ( P=.02) compared to pts without Tocilizumab treatment. The bone formation marker OCN showed a significant increase in responders between apheresis and d 100 ( P=.01), as well as between d30 and d100 ( P=.02), while there were no significant changes in OCN levels over the time in pts with PD (Figure 2). Conclusion Pts responding to treatment with anti-BCMA CAR T cells, showed an increased bone turnover shortly after infusion. The increase of bone resorption marker levels appeared to be a short-term trend and could possibly be related to inflammation and high interleukin levels during the first days after infusion. However, we also saw a steady increase of bone formation marker OCN, which remained significant till d 100 in responders. Our data implies, that response to anti-BCMA CAR T cells is accompanied by increasing bone formation. Further analyses are needed to evaluate, whether this treatment can have positive long-term effects on MBD.

Selinexor, Daratumumab and Dexamethasone for Patients with Multiple Myeloma Previously Treated with Lenalidomide at First Relapse: A Real-World Study

CONCLUSIONS As lenalidomide becomes increasingly established standard of care for patients with newly diagnosed multiple myeloma (NDMM), a significant number of patients may develop resistance to lenalidomide in their treatment, representing a clinically important population in need of effective therapies. Lenalidomide-refractory patients, who relapse quickly and have very poor outcomes, constitute a population with unmet medical needs. Selinexor is a selective inhibitor of exportin-1, leading to the accumulation of tumor suppressor proteins and growth regulator proteins in the nucleus. This results in reduced expression of several oncoproteins, leading to cell cycle arrest and apoptosis of cancer cells. Previous data indicate that the biology associated with resistance to the monoclonal antibody daratumumab is linked to sensitivity to selinexor (ASH 2021), and selinexor conbombined with daratumumab and dexamethasone (SDd) is a well-tolerated and effective option for patients with relapsed/refractory multiple myeloma (RRMM) (Gasparetto C, 2020). Here, we present the safety and preliminary efficacy findings from the first study of SDd combination therapy in Chinese patients with multiple myeloma who refractory to lenalidomide at first relapse (NCT05559788). This study is a single-arm, prospective, non-interventional, real-world study that enrolled pts who had previously received one-line anti-myeloma treatment. Subjects were treated with selinexor (60 mg QW) in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) in 28-day cycles until PD, death or patients' withdrawal. Data collected included treatment response, patient characteristics such as age, sex, multiple myeloma features (cytogenetics by fluorescence in situ hybridization, type, stage, anti-myeloma treatment, and stem cell transplantation [SCT] status), and patients' survival. Between Feb 1, 2023, and May 30, 2023, a total of 8 RRMM pts were enrolled and received treatment at The First Affiliated Hospital of Soochow University. The median age was 63 years (range 44-78), with all pts (100%) had R-ISS stage II/III disease. Among them, 6 (75%) pts were classified as high risk or above by mSMART risk stratification, and 4 (50%) pts had extramedullary disease (EMD). All 8 (100%) pts were refractory to lenalidomide, and 7（87.5%）have received autologous stem cell transplantation (ASCT) (Table 1). At the end of one course, 6 patients (75%) achieved remission (3 very good partial responses [VGPR] and 3 partial responses [PR]). Among the 4 pts with EMD, 1 pt showed progressive disease (PD) after two courses, 1 pt showed stable disease (SD), and 2 pt achieved PR and VGPR but progressed after four and two courses, respectively. The data suggests that SDd combination therapy brings about rapid remission in EMD patients, while the duration of response may be shorter. Therefore, for these patients, it is crucial to closely monitor and plan for the next steps of treatment after achieving rapid remission. All four remaining non-EMD pts achieved remission, three of whom are continuing treatment (one died of COVID-19). Four patients were infected with COVID-19 during the treatment process. One pt was asymptomatic and detected positive with virus infection by antigen test screening. Among the three pts with symptoms, one had fever, cough, and pneumonia, and one had multiple organ failure (MOF). Three pts received antiviral medication (two with Paxlovid and one with Molnupiravir), and three recovered, but the one with MOF died. The SDd treatment was interrupted in all four pts, with a median time of 18 days (range: 12 to 21 days), until COVID-19 turned negative. The most common grade 3 adverse events (AEs) were thrombocytopenia (25%), anemia (13%), and neutropenia (13%). Non-hematological AEs were mainly grade 1-2. Three patients had dose reductions due to myelosuppression. This real-world study demonstrates that SDd combination therapy led to early, deep responses in lenalidomide-refractory multiple myeloma patients at their first relapse. Considering that patients with extramedullary disease had limited benefit from SDd treatment, future study designs may restrict the recruitment of such patients.

