Talvey (talquetamab-tgvs)

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.

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

P2, N=450, Recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2026 --> Dec 2026

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

P1, N=38, Not yet recruiting, Thomas Martin, MD

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

P1, N=182, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Dec 2024 --> Jul 2025

P1, N=15, Active, not recruiting, Janssen Pharmaceutical K.K. | Trial completion date: Dec 2024 --> Aug 2024

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

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

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

P2, N=450, Recruiting, Janssen Research & Development, LLC | N=320 --> 450

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

P1, N=15, Active, not recruiting, Janssen Pharmaceutical K.K. | Recruiting --> Active, not recruiting

P1, N=182, Recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

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

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=320, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jul 2022 --> Mar 2026

Background: Dysgeusia is a common, yet underexamined side-effect of anti-tumor therapy. Our results demonstrate the importance of monitoring taste perception and quality of life changes caused by cancer therapies. The frequency of dysgeusia is underreported in MM patients receiving BCMA bispecifics and melphalan therapy. For optimal nutritional management, hospitals should consider patients' individual taste preferences.

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.

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.

Our findings highlight that the baseline BM immune repertoire and the PB immune changes during Tal treatment may predict long term outcomes. Further in vitro mechanistic studies of T cell function and fitness and validation of these results in independent cohorts will be critical to develop these into predictive biomarkers of long-term response to Tal.

Introduction: Talquetamab (tal), a novel GPRC5D×CD3 bispecific antibody (BsAb), has shown deep and durable responses with overall response rates (ORRs) >71%, including in high-risk populations, and a clinically manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (MM) in the MonumenTAL-1 study (NCT03399799/NCT04634552). Baseline immune profiling in heavily pretreated pts from MonumenTAL-1 suggested that compared to pts with prior TCR, pts with no prior TCR had a favorable immune fitness profile (less T-cell dysfunction and immune suppression). In both cohorts, baseline and longitudinal correlative analyses suggest a mechanism of resistance for nonresponders including lower T-cell counts and higher frequency of Tregs and expression of coinhibitory markers on CD8+ T cells, whereas responders show greater T-cell activation and recovery of CD3+ T cells that was sustained longitudinally. Progression data indicated an exhausted T-cell phenotype for pts who relapsed on tal.

P2, N=50, Not yet recruiting, University of Miami

P1b, N=182, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Sep 2024 --> Dec 2024

Tal+dara showed deep and durable responses with promising mPFS in heavily pretreated patients with RRMM, including refractory to anti-CD38/BCMA and BsAb. Safety profile was clinically manageable; no new signals were identified.

Teclistamab was approved for relapsed/refractory MM therapy in 2022, while elranatamab, linvoseltamab, F182112, talquetamab, and cevostamab are currently undergoing clinical trials. This study summarizes several latest reports on bsAbs for the treatment of MM from the ASCO 2023 Annual Meeting.

Various T-cell redirecting BsAbs are in advanced stages of clinical development with promising activity and a manageable toxicity profile. Ongoing studies are evaluating combination strategies, fixed-duration treatment, and use of BsAbs in earlier lines of therapy. TsAbs hold great promise for the future.

These results demonstrate the potential of talquetamab as a treatment option in people who have used up other available therapy options. The 2 doses of talquetamab identified here are being examined in a larger group of participants to further test for safety and to test how well people respond.

P3, N=1590, Recruiting, Janssen Research & Development, LLC | N=1060 --> 1590 | Trial completion date: May 2033 --> Aug 2033

P1b/2, N=164, Recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1b/2 | Trial completion date: Mar 2024 --> Dec 2025 | Trial primary completion date: Nov 2023 --> Dec 2025

These BsAb show impressive clinical activity for the relapsed/refractory population targeted and will likely become an essential part of MM treatment protocols in the future. In this podcast, the authors summarize and highlight some of the T cell-redirecting BsAb currently in development for the treatment of relapsed/refractory MM with a focus on the data reported at the oral session for BsAb at the American Society of Hematology's 2022 meeting from clinical phase 1 and 2 studies. The six presentations reported the latest safety and efficacy data for the BsAb: talquetamab, elranatamab, teclistamab, forimtamig, and alnuctamab.

BsAbs have shown promising efficacy against RRMM cohorts with a good safety profile. Upcoming phase II/III trials are much awaited, along with the study of other agents in concert with BsAbs to gauge response.

P1b, N=182, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Aug 2023 --> Sep 2024

This activity is supported by educational grants from AbbVie Inc, Genentech, a member of the Roche Group, Genmab US Inc, Karyopharm Therapeutics, Lilly, Regeneron Pharmaceuticals Inc, Sanofi, and Seagen Inc. Clinical and biological factors affecting the selection of up-front therapy for patients with MMLong-term findings with daratumumab-containing regimens for newly diagnosed MM; role for transplant-eligible and ineligible patientsPublished data with novel daratumumab-based quadruplet regimens for transplant-eligible patients with newly diagnosed MMSimilarities and differences between daratumumab and isatuximabKey findings from the Phase III GMMG HD7 trial comparing isatuximab with RVd to RVd alone for transplant-eligible patients with newly diagnosed MMOngoing Phase III studies of isatuximab as a part of induction therapy for transplant-eligible and ineligible patientsAvailable data with and current role of minimal residual disease assessment in therapeutic decision-makingOptimal maintenance approach for transplant-eligible and ineligible patientsResults from Phase III trials evaluating isatuximab-based combination regimens for relapsed/refractory (R/R) MMKey results from the Phase III BOSTON trial leading to the FDA approval of selinexor in combination with bortezomib/dexamethasone for R/R MM; available data with other selinexor-based combinationsStructural makeup and manufacturing of available B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell platformsEfficacy and safety findings from the KarMMa (idecabtagene vicleucel) and CARTITUDE-1 (ciltacabtagene autoleucel) trials for R/R MMAvailable and emerging data with and ongoing studies of BCMA-targeted CAR T-cell therapies in earlier lines of treatmentSimilarities and differences in the cellular targets and mechanisms of action of bispecific antibodies in MMActivity and responses observed with available (teclistamab) and investigational (elranatamab, linvoseltamab, ABBV-383) BCMA-targeted bispecific antibodies in R/R MMBiological rationale for and available data with non-BCMA-targeted bispecific antibodies (eg, talquetamab, cevostamab, forimtamig); FDA breakthrough therapy designation for talquetamabSpectrum, incidence and severity of toxicities, including cytokine release syndrome and neurotoxicity, with bispecific antibodies in patients with MM; mitigation and management protocolsPublished data with and current role of venetoclax-based therapy for patients with MM and t(11;14) or Bcl-2 overexpressionOther promising novel strategies in clinical development for patients with MM

Both schedules of talquetamab demonstrated superior effectiveness vs RWPC treatment for all outcomes assessed. These data highlight the potential of talquetamab as an effective treatment option in patients with TCE RRMM and further support the rationale of planned prospective trials to compare talquetamab- based therapy and standard of care regimens in this patient population.