IDP-023 Plus Isatuximab Elicits Responses in Daratumumab-Refractory Multiple Myeloma

The allogeneic g-NK cell therapy IDP-023 combined with isatuximab-irfc (Sarclisa) produced responses and progression-free survival (PFS) that compared favorably with historical isatuximab monotherapy data in patients with heavily pretreated, daratumumab (Darzalex)–refractory relapsed/refractory multiple myeloma, according to findings from a first-in-human phase 1/2 study (NCT06119685) presented at the 2026 SITC Annual Meeting.¹

The combination was well tolerated, with no dose-limiting toxicities (DLTs), treatment-related discontinuations, or treatment-related deaths reported. The most common adverse effects (AEs) were cytopenias related to lymphodepleting chemotherapy; all instances of cytopenia resolved.

Among efficacy-evaluable patients in the isatuximab cohort (n = 11), the objective response rate (ORR) was 45% per 2026 International Myeloma Working Group (IMWG) criteria, comprising 1 complete response (CR) and 4 partial responses (PRs); per 2016 IMWG criteria, the ORR was 36%. The median PFS was 6.3 months (95% CI, 2.0-not estimable [NE]). By comparison, a phase 2 study (NCT02514668) of isatuximab monotherapy in patients with daratumumab-refractory disease (n = 31) reported an ORR of 0% and a median PFS of 1.6 months (95% CI, 1-3.2).² Among patients who received 2 cycles of IDP-023 plus isatuximab (n = 4), the ORR was 75%, and the median PFS was 7.4 months (95% CI, 6.3-NE).¹

“We've observed clinical proof of concept in these highly advanced patients with relapsed/refractory multiple myeloma, with an increase in the ORR and PFS relative to historical data,” presenting author Mark W. Frohlich, MD, chief executive officer of Indapta Therapeutics, said in the presentation.

How do g-NK cells work?

A subset of natural killer cells, g-NK cells are found in approximately 25% of people who have been exposed to cytomegalovirus (CMV). According to Frohlich, CMV exposure triggers durable epigenetic changes that give these cells a distinct, stable phenotype marked by reduced levels of the signaling protein FcεRIγ, a lack of the inhibitory receptor NKG2A, and abundant expression of the activating receptor NKG2C. These features translate into potent antibody-dependent cellular cytotoxicity, the ability to eliminate target cells that express HLA-E, and the potential to reshape the tumor microenvironment.

IDP-023 is an allogeneic, ready-to-use product derived from healthy CMV-seropositive donors who are selected for high numbers of highly functional g-NK cells. After the g-NK cells are selectively expanded, the product is frozen and stored, then delivered to treatment centers as needed.

The FDA previously granted fast track designation to IDP-023 for non-Hodgkin lymphoma and multiple myeloma.³

How was the study designed?

The phase 1 portion of the study began with a completed safety run-in (n = 10), in which investigators tested IDP-023 as a single dose and as repeated doses, with and without interleukin-2 (IL-2), and on 2 different schedules.¹

A completed dose-escalation phase (n = 18) then tested 3 infusions of IDP-023 at increasing dose levels alongside an anti-CD38 or anti-CD20 monoclonal antibody, as well as further treatment cycles and combinations with targeting agents; 3 patients with non-Hodgkin lymphoma were enrolled across these stages.

In the isatuximab cohort, patients received lymphodepletion with fludarabine and cyclophosphamide, followed by IDP-023 at dose level 2 (10 billion cells) or dose level 3 (20 billion cells).

In the intention-to-treat population (n = 12), the median age was 67.5 years (range, 57-77), and 42% of patients were older than 70 years. Seventeen percent of patients had Revised International Staging System stage 3 disease, and 25% had extramedullary disease. Among patients with available genotype data (n = 10), 80% had ultra–high-risk and 20% had high-risk disease.

Patients had received a median of 7 prior lines of therapy (range, 2-17); 67% had undergone autologous stem cell transplant, 83% had received BCMA-directed therapy, 67% had received CAR T-cell therapy, and 67% had received a T-cell engager, including talquetamab-tgvs (Talvey) in 33%. Overall, 92% of patients were triple-class refractory, 58% were penta-refractory, and all were refractory to daratumumab.

What other data did the safety analysis show?

