AFFILIATIONS
1 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
2 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
3 Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
4 Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
5 Department of Internal Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
6 Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, Department of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany
7 2Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
8 6Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
9 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
10 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
11 Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
12 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
13 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
14 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
15 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
16 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
17 Department of Hematology, Oncology and Stem Cell Transplantation, Medical Centre - University of Freiburg, Faculty of Medicine, Freiburg, Germany
18 University Medical Center Hamburg-Eppendorf, Hamburg, Germany University of Freiburg, Freiburg, Germany
19 Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
20 Department of Medicine III, TUM Klinikum, Technische Universität München, München, Germany
21 Asklepios Tumorzentrum Hamburg, Asklepios Klinik Altona and Asklepios Klinik St. Georg, Hamburg, Germany
22 Johnson & Johnson, Beerse, Belgium
23 Johnson & Johnson, Leiden, Netherlands
24 Johnson & Johnson, Beerse, Belgium
25 Johnson & Johnson, Spring House, United States
26 Johnson & Johnson, High Wycombe, United Kingdom
27 Johnson & Johnson, High Wycombe, United Kingdom
28 Heidelberg Myeloma Center and German speaking Myeloma Multicenter Group (GMMG), Department of Medicine V, Heidelberg University Hospital and Medical Faculty Heidelberg, Heidelberg, Germany
29 Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
30 Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
ABSTRACT
Background:
Ramantamig (Ram) is a T-cell redirecting trispecific antibody comprising novel CD3-, BCMA-, and GPRC5D-binding domains, designed to engage T cells while dually targeting BCMA and GPRC5D on myeloma cells, with the potential to overcome disease heterogeneity and mitigate antigen escape. In a phase 1 study in late line RRMM, Ram demonstrated robust efficacy and similar or lower rates of cytokine release syndrome (CRS) and oral adverse events (AEs) compared with reports of bispecific antibodies (BsAbs) targeting either GPRC5D or BCMA. The dual antigen targeting anti-myeloma activity of Ram may be augmented by the standard combination of R with Dara, an anti-CD38 monoclonal antibody that combines direct on-tumor and immunomodulatory mechanisms of action, enabling expansion and activation of cytotoxic T cells. Ram is administered in a dosing schedule of 100 mg every 4 weeks (Q4W) with a single 5 mg step-up dose (SUD). We report the results from Arm G of the phase 2 GMMG-HD10/DSMM-XX/MajesTEC-5 trial evaluating Ram+Dara+R (Ram-DR) for 6 cycles followed by Ram+Dara maintenance without transplant in pts with TE-NDMM.
Methods:
Eligible pts aged 18–70 years with TE-NDMM received Ram-DR induction therapy: Ram 100 mg subcutaneous (SC) Q4W, preceded by one 5 mg SUD in cycle (C)1; D 1800 mg SC weekly in C1–2 and every other week in C3–6; oral R 25 mg in C2–6; and oral/IV dexamethasone 20 mg in C1–2 only. Prophylactic (ppx) tocilizumab (toci) was permitted but not required. Infection prophylaxes were strongly recommended and administered per institutional guidelines. Primary endpoint was the incidence and severity of AEs and serious AEs (SAE). Secondary endpoints included minimal residual disease (MRD) negativity, overall response, complete response or better (≥CR), and very good partial response or better (≥VGPR). Results from the first 6 treatment cycles are presented.
Results:
Twenty-one pts (median age: 61 yrs; IMS-IMWG high-risk MM: 3/21) received Ram-DR induction therapy. As of June 2026, all 21 pts remained on study treatment with a median (range) follow-up of 7.1 (4.3–8.2) months and a median of 6 treatment cycles completed. All pts experienced ≥1 AE. Grade (gr) 3–4 AEs and SAEs occurred in 16/21 and 5/21 pts, respectively. Cytopenias were the most common gr 3–4 AEs (14/21), including neutropenia (10/21). No instances of CRS occurred in the 3 pts who received ppx toci; in those who did not receive ppx toci CRS was reported in 17/18 pts (gr 1, 10/18; gr 2, 7/18). Gr 3 infections occurred in 3/21 pts. There were no gr ≥4 non-hematologic AEs, including infections, and no gr 5 AEs overall. Fifteen of 21 pts had ≥1 post-baseline IgG value of <400 mg/dL. Eighteen of 21 pts received ≥ 1 dose of IgG replacement therapy. Ten pts experienced weight loss of 5–20%, with no pts experiencing ≥20% weight loss from baseline. Taste changes (16/21), nail (7/21), and oral AEs (16/21), and were mostly gr 1 with none >gr 2. Non-rash skin (9/21) and rash (gr 1–2, 7/21; gr 3, 3/21) AEs were also mostly low gr. No events of neurotoxicity, ICANS, or ataxia/balance disorders were reported. Only 1 pt discontinued Ram (gr 3 rash). Among the 19 patients who underwent stem cell mobilization after C3, median (range) stem cell yield was 5.6 (2.6–12.3) × 106/kg. ORR (95% CI) was 100% (83.9%–100%), with 100% (83.9%–100%) and 81.0% (58.1%–94.6%) achieving ≥VGPR and ≥CR, respectively. Of 20 pts evaluable for MRD at C3, 100% achieved MRD negativity (10–5, NGF).
Conclusions:
Ram-DR induction demonstrated promising early safety and efficacy results in TE-NDMM, with high rates of response and 100% MRD negativity. Stem cell mobilization was also feasible with Ram-DR. The safety profile was favorable with a low rate of severe infections. AEs leading to discontinuation of Ram were infrequent, and were reported in a single pt. The safety profile and monthly dosing schedule with a single SUD support further evaluation of Ram as part of a steroid-sparing complementary dual BCMA/GPRC5D myeloma antigen–targeting immunotherapy regimen with applicability across practice settings. The safety and efficacy of Ram + Dara in place of transplant is being evaluated in the maintenance phase of this study.