Carvykti (ciltacabtagene autoleucel)

Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and one of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from one patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.

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.

These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma.

P1/2, N=126, Completed, Janssen Research & Development, LLC | Phase classification: P1b --> P1/2

P2, N=86, Completed, Janssen Scientific Affairs, LLC | Active, not recruiting --> Completed

Notably, CAR-T re-expansion is found in three patients, including a fatal case characterized by somatic TET2-mutation, clonal expanded cytotoxic CAR-T, broadened cytokine profiles and irreversible hepatic toxicity. Together, our findings show that a latent phase with distinct immunological changes precedes manifest CRS, providing an optimal window and potential targets for CRS therapeutic intervention and that CAR-T re-expansion warrants close clinical attention and laboratory investigation to mitigate the lethal risk.

P1, N=10, Recruiting, Peter MacCallum Cancer Centre, Australia | N=15 --> 10 | Trial completion date: Aug 2025 --> Jan 2027 | Trial primary completion date: Aug 2025 --> Jan 2026

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.

P1, N=15, Recruiting, Peter MacCallum Cancer Centre, Australia | Not yet recruiting --> Recruiting

P3, N=650, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jan 2034 --> Dec 2034

P2, N=169, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2027 --> Nov 2028

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.

Over 50% of the centers interviewed have recently started to administer tocilizumab to treat mild grade 1 cytokine release syndrome (CRS) in an outpatient setting. Overall, this study further supports the notion that centers can safely administer cilta-cel in an outpatient setting, if appropriate infrastructure is in place. Additional best practices for new outpatient sites include adequate infrastructure, SOPs, a well-trained and multidisciplinary team, and education of patients and caregivers (Table 1). Outpatient management and earlier intervention for low-grade AEs is currently evolving, with more real-world research required.

26) vs standard of care in lenalidomide-refractory patients with multiple myeloma and 1-3 prior lines of therapy...The patient received CHOEP-21 (cyclophosphamide-doxorubicin-vincristine-prednisone-etoposide) and achieved metabolic CR but relapsed soon after treatment was stopped. Subsequent treatment with gemcitabine-dexamethasone-cisplatin-alemtuzumab was followed by consolidation with fludarabine plus melphalan and matched allogeneic stem cell transplant... To our knowledge, this is the first case of CAR+ TCL occurring after infusion of a CAR-T therapy produced via lentiviral transduction (cilta-cel). This rare malignancy was potentially driven by genetic mutations (e. g.

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.

Our findings on remanufacturing and recollection outcomes may inform physician decisions and help optimize time-to-treatment in patients receiving cilta-cel. Additional studies (eg, NCT05347485) are underway to evaluate the safety and efficacy of OOS cilta-cel.

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.

P3, N=750, Recruiting, European Myeloma Network

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.

P2, N=169, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: May 2025 --> Jun 2027

Sponsored by Johnson & Johnson

In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated better efficacy than physician's choice (daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with an overall response rate (ORR) of 84.6% versus 67.3% and ≥complete response (CR) of 73.1% versus 21.8% (San-Miguel et al. Overall, cilta-cel offers substantial clinical and economic benefit for patients with RRMM. The CPR analysis of data from CARTITUDE-4 estimated that, for patients with RRMM, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower compared to physician's choice (DPd or PVd). Treatment acquisition and subsequent treatment costs appear to be key drivers for total direct medical costs.

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.

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.

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.

Introduction: Cilta-cel is a dual-binding, BCMA-targeting CAR-T cell therapy that has shown high rates of deep and durable response in patients (pts) with relapsed/refractory multiple myeloma (RRMM), and significantly prolonged PFS vs SOC in pts with lenalidomide-refractory MM after 1–3 prior lines of therapy (LOT; HR, 0.26) in the phase 3 CARTITUDE-4 trial...90% of pts with CNP had preceding CRS (all gr 1/2; median onset, d 7; median duration, 3 d); 13 received tocilizumab for CRS... Pts treated with CAR-T cells, including cilta-cel, may experience CNP. The pathogenesis of the events in these 3 studies was unknown/idiopathic, but it is important to rule out etiology of infection or MM progression. Most cases were low-grade and resolved with a limited course of corticosteroids.

We observed that venetoclax-resistant clones were resistant to most standard-of-care anti-MM agents including alkylating agents (Melphalan, cyclophosphamide, bendamustine), proteasome inhibitors (bortezomib and carfilzomib) or immunomodulatory drugs (lenalidomide and pomalidomide) than parental cells, suggesting a broad resistance to anti-cancer agents possibly due to reduced apoptotic signaling...Simultaneous inhibition of MCL1 (via S63845) or BCL-XL (via A155463) and BCL2 (via venetoclax) increased BIM release and enhanced cell death in the resistant clones compared to single agents, with combination index (CI) values < 0.3 in all doses tested...We observed that both antibody-dependent cellular cytotoxicity (ADCC) induced by Daratumumab and BCMA targeting CAR-T cells induced comparable cell death in venetoclax-resistant clones and parental cells. Moreover, myeloma cells from a patient with t(11; 14) MM progressing on venetoclax, showed significant cytotoxicity to anti-BCMA CAR T cells in vitro and achieved a deep response subsequently when treated with Cilta-cel. In conclusion, we report that resistance to venetoclax confers broad resistance to standard-of-care myeloma drugs and that immunotherapies, especially CAR-T cells and CD38 monoclonal antibody, may remain effective, thus conferring potential benefits in managing acquired resistance to venetoclax.

