Blenrep (belantamab mafodotin-blmf)

P1/2, N=68, Active, not recruiting, Australasian Myeloma Research Consortium | Recruiting --> Active, not recruiting

P2, N=33, Not yet recruiting, Cristiana Costa Chase, DO | Initiation date: Mar 2024 --> Jun 2024

P1/2, N=5, Completed, Mayo Clinic | Active, not recruiting --> Completed | Trial completion date: May 2026 --> Mar 2024 | Trial primary completion date: May 2025 --> Mar 2024

P1/2, N=300, Active, not recruiting, Karyopharm Therapeutics Inc | Phase classification: P1b/2 --> P1/2 | N=518 --> 300 | Trial completion date: Jan 2025 --> Apr 2027 | Trial primary completion date: Jan 2025 --> Apr 2027

P1/2, N=10, Active, not recruiting, University of Maryland, Baltimore | Recruiting --> Active, not recruiting | N=64 --> 10 | Trial primary completion date: Mar 2024 --> Jun 2023

P1/2, N=37, Recruiting, University of Texas Southwestern Medical Center | Not yet recruiting --> Recruiting

P2, N=20, Recruiting, Roswell Park Cancer Institute | Trial completion date: Feb 2026 --> Sep 2026 | Trial primary completion date: Feb 2026 --> Sep 2026

P2, N=50, Not yet recruiting, Massachusetts General Hospital | Initiation date: Nov 2023 --> Jun 2024

P1/2, N=88, Not yet recruiting, Alliance for Clinical Trials in Oncology

P2, N=33, Not yet recruiting, Cristiana Costa Chase, DO | Initiation date: Nov 2023 --> Mar 2024

P2, N=221, Active, not recruiting, GlaxoSmithKline | Trial completion date: Aug 2023 --> Jul 2024

P1/2, N=24, Recruiting, Yale University

P1, N=124, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting | Phase classification: P1/2 --> P1 | Trial completion date: Jun 2027 --> Feb 2028 | Initiation date: Feb 2023 --> Jun 2023 | Trial primary completion date: Jun 2027 --> Sep 2027

P=N/A, N=30, Completed, Duke University | Enrolling by invitation --> Completed

P1/2, N=197, Recruiting, Sanofi | N=123 --> 197 | Trial completion date: Nov 2028 --> Dec 2027 | Trial primary completion date: Nov 2028 --> Dec 2027

P1/2, N=9, Terminated, GlaxoSmithKline

Median time since diagnosis was 9 years with a median of 5 prior therapies (range: 4- 7) including Auto-SCT (n=7), Allo-SCT (n=1); all patients had received lenalidomide, pomalidomide, bortezomib, carfilzomib & daratumumab, 2 patients had BCMA CAR T cell therapy. The RP2D of BelCyd is 2. 5 mg/kg Q6W plus Cy 500 mg & dexa 40mg; no new safety signal was seen. BelCyd activate NK, cytotoxic T cells & macrophages adding to Bel direct MM cytotoxicity.

A single dose of CAR2 Anti-CD38 CAR-T cells was administered 2 days post lymphodepletion with single-agent cyclophosphamide 1. This phase I trial demonstrated that CAR2 anti-CD38 A2 CAR-T cells were generally well tolerated at the Cohort 2 (MTD) dose and demonstrated objective though short responses even in patients progressing after daratumumab and belantamab mafodotin. More clinical studies are needed to optimize the efficacy and tolerability of CAR-T cell therapies for patients with RRMM. This study was completed, and no more patients will be enrolled.

The Phase 3 DREAMM-3 trial (NCT04162210) evaluated single-agent belamaf vs. pomalidomide plus low-dose dexamethasone in patients with RRMM at second relapse or later (Weisel et al. PopPK and E-R analyses for DREAMM-3 demonstrated the impact of disease factors and patient characteristics on PK, efficacy, and safety endpoints following single-agent belamaf, consistent with prior results for later-line populations.

P1/2, N=36, Recruiting, Hellenic Society of Hematology | Not yet recruiting --> Recruiting

P2, N=62, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

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.

