Elrexfio (elranatamab-bcmm)

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

P2, N=120, Recruiting, Pfizer | N=92 --> 120

P1, N=90, Recruiting, Pfizer | N=14 --> 90

P2, N=50, Recruiting, PETHEMA Foundation | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Nov 2023

P2, N=187, Active, not recruiting, Pfizer | Trial completion date: Apr 2024 --> Dec 2025

P1, N=100, Recruiting, Pfizer | Not yet recruiting --> Recruiting | Trial completion date: Jun 2028 --> Mar 2028 | Trial primary completion date: Aug 2026 --> Apr 2027

P2, N=50, Not yet recruiting, PETHEMA Foundation

P1, N=101, Completed, Pfizer | Active, not recruiting --> Completed

P2, N=20, Not yet recruiting, Odense University Hospital | Initiation date: Jan 2024 --> May 2024

P3, N=492, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1, N=100, Not yet recruiting, Pfizer

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=92, Recruiting, Pfizer | Phase classification: P1b/2 --> P2 | Trial completion date: Sep 2027 --> Jun 2027 | Trial primary completion date: Mar 2025 --> Jul 2025

P2, N=50, Not yet recruiting, European Myeloma Network

P2, N=39, Active, not recruiting, Pfizer | Phase classification: P1b/2 --> P2

P=N/A, N=1, Completed, Pfizer | N=646 --> 1

The most common (occurring in ≥3 &lsqb;15%] patients) cytopenias were neutropenia (30%; G3/4 25%), lymphopenia (20%; G3/4 15%), and thrombocytopenia (15%; G3/4 10%). CONCLUSIONSEarly safety data (median treatment duration <1 month) from this ongoing expanded access protocol of elranatamab in patients with RRMM are consistent with results from the phase 2, registrational MagnetisMM-3 trial, with no new safety signal identified.

Treatment regimens in the RWD sources included various combinations of PIs (carfilzomib- and bortezomib-based regimens were each used by 43% and 15% of patients, respectively), IMiDs (lenalidomide- and pomalidomide-based regimens were used by 9% and 41% of patients, respectively), and mAbs (daratumumab- and isatuximab-based regimens were used by 32% and 1% of patients, respectively), among other agents (eg, selinexor-based regimens were used by 5% of patients). 66, respectively). CONCLUSIONSAmong BCMA-naïve patients who resemble those enrolled in the MM-3 trial, those treated with ELRA exhibit significantly longer PFS and OS compared with real-world treatments.

CONCLUSIONSIn this MAIC, elranatamab demonstrated significantly higher ORR, higher ≥CR rate, longer PFS, and longer OS compared with PCT in the real-world. These results suggest that elranatamab offers significantly improved outcomes versus standard treatments used in patients with TCE/R MM in clinical practice.

P3, N=492, Not yet recruiting, Pfizer

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

Belantamab Mafodotin (BeMa) is an anti-BCMA antibody-drug conjugate licensed for treatment of relapsed-refractory Multiple Myeloma (MM) patients...Treating the same cell lines with Elrnatamab (a bi-specific a-BCMA antibody), in presence of T cells for 4- 24 h at an E:T ratio of 1:5 and 1:10, we found that cytoplasmatic LDs decreased in U266-S compared to OPM2-R, associated in U266 to increased levels of LOOH, GPX4 and SLC7A11 confirming a ferroptosis-primed resistant phenotype when BCMA is targeted also by Elranatamab...In this study, for the first time, we defined ferroptosis as novel mechanism of action of BeMa, addressing the role of ferroptosis inducers as an emerging class of agents to get combined for next generation immunotherapy. 218

P1, N=14, Recruiting, Pfizer | Phase classification: P1b --> P1

Second, we studied the lipid metabolic changes upon anti-BCMA exposure with Elranatamab (EL), an investigational, off-the-shelf, humanized BCMA-CD3-directed bispecific antibody engineered to elicit potent T-cell-mediated anti-MM activity. Conversely, in OPM2, inducing iron-dependent lipid peroxidation through RSL3 (3 µM) treatment rescued EL resistance, resulting in a time-dependent increase in cytosolic lipid peroxidation beginning at 6 hours, and overt cell death via ferroptosis at 18 hours. Taken together, our findings suggest that MUFA/PUFA ratio drives ferroptosis and mediates EL sensitivity, addressing lipid handling as a novel means to tailor immunotherapy in RRMM.

These data demonstrate that My-DST can identify drug resistance to bispecific antibodies with ex vivo cultures that contain the patients' own T cells. The results suggest that most cases of bispecific antibody resistance are due to T cell health or number, rather than low BCMA expression. This supports BCMA-targeted re-treatment in patients with adequate T cell health.

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.

P4, N=72, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1b/2, N=105, Recruiting, Pfizer | Trial completion date: Feb 2028 --> Sep 2027 | Trial primary completion date: Aug 2025 --> Mar 2025

Both Elranatamab (ELR) and Teclistamab (TEC) target B-cell maturation antigen (BCMA)...received tocilizumab (toci) and 2 toci and steroids, respectively (all 4 ELR)... Despite its limitations (small groups, short follow-up), this preliminary real- world data shows promising response rates for BCMA-targeting TCEs with an ORR of 71% and a PFS of 7.1 mos. within extensively pretreated patients. Immune-mediated AEs were manageable using standard procedures for CRS.

Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359 .

Cytokine induction in pts experiencing CRS in prior-exposed BCMA patients was often different compared to BCMA naïve patients. Distinct immune cell signatures derived from gene expression analysis of the TME were observed in pts with prior BCMA-directed CAR-T therapy.

MRD-negativity was achieved in 89.7% of evaluable patients. Consistent with available evidence, initial results confirmed better long-term outcomes in MRD-negative patients.

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.

Currently, elranatamab is being investigated in a few clinical studies, and the preliminary results are very encouraging. At the time of writing this review there were no full papers published and all of the data in the literature were based on abstract presentations which carry limitations.

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.

P=N/A, N=1, Not yet recruiting, Pfizer

P1, N=110, Not yet recruiting, Genentech, Inc.

P1b, N=14, Recruiting, Pfizer | N=56 --> 14

P1b/2, N=39, Active, not recruiting, Pfizer | N=17 --> 39

P3, N=854, Recruiting, Pfizer | Trial completion date: Dec 2025 --> Aug 2026

P3, N=854, Recruiting, Pfizer | N=589 --> 854