Tecvayli (teclistamab-cqyv)

Primary resistance is characterized by a low T-cell/MM cell-ratio and Treg-driven immunosuppression, while reduced T-cell fitness due to continuous BsAb-mediated T-cell activation may contribute to development of acquired resistance.

P=N/A, N=180, Recruiting, Janssen-Cilag Ltd. | Trial completion date: Jul 2024 --> Jan 2026

P3, N=795, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jun 2027 --> Apr 2026

These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov, NCT03145181/NCT04557098.

P2, N=20, Not yet recruiting, Case Comprehensive Cancer Center

P2, N=103, Not yet recruiting, Nantes University Hospital

P3, N=1590, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: May 2029 --> Apr 2031

P1, N=289, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2024 --> Aug 2025

P3, N=587, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Oct 2026 --> Dec 2028

P1, N=282, Recruiting, Janssen Research & Development, LLC | Trial completion date: Mar 2026 --> Jul 2026

P=N/A, N=180, Recruiting, Janssen-Cilag Ltd.

P1, N=140, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jun 2024 --> Oct 2024

P4, N=15, Not yet recruiting, University Health Network, Toronto

P3, N=795, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

P3, N=795, Not yet recruiting, Janssen Research & Development, LLC

P2, N=300, Recruiting, University of Alabama at Birmingham | Not yet recruiting --> Recruiting

P1, N=282, Recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2025 --> Mar 2026

P1, N=140, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

P1, N=152, Recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

P1/2, N=40, Active, not recruiting, Janssen Pharmaceutical K.K. | Recruiting --> Active, not recruiting

P1, N=290, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

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.

CRS prophylaxis with tocilizumab was reported by 11% of practices. As patient care models evolve, outpatient or community-based SUD may become more common in the future. Ongoing evidence generation on RW treatment outcomes of various SUD models and AE management strategies is warranted.

Instead, we generated datasets employing in vitro and in vivo models for ISB 2001 and teclistamab (possessing a similar mode of action). However, to our knowledge this is the first time that a starting dose in clinical studies of a trispecific TCE, lacking species cross-reactivity and therefore a GLP toxicology preclinical package, has been derived based on integrated preclinical data analysis utilizing a QSP model. Clinical evaluation of ISB 2001 is ongoing in a phase I dose escalation and dose expansion study in subjects with relapsed/refractory MM (NCT05862012).

He was then treated with gemcitabine, oxaliplatin, and daratumumab but progressed after eight cycles on treatment with abdominal and perisplenic masses confirmed on biopsy to be PBL He was then initiated on teclistamab, which was continued weekly. In our cases, teclistamab was a well tolerated therapy, even in our patient with significant comorbidities. This report provides a foundation for future prospective, multicenter clinical trials to evaluate the efficacy and safety of teclistamab in the treatment of relapsed and refractory PBL.

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=70, Recruiting, University of Heidelberg Medical Center | N=50 --> 70 | Trial completion date: May 2027 --> Oct 2027 | Trial primary completion date: May 2026 --> Oct 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.

P1/2, N=164, Recruiting, Janssen Research & Development, LLC | Phase classification: P1b/2 --> P1/2

P2, N=50, Recruiting, University of Miami | Not yet recruiting --> Recruiting

P2, N=194, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: May 2025 --> Sep 2025

Teclistamab and Belantamab Mafodotin (Belamaf) are currently approved for RRMM in Europe with several Bispecific T Cell Engagers (TCE) under investigation...All patients received aciclovir prophylaxis, PJP prophylaxis (co-trimoxazole/ azithromycin) was given in 100% with TCE and 82% with Belamaf, with anti-fungal prophylaxis in 1 TCE patient... Patients treated with Belamaf were frailer than those receiving TCE. Hypogammaglobulinemia was more profound with TCE and the per patient risk of infections was higher. IVIg use was substantially higher for TCE than Belamaf.

This sample came from a patient who relapsed after an initial response to a BCMA CAR-T, followed by a progression occurring quickly while on a BCMA bispecific antibody Teclistamab, suggesting the loss of BCMA expression as a mechanism of resistance in both treatments...Conclusions. DNA sequencing approaches are cost-effective alternatives to FISH, the current standard diagnostic technology, to detect genomic abnormalities in multiple myeloma and they can identify clinically meaningful markers related to prognosis and treatment, particularly in the emerging era of immunotherapeutics where antigen evasion is a key mechanism of molecular resistance.

The modeling and simulation results showed that a single dose of tocilizumab given prophylactically at 8 mg/kg could block IL-6R RO for approximately 10 days following the 1st step up dose of teclistamab. The results further support this approach for lowering overall risk of CRS during the SUD schedule in multiple myeloma patients treated with teclistamab.

Tocilizumab is a monoclonal antibody targeting the interleukin-6 receptor (IL-6R) which is used to manage CRS resulting from T-cell redirection therapy. Follow-up of participants during the study will include monitoring for all adverse events, disease progression, and survival until end of study. By studying the feasibility and safety of administering the step-up dosing schedule in an outpatient setting, teclistamab may become more accessible to pts with RRMM and limited treatment options.

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.

The prior administration of the bispecific antibody teclistamab had no significant impact on the quantitative cellular composition at the time of leukapheresis... We demonstrate that differences between MM patients achieving a CR and patients with suboptimal response upon anti-BCMA CAR T cell therapy can already be identified at the time of leukapheresis. Long-term changes associated with CR include a diversification of the TCR repertoire. Successful CAR T cell manufacturing is hampered by exposure to bispecific antibodies but can be successfully achieved by allowing for a wash-out phase of ca.

Patients responding to tec exhibited a differential immune profile in early cycles compared with nonresponders, with greater transient T-cell activation. In contrast, an exhausted T-cell phenotype was sustained in nonresponders during the first 2 treatment cycles. While mutations in BCMA cannot be excluded, we did not detect BCMA loss as a mechanism of relapse, but observed a dysfunctional immune phenotype at PD, with increased T-cell exhaustion and higher frequency of gamma delta T cells and immunosuppressive Tregs.

Additionally, we evaluate the influence of teclistamab (T-cell engager CD3/BCMA bispecific antibody) on CD8+ T cell activity against autologous MM cells, as well as the efficacy of CAR-T cells in killing MM cells. Through the testing of standard-of-care drugs alongside immune agents, our pipeline has identified the combination of bortezomib + daratumumab as a synergistic approach with significant translational potential, warranting further investigation...The advantages offered by our system are threefold: i) it enables pharmaceutical companies to test new compounds in a bona fide, patient-derived model; ii) it assists clinicians in selecting the best therapy for their patients, and iii) it helps prevent cancer patients from receiving non-suitable therapies. This approach can also be promptly applied to other liquid cancers, such as leukemia and lymphoma.

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.

Here we present genetic profiling of a multi-refractory MM patient who relapsed to PIs, anti-BCMA (Teclistamab), and anti-GPRC5D (Talquetamab) BsAbs. However, the role of B2M alterations in disease progression and drug resistance needs to be elucidated. Predicting the biological impact based on 3D structural models remains speculative, thus, functional confirmation introducing the BCMA and B2M alterations in cell line models by genetic engineering is pending.