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.

Tolerability and Clinical Activity of Novel First in Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Background Inobrodib (CCS1477) is a first in class potent, selective, and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyltransferases with oncogenic roles in hematological malignancies. Inobrodib exhibits potent anti-tumor cell activity in a range of hematological cell lines, including multiple myeloma, and demonstrates additive/synergistic activity with pomalidomide. Aims: We report preliminary safety (primary objective) and efficacy (secondary) data for inobrodib in combination with pomalidomide (pom) and dexamethasone (dex) from relapsed/refractory multiple myeloma (RRMM) patients treated in the Phase I/IIa trial (NCT04068597). Methods : Eligible patients (pts) had confirmed RRMM and had exhausted available or suitable standard of care treatment options. Two dose escalation combination cohorts were completed; pts received inobrodib at doses of 25 mg or 35 mg bidaily on a 4 days on/3 days off intermittent schedule, as well as standard dosing of pom and dex in 28-day cycles. Adverse events were graded by CTCAE v5.0. Responses were investigator assessed per IMWG. Results: Initial dose escalation cohorts enrolled 15 RRMM pts with a median age of 71 yrs (range 41-80). Median prior lines of therapy was 5 (range 3-9). Median follow-up was 56 days (range 13-189), with a median number of 3 cycles received (range 1-7). Almost all patients were pomalidomide-refractory (13/15, 87%), 13/13 (100%, 2 pts data missing) were triple class refractory and 3 pts (20%) received prior BCMA therapy. At the data cut-off (5 th June 2023), Grade (gr) 3 /4 treatment-emergent adverse events (TEAEs) were reported in 11 of 15 (73%) pts. Over half of the patients remain on treatment and all but three remain in follow-up for survival analysis. Of these three patients, two died due to disease progression and one due to an unrelated cardiac event at the end of cycle 2. The most frequent gr 3/4 events were infections (41.1%). The majority of the other gr 3/4 TEAE were hematological and seen in 5 of 13 (38.5%) pts; neutropenia (23.5%) thrombocytopenia (5.9%, all gr 3) and anemia (11.8%, all gr 3). Seven of 15 (47%) pts experienced TEAEs considered related to inobrodib; all events were gr 1/2 apart from a single patient with gr 3 electrolyte abnormalities. No DLTs were noted; two pts (13%) discontinued due to related events. The majority of patients 13/15 (87%) showed signs of activity with disease markers decreasing over time. At the point of data cut off, 7/15 (47%) heavily pre-treated patients achieved confirmed responses (MR or better) per IMWG criteria; 2 VGPR, 3 PR and 2 MR. Of note, two further patients, who initially received inobrodib monotherapy but progressed were transferred into the pom-dex combination cohort and subsequently achieved objective responses (VGPR and PR). Summary: The first in class agent inobrodib in combination with pom-dex shows promising early efficacy in heavily pre-treated, including pom-refractory, RRMM patients. The combination is tolerable, with the most common events being infections, as expected in this patient population. Dose optimisation continues as part of this study with expansion arms in an earlier setting planned.

Updated results of a phase I, open-label study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM).

