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Background Patients with triple-class (Protease Inhibitor [PIs], Immunomodulatory Drug [IMiD], and anti-CD38 monoclonal antibody [mAb]) exposed multiple myeloma (MM), have a poor prognosis, with limited therapeutic options. Further, older patients and those who receive multiple lines of therapy poorly tolerate available agents. Effective, well-tolerated therapies with novel mechanisms of action are urgently needed.IDP-023 is an investigational allogeneic g-NK cell product with potent antibody-dependent cellular cytotoxicity and high NKG2C/low NKG2A expression enabling HLA-E targeting. We report safety, preliminary efficacy and recommended phase 2 dose (RP2D) determination from a multicenter, first-in-human dose-escalation study of IDP-023 in RRMM.Methods Eligible patients had RRMM with prior exposure to PIs, an IMiD and CD38-mAb ( NCT06119685). Patients received lymphodepletion conditioning with cyclophosphamide/fludarabine followed by 1-3 doses of 5x109, 10x109, or 20x109 IDP-023 cells on either a weekly (QW) or every-other-day dosing (QOD) schedule without (n=3) or with (n=19) IL-2 cytokine support and without (n=9) or with (n=13) CD38-mAb. The primary objectives were to determine overall safety/tolerability, maximum tolerated dose (MTD)/maximum assessed dose (MAD) and RP2D. Adverse Events (AEs) were reported per CTCAE v5.0. The dose limiting toxicity (DLT) windows were 21 and 28 days for the QOD and QW schedules, respectively. Anti-tumor activity was assessed according to International Myeloma Working Group criteria.Results As of September 5, 2025, 22 patients were enrolled in 5x10 9 (n=12), 10x109 (n=7), and 20x109 (n=3) dose cohorts. The median age was 68 (range, 56 - 77) years. The median number of prior therapies was 6 (range, 2 - 17) and 11 patients (50%) received prior BCMA-targeting therapy, including CAR-T. No DLTs, ICANS or >Gr2 CRS were reported. Treatment-emergent AEs (TEAEs) occurring in >30% of the patients were neutropenia (18, 81.8%), leukopenia (14, 63.6%), anemia (12, 54.5%), lymphopenia (12, 54.5%), thrombocytopenia (11, 50%), hypokalaemia (9, 40.9%), diarrhoea (8, 36.4%) and cytokine release syndrome (7, 31.8%). 18 patients (82%) experienced grade > 3 TEAEs. No patients experienced TEAEs that led to treatment discontinuation. The RP2D in combination with CD38-mAb will be reported.Deep responses, including Very Good Partial Responses or better were observed in heavily pretreated RRMM patients across risk categories. Follow-up is ongoing; updated efficacy outcomes will be presented.Conclusions IDP-023 off-the-shelf allogeneic g-NK-cell therapy alone or in combination with CD38-targeting mAb at doses up to 20x10 9 x 3 was well tolerated in patients with RRMM with promising safety and preliminary efficacy profile. Patient follow-up is ongoing for mature response and durability.Acknowledgements We would like to thank the patients and their families for contributing in this study.Trial Registration NCT06119685Ethics Approval Participants have given informed consent before taking part in the study. The study has obtained ethics approval at all active sitesand the specific IRB information is below: Site No. | Site Name | IRB Name | IRB Registration No. | IRB Approval Date ---------|-----------------------------------------------------------|------------------------|----------------------|------------------- 1104 | MDACC | MDACC | IRB00000121 |7/14/23 1393 | NEXT Virginia | Salus IRB | IRB00006833 | 9/19/23 1409 | Providence Cancer Institute | Advarra | IRB00000971 |2/14/24 1410 | M Health Fairview - University of Minnesota Masonic Cancer| University of Minnesota| IRB00010642 | 10/4/23 |Center | | | 1074 | Weill Medical College of Cornell University | Advarra | IRB00000971 | 11/9/23 1425 | SCRI Oncology Partners |Castle IRB | IRB00012054 | 7/24/24 1428 | Valkyrie Clinical Trials | Advarra | IRB00000971 | 7/24/24Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.