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

P3, N=16, Terminated, GlaxoSmithKline | N=25 --> 16 | Trial completion date: Jun 2023 --> Nov 2022 | Recruiting --> Terminated | Trial primary completion date: Jun 2023 --> Nov 2022; The study has been terminated for reasons pertaining to feasibility

P1, N=15, Active, not recruiting, GlaxoSmithKline | Trial completion date: Jun 2023 --> Dec 2024

P1/2, N=464, Recruiting, GlaxoSmithKline | Trial completion date: Feb 2028 --> Feb 2029 | Trial primary completion date: Feb 2025 --> Feb 2026

In conclusion, selinexor-based therapy provides an additional treatment option in the real word setting and with appropriate dosing and toxicity management a subset of patients may have significant benefit.

Twenty-one (75%) pts had previously received daratumumab (dara) (12 [42.9%] dara refractory pts), while 24 (86%) pts had previously received bortezomib, both with median of 4 (1-10) prior treatment lines. Results suggest belamaf could be a treatment option for RRAL amyloidosis, a difficult to treat population. Further evaluation of belamaf in combination with other active agents could allow longer intervals (i.e., 8-12 weeks) between belamaf doses, which has shown to reduce ocular toxicity, while maintaining efficacy.

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.

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.

Additionally, 52% had prior exposure to anti-BCMA therapies, including belantamab mafodotin (31%), anti-BCMA CAR T-cell therapies (37%), and anti-BCMA bispecific antibody therapies (4%), with some having exposure to multiple prior anti-BCMA therapies (17%). Tec is an effective therapy in RRMM with a slightly lower efficacy observed in patients with prior anti-BCMA therapy exposure. PFS reductions among these anti-BCMA exposed patients may be partly due to independent disease associated risk factors. A pre-Tec peripheral blood T-cell population enriched with highly cytotoxic effector T-cells was associated with response to therapy, while suppressive TIGIT+Tregs were associated with nonresponse, suggesting a potential therapeutic role for TIGIT blockade or CD25+ cell depletion to enhance the therapeutic efficacy of bispecific antibodies.

P3, N=357, Recruiting, GlaxoSmithKline | Trial completion date: Dec 2027 --> May 2029 | Trial primary completion date: Oct 2023 --> Sep 2024

P1/2, N=66, Active, not recruiting, Hellenic Society of Hematology | Recruiting --> Active, not recruiting | Trial completion date: Feb 2027 --> Nov 2028 | Trial primary completion date: Jul 2021 --> Sep 2028

P1/2, N=36, Recruiting, Hellenic Society of Hematology | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2023 --> Feb 2027 | Trial primary completion date: Jun 2023 --> Feb 2027

P2, N=47, Recruiting, University of Pennsylvania | Active, not recruiting --> Recruiting

P2, N=83, Recruiting, University of Chicago | Not yet recruiting --> Recruiting

P3, N=325, Active, not recruiting, GlaxoSmithKline | Trial completion date: Mar 2025 --> Jun 2025

First, we produced CD19 and SLAMF7 CAR-T cells with truncated EGFR as transduction marker and incubated the cells with clinically relevant doses of fludarabine, mafosfamide and dasatinib in an unspecific approach. To generate construct-specific effects, we next co-cultured CAR-T cells with PBMC or subsets thereof, in the presence or absence of the anti-EGFR antibody cetuximab. Additionally, we transduced CAR-T cells to express BCMA and exposed them to the antibody-drug conjugate (ADC) belantamab-mafodotin, a monoclonal antibody against BCMA conjugated with cytotoxic agent mafodotin... We demonstrate that different CAR-T cell depletion strategies have unique advantages and challenges. ADCC based depletion strategies are highly CAR specific, but rely on a functional NK cell compartment. Similar specificity with diminished NK cell dependency can potentially be reached by the use of ADCs.

Three months after initiation of belamaf, the pt had progressive disease and teclistamab was initiated, but failed to induce another response. BCMA-directed treatment, especially CAR-T cell treatment, opens a new therapeutic era in RRMM. So far, limited data exist on mechanisms of resistance. Here, we report genetic alterations in the TNFRSF17 gene in 2 pts with underlying HR disease and early and atypical relapse after CAR-T treatment.

P2, N=33, Not yet recruiting, Cristiana Costa Chase, DO | Trial completion date: Apr 2027 --> Sep 2027 | Initiation date: Jun 2023 --> Nov 2023 | Trial primary completion date: Apr 2025 --> Sep 2025