8005 Background: GC012F is a chimeric antigen receptor (CAR)-T cell therapy with B cell maturation antigen (BCMA) and CD19 dual-target developed on the novel FasT CAR-T platform enabling 22-36 h manufacturing. Our previous results were presented at ASCO and EHA 2022 for 29 pts (NCT04236011; NCT04182581), which demonstrated GC012F treatment led to deep and durable response in RRMM pts. Furthermore, initial results showed that GC012F showed considerable efficacy and safety in high-risk transplant-eligible newly diagnosed MM pts (Blood 2022; 140 (Supplement 1): 889–890). Here we present update on RRMM study with a longer median follow-up. Methods: From October 2019 to January 2022, 29 heavily pretreated RRMM pts (age 27-76) with a median of 5 prior lines therapies (range 2-9) received GC012F. 26 (89.7%) pts were high risk (HR- mSMART), 8 (27.6%) pts had EM disease, 24 (82.8%) pts were refractory to last therapy. 10 (34.5%) pts had received prior anti-CD38 and 11 (37.9%) pts were treated with auto-HSCT. After lymphodepletion over 2-3 days (30 mg/m2/d, 300mg/m2/d Flu/Cy), GC012F was administered as single infusion at 3 dose levels: 1x105/kg (DL1) n=2, 2x105/kg (DL2) n=10 and 3x105/kg (DL3) n=17. Results: At the time of data cut-off (January 30, 2023), 29 eligible pts had been evaluated for response with the last patient completed 12 months efficacy follow up. Overall response rate was 93.1% (27/29), stringent complete response rate was 82.8% (24/29), ≥very good partial response rate was 89.7% (26/29). All patients dosed (29/29) achieved MRD negativity by flow cytometry (sensitivity 10-4-10-6). To date 24/29 patients (82.8%) achieved MRD- sCR across all dose levels. According to the Kaplan-Meier method, the median duration of response (DOR) was 37.0 months (95%CI, 11.0-NR) and the median progression free survival (PFS) was 38.0 months (95%CI, 11.8-NR). Cytokine Release Syndrome (CRS) was reported in 25 (86.2%) pts, which was mostly ≤grade 2 (n=23, 79.3%) and 2 (6.9%) pts were grade 3. No ICANS was observed (Graded by ASBMT criteria). Median duration of CRS was 3 days (1-8 d). PK results showed no difference amongst dose levels DL1 to DL3. The median time of persistence was 410 days (range: 51-1183) and GC012F was still detectable in 23 (79.3%) pts at 6 months and in 16 (55.2%) pts at 12 months after infusion. sBCMA plasma levels started declining at day 4 in 80% (8/10) patients, falling sharply at day 10 in 100% (19/19), and reaching minimal levels from 30 to 60 days post infusion in 100% (29/29) patients. Conclusions: The updated results showed GC012F continues to provide deep and durable responses, and a very high MRD negativity ratein RRMM pts, including in pts refractory to anti-CD38, PIs and IMIDs. Based on these promising results of the study of GC012F for RRMM, further clinical studies will be conducted to confirm the efficacy of GC012F. Clinical trial information: NCT04236011 ; NCT04182581 .

Global Treatment Standard in Multiple Myeloma Remains Elusive: Updated Results from the INSIGHT MM Global, Prospective, Observational Study

