Abecma (idecabtagene vicleucel)

P3, N=618, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

P2, N=50, Not yet recruiting, Wake Forest University Health Sciences | Trial completion date: Aug 2027 --> Nov 2027 | Initiation date: Aug 2024 --> Nov 2024 | Trial primary completion date: Aug 2027 --> Nov 2027

P2, N=50, Not yet recruiting, Wake Forest University Health Sciences

P1/2, N=49, Not yet recruiting, Omar Nadeem, MD

The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future.

P3, N=618, Recruiting, Celgene

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

P2, N=78, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Apr 2024 --> Dec 2024

P2, N=32, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting

P=N/A, N=50, Recruiting, Bristol-Myers Squibb

P=N/A, N=144, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=240 --> 144 | Trial primary completion date: Jun 2028 --> Feb 2024

P2, N=264, Recruiting, Celgene | Trial primary completion date: Dec 2023 --> Jul 2025

P1, N=15, Recruiting, City of Hope Medical Center | Initiation date: Dec 2023 --> Mar 2024

P2, N=149, Completed, Celgene | Active, not recruiting --> Completed

P2, N=40, Active, not recruiting, Marcelo Pasquini, MD | Recruiting --> Active, not recruiting | Trial primary completion date: Apr 2024 --> Jan 2025

Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells...We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.

P2, N=78, Not yet recruiting, National Cancer Institute (NCI)

This review will explore the earliest CAR-T trials in myeloma, discuss important issues involved in CAR-T manufacturing and processing, as well as review current clinical trials that led to the approval of the two commercially available CAR-T products, Idecabtagene vicleucel and ciltacabtagene autoleucel. The next generation of MM-specific CAR-T will likely include new targets such as G-protein-coupled receptor class C, Group 5, member D (GPRC5D) and signaling lymphocyte activation molecular Family 7 (SLAMF7). The role of CAR-T in the treatment of MM will undoubtedly increase exponentially in the next decade.

P=N/A, N=350, Active, not recruiting, Bristol-Myers Squibb

Introduction: The rapid evolution of novel chimeric antigen receptor T-cell (CAR-T) therapies, including Carvykti (ciltacabtagene autoleucel) and Abecma (idecabtagene vicleucel), have revolutionized the treatment landscape for multiple myeloma (MM) patients...Management strategies mentioned included earlier and more aggressive supportive care, the use of cytokine-targeting therapies such as tocilizumab for any grade CRS, steroids such as dexamethasone for immune effector cell-associated neurotoxicity syndrome, and prophylactic antiseizure medications for all patients regardless of neurotoxicity... The study findings highlight the importance of demystifying cost perceptions against the added value to patients, HCPs and payers, and implementing comprehensive post-CAR-T care protocols aligned with the concerns expressed in social media discussions for improvement in CAR-T therapies for multiple myeloma. By leveraging the power of social media data, this study offers valuable real-world insights that can inform clinical decision-making, enhance patient-centered care, and contribute to the development of strategies to overcome challenges associated with CAR-T therapies in multiple myeloma.

This has led to the approval of idecabtagene vicleucel, ciltacabtagene autoleucel and teclistamab by the FDA, EMA and other regulatory agencies...Tocilizumab was used as cytokine release syndrome (CRS) prophylaxis only by one responder. Keppra neurologic prophylaxis was used by 47... Trends of CAR-T and BiTE therapy use and patterns of concurrent prophylactic and supportive care in MM vary widely among academic centers across the globe, demonstrating a need for further understanding of toxicity pathogenesis, toxicity management and consistent guidelines. This survey also demonstrates the great unmet need for access beyond urban centers among the international myeloma community. Prospective studies and claims data analysis should be utilized to evaluate the longitudinal cost of care, quality of life, duration of response and management of infectious disease, neurological or related complications of CAR-T and bispecific TCE therapies.

N=24 patients initiated a CAR-T therapy as their index therapy (equally split between ide-cel and cilta-cel); the remaining N=31 patients predominantly initiated a treatment regimen containing an IMiD (52%), a PI (55%), an anti-CD38 antibody (13%), or an alkylating agent (36%). Patients did, however, directly report improvement in their disease state as early as Month 1 based on the PGIC. Non-CART patients generally showed a QOL plateau with some modest improvement in disease symptoms which was also reflected in their self-reported assessment of disease state improvement based on the PGIC.

MethodsWe 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...Within 14 d after infusion, 82% developed a cytokine release syndrome (CRS, °I or II), in 30% of which Tocilizumab was applied...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.

We review common toxicities associated with agents approved for RRMM in the past 5 years, including the anti-CD38 monoclonal antibody isatuximab, the antibody-drug conjugate belantamab mafodotin, the bispecific antibody teclistamab, the chimeric antigen receptor (CAR) T cell products idecabtagene vicleucel and ciltacabtagene autoleucel, the selective inhibitor of nuclear export compound selinexor, and the drug-peptide conjugate melflufen, as well as toxicities associated with emerging agents for RRMM including additional bispecific antibodies, the BCL-2 inhibitor venetoclax, and the cereblon E3 ligase modulators iberdomide and mezigdomide. We searched the published literature using PubMed, plus congress abstracts, for the above list of drug names or classes and 'myeloma.' Optimal management of toxicities associated with these recently approved and emerging therapies will be critical in maximizing clinical benefit and aiding widespread adoption in routine clinical practice. We summarize current recommendations and guidelines and provide expert insights into supportive care requirements.