CAR T-cell products were axi-cel, n= 101 (25%); brexu-cel, n = 24 (6%); cilta-cel, n = 21 (5%); liso-cel, n = 46 (11%); ide-cel, n = 25 (6%); tisa-cel, 12 (3%); and investigational CD19 or CD20 CAR T-cell products, n = 174 (43%). A logistic regression model using pre-LD ANC, platelet, Hb, LDH, CRP, and ferritin showed improved discrimination and sensitivity compared to CAR-HEMATOTOX in our training set, but both models had low specificity (poor ability to "rule in" pts at risk of severe hematotoxicity) and thus low clinical utility at this time. We plan to further improve our predictive models by incorporating post-infusion biomarkers of systemic inflammation that we have previously shown to be associated with delayed count recovery after CAR T-cell therapy (Juluri, Blood Advances 2022).

To determine how antigen levels affect response to BCMA-directed CAR T-cell therapy, we performed quantitative flow cytometric measurements of BCMA antibody binding capacity (ABC) on fresh tumor samples from patients with rel/refractory multiple myeloma (RRMM), including 27 patients treated with idecabtagene vicleucel or ciltacabtagene autoleucel. BCMA expression in patients with RRMM is lower than CD19 expression typically seen in patients with B cell malignancies. Furthermore, while complete loss of BCMA after CAR T cell therapy is uncommon, resistant or relapsed disease frequently expresses low levels of antigen. In vitro and in vivo modeling show that these levels are below the threshold required for optimal CAR T cell function.

Further, certain baseline patient-intrinsic and tumor characteristics may explain the longer DOR in the RRMM setting. These investigations help identify markers of response to cilta-cel and may lead to CAR-T cell design or manufacturing strategies that enhance drug product characteristics and thus clinical efficacy.

Seven patients (30.4%) were previously treated with belantamab...Post-CAR T ferritin max correlated with the baseline b2m (p<0.001) and tocilizumab dose number (p=0.009) but none correlated with peak CAR T expansion (p=0.315)... In our single-center study of comparative analysis of commercial BCMA targeting CAR T-cell treatments, peak CAR T-cell expansion showed a positive correlation with +1 and +3 month post-CAR-T clinical responses. Despite the delayed peak expansion with ciltacel, the expansion was more robust with a higher level of circulating CAR T-cells. Baseline ALC or fludarabine dose reduction did not have an impact on overall CAR T expansion in combined cohort.

Noting superior target binding, functional efficacy and minimal basal activation of effector cells expressing the D8 binder in Fab format we then assessed this construct against standard BCMA targeting CARs based on the bb2121 and LCAR-B38M binders used in Ide-Cel and Cilta-Cel respectively. We report a unique approach to prolong CAR persistence in MM by developing a CAR T cell co-expressing a sensitive BCMA CAR construct and CD19 CAR with proven durability. We report feasibility of double transduction, the first clinical use of a FabCAR and a unique trial design allowing comparison of treatment with single vs dual targeting CAR constructs.

We also provide additional evidence associating immunosuppressive MDSC populations in BM and PB patients with a shorter PFS. Ongoing studies will further analyze the role of the immune microenvironment and clonal T cell dynamics in relation to patient outcomes.

A total of 101 patients treated with CAR T cells were included – 45 with ciltacabtagene autoleucel, 37 with idecabtagene vicleucel, and 19 with other products on clinical trials. Although CAR T-cell therapy is a highly effective treatment option for patients with multiple myeloma, outcomes of infused patients can be highly variable. Serologic biomarkers like fibrinogen and ferritin are routinely assessed in patients undergoing CAR T-cell therapy and could offer value as predictors of outcomes. We found that higher fibrinogen and ferritin values at baseline were associated with inferior OS after CAR T-cell therapy, even after controlling for tumor burden.

P3, N=750, Recruiting, European Myeloma Network | Not yet recruiting --> Recruiting

"1 A total of 252 plasma, germline and tumor samples from 28 patients receiving BCMA directed standard of care CAR-T therapy (idecabtagene vicleucel, n=23 or ciltacabtagene autoleucel, n=5) were sequenced to assess the dynamics of ctDNA. ctDNA-MRD levels correlate with clinical MRD, and ctDNA negativity on day 90 is associated with improved PFS. ctDNA-MRD can potentially provide comparable information to clinical bone marrow MRD."

Currently, two B-cell maturation antigen (BCMA)-directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.

The highest number of AEs mentioned by the report was observed for tisagenlecleucel (mean = 6.7), with the lowest for ciltacabtagene (mean = 1.3). Cytopenias represent one of the most frequently reported AEs in FAERS, a CAR T-cell therapy is indicated, with haematopoetic leukopenia being the most common. When comparing different CAR-T cell therapies, the cytopenias' reporting odds ratio was particularly high for tisagenlecleucel, especially in relation to hematopoietic erythropenia.