Introduction INSIGHT MM (NCT02761187) is the largest global, prospective, observational multiple myeloma (MM) study to date, with 4188 newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM) patients (pts) included in this cross-sectional analysis. The study aims to describe contemporary, real-world patterns of pt & disease characteristics, treatment patterns, & outcomes. An interim analysis of the first 1000 pts enrolled to INSIGHT MM suggested considerable regional variation in treatment patterns (Boccadoro et al, EHA 2018). The aim of the current analysis is to characterize treatment patterns by world regions & line of therapy (LOT) in the overall INSIGHT MM study population. Methods Pts were enrolled at academic & community treatment facilities in 15 countries between July 2016 & July 2021. Data on prior & current treatments were collected at baseline & every 3 months. Full study methods have been reported previously (Costello 2019). We report a cross-sectional analysis of treatment regimens used in NDMM & RRMM pts at a data cut-off of Sept 30, 2021. A subset of pts with no protocol deviations (pts meeting all inclusion criteria who started index regimen <90 days before enrollment & enrolled at centers where data quality checks could be conducted) were included in an analysis of treatment shift patterns from first to second & subsequent LOTs. Results Among the 4188 pts, there were 2338 (55.8%) NDMM & 1850 (44.2%) RRMM cases at enrollment. This includes 2046 pts from Europe (EUR; Belgium, France, Germany, Greece, Italy, Spain, Turkey, United Kingdom; also includes Israel); 1317 pts from the United States (US); 470 pts from Latin America (LA; Brazil, Columbia, Mexico); & 355 pts from Asia (China, Taiwan). Median follow-up was 27.9 months. In NDMM pts, triplet therapy was the most common frontline approach across all regions (71.1% of pts overall); only 12.0% of pts received frontline doublet therapy. Triplet therapy typically included a proteasome inhibitor (PI) & dexamethasone (d; 62.5%). The most commonly used regimen was bortezomib (V), lenalidomide (R), & d (VRd; 23.5%); V-based triplet therapy with d & an IMiD was prescribed to 34.7% of NDMM pts overall. V-based triplets were the most widely used regimens across all regions. The US was the only region where carfilzomib (K) was included in one of the three most frequently used regimens (KRd in 8.3% of pts). Choice of IMiD varied regionally: R was most commonly used in the US, & thalidomide in EUR, LA, & Asia. In EUR & LA, cyclophosphamide (alkylating agent) was more commonly used than IMiDs. Vd (4.1%) & Rd (4.0%) doublets were the fourth & fifth most common regimens overall. Among RRMM pts, 49.6% received triplets & 33.7% received doublets. Triplet therapy was the most common approach across all LOTs & all regions except Asia; in Asia, doublets were more widely used than triplets (48.9% vs 42.4%). Rd was the most common regimen overall (15.4% across all regions & LOTs), & ixazomib-Rd (IRd) was the most common triplet (7.9% in all regions & LOTs; KRd was the second most common triplet overall [5.2%]). Unlike NDMM pts, RRMM pts were more likely to receive alternative PIs to V in ≥2nd LOT (IRd 6.8%; KRd 6.7%; VRd 2.7%), & daratumumab (D) was used instead of or alongside PIs in some triplets (DRd 4.9%; VDd 4.5%). Overall, 20.8% of pts received D as part of single-agent, doublet, triplet, or >triplet therapy. D was more widely used in the US (33.5%) than other regions (14.4-16.2%). Treatment shift patterns were examined in 3263 pts for whom robust data were available (1236 who underwent stem cell transplantation [SCT] in first line of therapy & 2027 who did not [NSCT]). A shift from predominantly PI- or PI/IMiD-based frontline therapy in both SCT & NSCT pts to more varied second-line regimens, including monoclonal antibody (mAb) therapy, was observed (Figure). Treatment shift patterns in later LOTs & across regions will be presented. Conclusions V-based triplets were the most common frontline treatment in NDMM pts in all regions. Regimens used in later LOTs in RRMM pts were more varied across regions, & generally included greater use of doublets, PIs other than V, & mAbs such as D. Acknowledging that treatment use is dependent on approval status & availability, this analysis shows that, while global frontline standard of care (SOC) is broadly established, there remains no consistent SOC in later LOTs; adoption of newer therapies, such as mAbs, varies across regions worldwide. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Multicenter Clinical Trial Assessing the Safety and Efficacy of Ixazomib Pomalidomide Dexamethasone Combination As Second or Third-Line Treatment for Patients with Triple Exposed Relapsed and Refractory Multiple Myeloma: Prespecified Interim Analysis (IPoD-790 trial)