P1, N=15, Recruiting, City of Hope Medical Center | Trial completion date: Jul 2025 --> Mar 2026 | Trial primary completion date: Jul 2025 --> Mar 2026

Patient 3 received 3 sequential therapies with Ide-cel (DOR = 3 mos), teclistamab (DOR = 6 mos), and then talquetamab with daratumumab with an ongoing response of 11 mos...Patient 5 with penta-refractory disease and high disease burden (> 90% BM infiltration) had no response to elranatamab, however achieved an ongoing sCR (DOR = 30 mos) with talquetamab, daratumumab and pomalidomide (Tal-DP)...Therefore, TCE resistance derived from BCMA mutations does not preclude retreatment with another anti-BCMA TCE or CAR T. We here describe variable non-overlapping mechanisms mediating resistance to sequential TCE and CAR T therapies. Dynamic surveillance for antigenic escape and functional evaluation of T cell fitness will optimize immunotherapy sequencing.

P2, N=32, Not yet recruiting, Massachusetts General Hospital

This presentation is intended for U.S. based registered meeting attendees. For In-Person Participants Only

Pts with RRMM who received 2-4 prior regimens, were TCE (IMiD agent, PI, and daratumumab), and had disease refractory to the last regimen were randomized 2:1 to receive ide-cel (target dose range: 150-450×106 CAR+ T cells) or a std regimen (DPd, DVd, IRd, Kd, or EPd per investigator). Presented previously at European Haematology Association Hybrid Congress, June 2023 Clinical Trial Identification: NCT03651128. Table 1.

Background: Cytokine release syndrome (CRS) is a potentially life-threatening, supraphysiologic response following immunotherapy resulting in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Table 1 summarizes data by indication. Incidence of CRS ranged from 56% (104/185) in DLBCL to 72% (66/92) in MCL. Excluding categories with small numbers of cases (<15), CRS incidence also varied by individual CAR-T therapy and underlying indication and ranged from 35% for idecabtagene vicleucel in MM to 73% for brexucabtagene autoleucel in MCL.

Introduction In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P < 0.001) and overall response rate (71% vs 42%, P < 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Methods In the phase 3 KarMMa-3 trial, pts with RRMM who received 2–4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). These data continue to support use of ide-cel in pts with TCE RRMM. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Tocilizumab was administered to 65%, 29% received steroids, and 2% received anakinra. These findings provide insights into potential avenues for toxicity prevention and therapeutic optimization in high-risk patients. Additional studies in a larger patient cohort are warranted to understand the complex relationships between inflammation, immunity, toxicity, and efficacy among TCE RRMM patients treated with ide-cel.

Methods We analyzed 27 RRMM patients (pts) treated with Idecabtagene vicleucel (Ide-cel) at our center. 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.

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...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.

Background and significance: The BCMA-targeted CAR T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are currently approved for relapsed/refractory multiple myeloma (RRMM) patients with ≥4 prior lines of therapy, including an IMID, proteasome inhibitor, and CD38 antibody. This phase 2 study is exploring the efficacy, safety, and feasibility of cevostamab consolidation following BCMA-directed CAR T cell therapy for RRMM, with the goal of sequential T cell engagement against 2 different antigens to eliminate residual disease. Accrual started in July 2023.

In addition, using immunohistological staining, we found that CD70 was expressed on 10 of 10 patients who had progressed on BCMA targeted therapies (seven who had progressed on belantamab mafodotin, an antibody drug conjugate, three who had progressed on idecabtagene vicleucel, a BCMA CAR-T), suggesting that CD70 could be a viable target in patients who have failed BCMA targeted therapy. In summary, we were able to demonstrate that CD70 can be a feasible target for the treatment of multiple myeloma, including in patients who have failed BCMA targeted therapy. Based on these results, we have initiated a Phase I/II clinical trial (NCT05092451) that is currently recruiting.

We performed a retrospective analysis of clinical parameters influencing both collection of autologous lymphocytes and the subsequent manufacturing of idecabtagene-vicleucel with a special focus on T cell senescence, defined as loss of CD27 and CD28...In contrast, a successful manufacturing was not influenced by patient age, sex, remission status at apheresis or number of previous treatment lines. Further analyses are required to determine measures appropriate for further optimization of autologous lymphocyte collections and improvement of collection outcomes in patients with MM.

Several studies have shown reduced efficacy of both FDA approved BCMA targeted chimeric antigen receptor T cell therapies (CAR-T) for myeloma, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), when administered after BCMA targeted bi-specific antibodies...Tocilizumab was administered to 4 (18%) pts... This single center study in patients with heavily pretreated and prior BCMA-TT demonstrated favorable ORR (63%) and CR (36%) rates, comparable to pts in the MajesTEC-1 trial, without prior BCMA-TT exposure. No new safety signals were identified. Results on progression free survival (PFS) and overall survival (OS) will be reported with continued follow up and will be presented in the meeting.

Ide-cel (39%), liso-cel (36%), and axi-cel (17%) were the most used CAR-T cell products. All patients received lymphodepleting chemotherapy with fludarabine/cyclophosphamide...CONCLUSIONS In our comprehensive plasma proteomic profiles analysis, we identified cutoffs for IL3, IL6, IL5 and IL10 that may be predictive for CRS and ICANS regardless of CAR-T cell product. Our results are clinically applicable and may be used to recognize patients at risk for CRS and/or ICANS who may be eligible for prophylactic therapies.