A multiple myeloma candidate with a new mode of action is now in Phase 2 patient trials following positive Phase 1 results showing it kills cancer cells without toxicity to patients.
Multiple myeloma (MM) is a cancer of plasma cells, accounting for about 200,000 annual new cases globally. Despite recent therapeutic advances, MM remains incurable and an area of substantial unmet medical need.
Professor Guido Franzoso in Imperial College London's Department of Immunology and Inflammation said: "Almost all patients with multiple myeloma eventually relapse and develop resistance. We urgently need new therapies that can be combined with other drugs to provide durable control of the disease."
It is highly encouraging that among this cohort of patients with heavily refractory cancers, the cancer in one of two cases treated at 30 mg/kg was strongly reduced. Dr Aristeidis Chaidos Chief Investigator, Hammersmith Hospital
The first-in-class investigational drug DTP3, developed by Professor Franzoso and his team, is designed to treat MM by inhibiting an interaction between two proteins known as GADD45β and MKK7, which most myelomas require for survival. The candidate also has the potential to treat other cancers including diffuse large B-cell lymphoma (DLBCL).
Following promising Phase 1 trial results that provided strong safety data and preliminary evidence of efficacy, a trial has now entered Phase 2a to obtain further data on the drug candidate's efficacy.
Imperial is also meanwhile commercial partners to support further development.
A new mode of action
DTP3 builds on research into a pathway (signalling process) called NF-κB, which is used by the body to mount an immune response to injury and infection, but is hijacked by cancers to promote their own survival.
While NF-κB has attracted significant interest as a potential target for cancer drugs since the 1990s, candidates designed to inhibit it have disappointed due to serious side effects.
But research by Professor Franzoso and colleagues has raised hope that some cancers could be treated instead by targeting a key survival mechanism located downstream of NF-κB.
The team found that most myelomas use NF-κB to upregulate a protein called GADD45β, which binds to protein kinase MKK7 to prevent apoptosis, the execution of genetic instructions that tell cancer cells to self-destruct. The research showed that the GADD45β/MKK7 complex is critical to the survival of these cancer cells, but not to healthy cells.
These insights led to the development of DTP3, a small molecule GADD45β/MKK7 inhibitor, which in pre-clinical tests proved effective at selectively killing cancer in animal models and myeloma cells from patients, without harming healthy cells.
Patient trials
The pre-clinical results have now been reinforced by a Phase 1 trial of the new drug led by Imperial College London.
The trial tested the tolerability of DTP3 in 15 patients, 14 with refractory (or treatment-resistant) MM and one with DLBCL, at escalating doses that differed between patients. It found that the drug was well tolerated at doses of up to 45 mg per kg of body weight.
The trial also yielded preliminary evidence of clinical efficacy. It showed the drug activated apoptosis selectively in the cancer cells in around 50% of patients. One of two MM patients given a dose of 30 mg per kg showed a more than 95% reduction in cancer burden without signs of toxicity, and cancers remained stable in around 50% of patients treated at lower doses.
Dr Aristeidis Chaidos, consultant haematologist at Hammersmith Hospital and Honorary Clinical Senior Lecturer at Imperial College London, the trial's chief investigator, said: "The Phase 1 data shows that DTP3 is very well tolerated in patients. It is also highly encouraging to see that among this cohort of patients with heavily refractory cancers – who had received multiple previous lines of treatment and stopped responding – the cancer in one of two cases treated at 30 mg/kg was strongly reduced. We are hopeful of finding strong evidence of reduction in cancer burden in Phase 2 now that we have identified a clinically effective dose."
The Phase 1 results were presented at the American Society of Haematology Annual Meeting 2025 held in Florida last December and a manuscript is currently in preparation for submission to a peer-reviewed journal.
The trial has now entered Phase 2a, which will test the drug candidate for efficacy at a consistent dose level of 30 mg/kg in a cohort of up to 24 patients with MM and 24 patients with DLBCL in hospitals across the UK.
The trial is expected to conclude in 2028, and Imperial is now seeking commercial partners to support the further clinical development of DTP3, aiming ultimately to make the drug available to patients.
The current trial is supported by funding from the Medical Research Council, UKRI, the Jon Moulton Charity Trust, and a philanthropic gift. It builds on a pilot study supported by the NIHR Imperial Biomedical Research Centre and NIHR Imperial Clinical Research Facility.
Combination treatment
If the trial results continue to be positive, the drug could eventually be used as a first-line treatment in combination with other drugs. The encouraging data so far with DTP3 and the ongoing unmet medical need in multiple myeloma raise the possibility of accelerated approval in Europe and the US.
While there is no evidence so far of curative treatments in MM, the researchers hope that a combination therapy consisting of multiple drugs using differing modes of action could one day prove curative by reducing the routes by which the cancer is able to develop drug resistance.
Professor Franzoso said: "If you combine a cocktail of enough drugs that are non-toxic and work via different mechanisms, it should eventually become impossible for cancer to acquire all the necessary mutations to make it resistant to all treatments. This boils down to statistics. But putting drugs in a cocktail also combines their toxicities, so the fact that DTP3 is very well tolerated and does not harm the healthy cells is a key advantage."
Recruitment into the trial has been being supported by the Imperial College Healthcare NHS Trust, Cardiff and Vale University Health Board, Leeds Teaching Hospitals NHS Trust, University Hospital Southampton NHS Foundation Trust, and the University College London Hospitals (UCLH) NHS Foundation Trust. The trial is also supported by the Institute of Cancer Research.