Introduction: Despite significant improvement in the outcomes of early treatment lines in myeloma, most patients (Pts) invariably relapse. As triple and quadruple regimens are being introduced at the upfront setting, many Pts are either triple-exposed or triple-refractory early in their disease course. We report here the outcomes of a pre-specified interim analysis of the IPoD-790 clinical trial (NCT04790474), an all oral ixazomib (IXA) pomalidomide (POM) dexamethasone (DEX) (IPd) combination, in Pts with relapsed refractory multiple myeloma (RRMM) previously treated with bortezomib (BTZ) lenalidomide (LEN) and daratumumab (DARA). Methods: A phase 2, investigator initiated, open-label, single-arm, prospective, multicenter study evaluating the safety, tolerability and efficacy of IPd as a second or third-line combination treatment for Pts with RRMM who progressed after receiving BTZ, LEN and DARA during the first and second treatment lines. IXA is administered twice-weekly during the first 3 cycles. Pts receive IXA: 3 mg days (d) 1, 4, 8, 11 of 21-d Cycles (Cy) 1-3; 4mg d 1, 8, 15 of 28-d Cy 4-24. POM 4mg: d 1-14 Cy 1-3; d 1-21 Cy 4-24. DEX 20mg: d 1,2,8,9,15,16 Cy 1-3; d 1,2,8,9,15,16, 22,23 Cy 4-24. Treatment continues until disease progression (PD) or unacceptable toxicity. After completion of 24 treatment cycles, Pts continue POM DEX as standard of care. The primary endpoint is progression free survival (PFS) according to IMWG criteria. Results: Twenty-two Pts (out of the 60 Pts planned) enrolled between February 2021-May 2022. The median age was 71 (range: 53-88), median time from Myeloma diagnosis to study enrollment was 3.7 years; 58% had high risk FISH cytogenetics (t(4:14), +1q21, del17p); 10% had extramedullary disease at study enrollment; 32%, 9%, 73% and 86% of the Pts were refractory to BTZ, cyclophosphamide, LEN and DARA, respectively. Forty-five percent had previously undergone an auto-transplant. At the interim analysis cutoff date of 28-Jun-2022, after a median follow-up of 5.8 months (mo) (95% CI 4.5-7.1), 13 Pts discontinued the study treatment due to disease progression (PD) (n=9, 41%), death (n=2, 9%, 1 each: COVID-19 and cerebrovascular accident) and withdrawal of consent (n=2, 9%). Eighty-six percent of the Pts had at least one treatment emergent adverse event (TEAE) and 59% had a TEAE grade ≥3. TEAE that occurred in ≥10% include neutropenia 27% (23% ≥Gr 3), thrombocytopenia 27% (14% ≥Gr 3), rash 23%, diarrhea 14%, dyspnea 14%, fatigue 14%, COVID-19 14% and pneumonia 14% (14% ≥Gr 3). No Pts discontinued therapy due to an AE. Overall response rate was 53% (10/19 of evaluable Pts); 2 (10%) complete or very good partial response (CR/VGPR); 8 (42%) partial response (PR); 6 (32%) stable disease; 3 (16%) PD. Median time to response was 0.7 (range: 0.4-6) mo. The median PFS and overall survival (OS) were 6.9 [95% CI 2.0-12.0] and not-reached (NR), respectively [Figure 1A]. Median PFS was 10.4 vs 2.2 mo among Pts who achieved at least a PR vs non-responsive Pts, respectively (p=0.005). [Figure 1B]. Conclusions: IPd combination with twice-weekly ixazomib provided an all-oral safe and efficacious therapy in triple-exposed RRMM Pts, most of whom were refractory to both DARA and LEN. Study enrollment is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P925: IMPACT OF PRIOR TREATMENT EXPOSURE ON THE EFFECTIVENESS OF IXAZOMIB-LENALIDOMIDE-DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS TREATED IN ROUTINE CLINICAL PRACTICE (THE INSURE STUDY)