In the isatuximab cohort, no clinically significant infections, bleeding, immune effector cell–associated neurotoxicity syndrome, or cytokine release syndrome (CRS) were reported. Investigators observed no grade 3 or higher treatment-related AEs affecting the cardiovascular, renal, hepatic, or nervous systems, and the safety profile was similar at DL2 and DL3.

The most common AEs of grade 2 or higher were neutropenia (83.3%), lymphopenia (83.3%), leukopenia (83.3%), thrombocytopenia (75.0%), anemia (66.7%), nausea (58.3%), hypokalemia (50.0%), hypophosphatemia (50.0%), febrile neutropenia (41.7%), constipation (33.3%), and CRS (33.3%). Cytopenias emerged and resolved on a predictable timeline, and every patient's blood counts recovered. Non-Hodgkin lymphoma developed in 2 patients: 1 case was characterized as post-transplant lymphoproliferative disorder, and the other, a diffuse large B-cell lymphoma, was detected on imaging. Frohlich noted that investigators will keep monitoring for these malignancies in future cohorts.

What additional findings were reported?

Efficacy did not appear to improve with the 20 billion–cell dose, prompting investigators to select dose level 2 as the recommended phase 2 dose.

One patient with a CR was a 72-year-old woman who had received 10 prior lines of therapy, including ASCT, BCMA-directed CAR T-cell therapy, and 2 T-cell engagers. She had extramedullary disease in the form of bulky pelvic lymph nodes, along with ultra–high-risk genetic features of TP53 loss, 1q21 gain, and a complex karyotype. By day 28, her bone marrow biopsy and serum and urine immunofixation tests were negative, and PET/CT showed no remaining pelvic lymphadenopathy. Her serum free light chain level fell from 25.39 mg/dL at screening to less than 0.14 mg/dL, and her kappa/lambda ratio went from 0.02 to a normal 1.09 by day 60. The CR was confirmed at days 60, 90, 120, 150, 180, 270, and 360.

One month after treatment, bone marrow samples showed higher levels of CD3-positive, CD8-positive, and gamma delta T cells and fewer myeloid-derived suppressor cells. Frohlich suggested that this immune remodeling may help explain the durability of responses and could make patients more responsive to retreatment with T-cell engagers.

What are the next steps for IDP-023?

Investigators intend to enroll 15 to 20 additional patients in a phase 1 extension cohort that mirrors the population envisioned for a registration trial: patients with highly refractory disease after at least 3 prior lines of therapy, including at least 1 T-cell engager or CAR T-cell therapy. These patients will receive IDP-023 at 10 billion cells every other day for 3 doses plus isatuximab, along with subcutaneous IL-2 at 6 million IU daily for 5 days, for up to 3 cycles spaced approximately 6 weeks apart.

Following an End-of-Phase 1 Type B meeting with the FDA in July 2026, the company plans to launch a randomized phase 3 trial if the extension cohort yields consistent results; the trial would compare the regimen with investigator's choice of combination therapy, with PFS as the primary end point and overall survival as a secondary end point.

“This patient population post–CAR T[-cell therapy and] post–T-cell engagers is only going to grow over time as we see these very effective therapies moving earlier in the treatment paradigm,” Frohlich concluded.

References

1. Patel K, Berz D, Gandhi M, et al. IDP-023 allogeneic g-NK cells combined with isatuximab in relapsed/refractory multiple myeloma: complete safety, efficacy, and tumor microenvironment remodeling from a phase 1/2 first-in-human study. Paper presented at: 2026 Society for Immunotherapy of Cancer Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract LBA 1185.
2. Mikhael J, Belhadj-Merzoug K, Hulin C, et al. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab. Blood Cancer J. 2021;11(5):89. doi:10.1038/s41408-021-00478-4
3. Indapta Therapeutics receives U.S. FDA fast track designation for lead clinical drug candidate IDP-023 for non-Hodgkin’s lymphoma and myeloma. News release. Indapta Therapeutics. February 29, 2024. Accessed November 6, 2026. https://www.businesswire.com/news/home/20240229681905/en/Indapta-Therapeutics-Receives-U.S.-FDA-Fast-Track-Designation-for-Lead-Clinical-Drug-Candidate-IDP-023-for-Non-Hodgkins-Lymphoma-and-Myeloma