Background: Results from INSURE, a pooled, global analysis of 3 observational studies, show that the effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) used to treat relapsed/refractory multiple myeloma (RRMM) in routine clinical practice is comparable to its efficacy seen in the TOURMALINE-MM1 trial (median progression-free survival [PFS], 19.9 vs 20.6 months [mos]), with no new safety concerns (Leleu ASH 2021 #2701). Data on effectiveness outcomes following retreatment with agents used in earlier lines of therapy (LoTs) are limited, but may be of particular value for MM pts previously treated with lenalidomide (LEN) or proteosome inhibitors (PIs). Aims: To characterize the impact of prior exposure & refractoriness to LEN or PIs on the effectiveness & safety of IRd in RRMM. Methods: INSURE is a pooled analysis of data from 3 studies: INSIGHT MM, UVEA-IXA, & REMIX. INSIGHT MM is a prospective, global study of 4307 MM patients (pts) from 15 countries. UVEA-IXA is a multicenter, longitudinal, retrospective cohort study of 309 RRMM pts receiving ixazomib (IXA)-based therapy via an early-access program in Europe. REMIX is a retrospective/prospective study of 198 RRMM pts treated with IRd via a compassionate-use program in France. INSURE included adult RRMM pts who had received IRd in ≥2nd LoT. Primary outcomes were PFS & time-to-next therapy (TTNT). Secondary outcomes included: duration of treatment (DOT), overall survival (OS), overall response rate (ORR), & safety (discontinuations due to adverse events [AEs] were reported separately for each study). In this prespecified analysis pts were grouped by prior LEN or PI exposure (naïve, exposed, or refractory). Results: 562 pts were included: 391/100/71 were LEN-naïve/exposed/refractory & 37/408/117 were PI-naïve/exposed/refractory. In LEN-naïve/exposed/refractory pts, median age was 69/68/68 years (yrs; 24/14/18% >75 yrs) & 18/13/22% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 (missing pts excluded from %); pts had received a median of 1/2/3 LoT(s) prior to IRd. In PI-naïve/exposed/refractory pts, median age was 71/68/69 yrs (38/22/15% >75 yrs) & 6/16/27% had an ECOG PS ≥2 (missing pts excluded from %); pts in all 3 subgroups had received a median of 2 LoTs prior to IRd. The Table shows effectiveness outcomes. Median DOT was 15.3/15.6/4.7 mos & median PFS was 21.6/25.8/5.8 mos in LEN-naïve/exposed/refractory pts. Median DOT & PFS in PI-naïve/exposed/refractory pts were 20.4/15.2/7.6 mos & not reached/19.7/12.9 mos, respectively. OS data were immature. The proportions of LEN-naïve/exposed/refractory pts in INSIGHT (n=114/39/28) & UVEA-IXA (n=161/15/19) who discontinued a study drug due to AEs were: IXA, 32/28/25% & 19/7/11%; LEN, 22/28/18% & 16/7/11%; dexamethasone (DEX), 18/21/14% & 11/0/11%, respectively. The proportions of PI-naïve/exposed/refractory pts in INSIGHT (n=9/130/42) & UVEA-IXA (n=18/125/52) who discontinued a study drug due to AEs were: IXA, 44/28/31% & 22/17/15%; LEN, 33/22/21% & 17/16/12%; DEX, 33/18/17% & 17/10/8%, respectively. Data for discontinuations due to AEs were not available for REMIX. Additional safety data will be presented. Image:Summary/Conclusion: IRd appeared to be effective in RRMM pts in routine clinical practice regardless of prior LEN or PI exposure, with better outcomes seen in LEN- &/or PI-non-refractory vs -refractory pts. PFS outcomes in the naïve/exposed populations are comparable to those reported in TOURMALINE-MM1. Pts with prior LEN or PI exposure can achieve clinical benefit when retreated suggesting that prior exposure should not preclude use of these agents in later LoTs.

Retrospective, single-center, real-world experience of belantamab mafodotin in relapsed/refractory multiple myeloma.

8060 Background: Belantamab mafodotin (belamaf) is a BCMA antibody drug conjugate approved for the treatment of relapsed refractory multiple myeloma (RRMM) patients (pts) based on the pivotal phase 2 DREAMM-2 study (Lonial et al, Lancet Oncology, 2019), which demonstrated an overall response rate (ORR) of 32%, median progression free survival (PFS) of 2.8 months, and overall survival (OS) of 13.7 months in triple class (proteasome inhibitor, IMiD, and anti-CD38) refractory (TCR) MM. In this single-center retrospective study, we report the efficacy and safety of belamaf in RRMM pts administered in a real-world, standard of care (SOC) setting. Methods: All MM pts who initiated therapy with SOC belamaf, either as monotherapy or in combination, between 11/1/2020 and 11/30/2021 at MD Anderson were included in this study. Response and progression were evaluated using International Myeloma Working Group standard criteria. Keratopathy and best corrected visual acuity (BCVA) adverse events (AEs) were graded per the Keratopathy and Visual Acuity (KVA) scale. The Kaplan-Meier method was used to estimate time to event endpoints. Results: A total of 39 consecutive pts with a median of 7 prior lines of therapy were included in the analysis, of whom 37 pts (95%) received single agent belamaf. Median age was 66 years (range 39-89), 14 of 37 (38%) pts with available FISH had high risk disease (del 17p, t(4;14, and/or t(14;16)), 14 pts (36%) had extramedullary disease, 37 (95%) pts were TCR, 32 (82%) pts were TCR and alkylator-refractory, and 8 pts (21%) were BCMA-refractory. Notably, the majority (69%) of pts in this analysis would have been ineligible for the DREAMM-2 trial based on key eligibility criteria. Median number of belamaf doses administered was 2 (range 1-9). Among 37 pts with measurable, response evaluable baseline disease, the best ORR (≥ PR) was 27% with ≥ VGPR of 3%. The clinical benefit rate (≥ MR) was 35%. Among 8 BCMA-refractory pts, there was 1 PR and 1 MR. Median PFS was 1.8 months and median OS was 9.2 months with a median follow-up of 10.1 months. Median duration of response has not been reached among 10 responding pts. Among 33 pts with a post-treatment ocular exam, 25 pts (76%) developed any grade keratopathy (Grade 1/2/3/4, 9%/55%/12%/0%, respectively) and BCVA changes (Grade 1/2/3/4, 42%/27%/6%/0%, respectively). Median time to first keratopathy or BCVA AE was 1.3 months. The most common reasons for treatment discontinuation were disease progression (75%) and AEs (9%). Conclusions: Our current study in heavily pretreated RRMM pts, of whom the majority would have been ineligible for the DREAMM-2 study, demonstrates an ORR, PFS, and ocular AE profile with SOC belamaf therapy comparable to outcomes reported in the pivotal registration study. Future studies are needed to further define the optimal use and sequencing of belamaf in MM pts, particularly in context of other BCMA-targeting modalities.

Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM).

8005 Background: GC012F is a B cell maturation antigen (BCMA)/CD19 dual-targeting CAR-T developed on the novel FasT CAR-T platform with overnight manufacturing and designed to improve depth of response and efficacy. Data was presented at ASCO and EHA 2021 for initial 19 pts. We present updated data for study (NCT04236011; NCT04182581) with longer follow up and 9 additional pts treated (n = 28) in 3 different dose levels. Methods: From October 2019 to November 2021, 28 heavily pretreated RRMM pts (age 27-76) median of 5 prior lines (range 2-9) were treated on a single-arm, open label, multicenter Investigator Initiated Trial receiving a single infusion of GC012F. 89.3% (25/28) were high risk (HR- mSMART), 8 pts had EM disease, 3 had never achieved a CR including after transplant, 1 pts presented with plasma cell leukemia, 24/28 pts were refractory to last therapy, 3 pts primary refractory. 9/28 pts had received prior anti-CD38, 27/28 pts prior IMiDs. 26/28 pts were refractory to PI, 26/28 pts to IMiDs. After lymphodepletion over 2-3 days (30 mg/m2/d, 300mg/ m2/d Flu/Cy) GC012F was administered as single infusion at 3 dose levels: 1x105/kg (DL1) n = 2, 2x105/kg (DL2) n = 10 and 3x105/kg (DL3) n = 16. Results: As of Jan 26th 2022, 28 pts - median follow-up (f/u) 6.3 mths (1.8-29.9) - had been evaluated for response. Overall response rate (ORR) in DL1 was 100% (2/2)- DL 2 -80% (8/10) DL 3 -93.8% (15/16) with 27 pts MRD negative by flow cytometry (sensitivity 10-4-10-6). 100% of MRD assessable pts (27/27) achieved MRD negativity. One patient out of 28 could not get assessed. At d28, 21/24 assessable patients were MRD negative (81.5%), 4/28 pts could not get d28 MRD assessment f/u due to COVID-19 restrictions however were assessed at a later timepoint. To date best response is MRD- sCR in 21/28 patients(75.0%) across all dose levels. Some pts after short f/u show responses that are still deepening. Cytokine Release Syndrome (CRS) was mostly low grade: gr 0 n = 3 (10.7%), gr 1-2 n = 23 (82.1%), gr 3 n = 2 (7.1%) – no gr 4/5 CRS and no ICANs were observed (Graded by ASBMT criteria). Median duration of CRS was 3 d (1-8 d). PK results showed no difference amongst dose levels DL1 to DL3. Overall, CAR-T median Tmax was 10 d (range 8-14 d), median peak copy number (Cmax) was 97009 (16,011-374,346) copies /μg DNA with long duration of persistence of up to d793 (data cut-off). CAR-T geometric mean AUC0-28 for DL1, DL2 and DL3 were 468863, 631540 and 581620 copies/μg DNA×day, respectively. Pts continue to be monitored for safety and efficacy including DOR. Conclusions: BCMA-CD19 dual FasT CAR-T GC012F continues to provide deep and durable responses with a favorable safety profile in additional RRMM pts across all dose levels demonstrating a very high MRD negativity rate including in pts refractory to anti-CD38, PI and IMIDs. GC012F is currently being studied in earlier lines of therapy as well as additional indications. Clinical trial information: NCT04236011; NCT04182581.