New Compound Safely Halts Advanced Myeloma Progression in Small Pilot Study

A new investigational compound targeting a central pathway in cancer development showed promising results in patients with relapsed or refractory multiple myeloma in a small Phase 1/2a pilot trial. 

The agent was able to trigger myeloma cell death and halt cancer progression in two out of three patients and, in contrast to prior treatments targeting the same pathway, appeared safe without any adverse events or significant toxicity.

Findings were published in the study, “Clinical proof of concept for a safe and effective NF‐κB‐targeting strategy in multiple myeloma,” in the British Journal of Haematology.

Despite advancements made in the management of multiple myeloma and the emergence of new treatments, the cancer still comes back in the majority of patients, underscoring the need for more effective treatments.

“We can now keep the disease under control for several years in most cases, but ultimately we almost always run out of treatment options,” Holger Auner, MD, senior lecturer and consultant at Imperial College London and one of the study’s authors, said in a press release.

Now researchers led by a team at Imperial College London in the U.K. have found a new treatment approach to tackle myeloma cells in the bone marrow, while leaving the patient’s healthy immune cells unharmed.

Based on earlier research, the team found a new way to block a signaling pathway central to several cancers, including multiple myeloma. The central player of this pathway is NF-κB, a group of proteins that bind to DNA and activate genes that enhance cell proliferation and survival.

For the past 30 years, the pharmaceutical industry has been trying to find ways of blocking NF-κB as a treatment strategy for cancer. But no safe and effective cancer-specific inhibitor has been found yet.

“Agents indicated in [myeloma], e.g., proteasome inhibitors and immunomodulatory drugs, inhibit NF‐κB, but also many other pathways, and neither specifically target cancer cells nor afford their clinical benefit through NF‐κB inhibition,” the researchers wrote in the study.

Researchers discovered a compound, called DTP3, which inhibits two important players of the NF‐κB pathway in myeloma cells — a protein called GADD45b and an enzyme called MKK7.

When these two proteins are bound together, they block the genetic instructions telling cells to “commit suicide,” a process known as apoptosis.

Apoptosis is a key process that occurs in the human body that stops abnormal cells from becoming cancerous and spreading. However, cancer cells have developed several “tricks,” including the GADD45b-MKK7 interaction, to overcome it.

“We developed a drug that could block this signalling mechanism in cancers, but not in normal cells,” said Guido Franzoso, MD, PhD, head of the Centre for Cell Signalling and Inflammation, professor at Imperial College London, and senior leader of the research. “The study showed it worked as effectively as other drugs commonly used to treat patients, killing myeloma cells in laboratory tests and in mice; but unlike existing drugs, it had no toxicity and no detectable side effects.”

In a dose-escalation Phase 1/2a pilot trial (EudraCT 2015-003459-23), researchers tested the safety and effectiveness of DTP3 treatment in three patients with relapsed or refractory myeloma, who had received at least two prior lines of therapy and whose cancer was worsening. 

Patients received either 0.5, 1, or 2 mg/kg DTP3 intravenous (into-the -vein) infusions three times a week. All three patients completed their first 28-day treatment round without complications.

After that first treatment cycle, the drug was able to activate the cell-suicide mechanism in myeloma cells from the bone marrow in two of the patients. Importantly, the treatment did so without triggering the death of healthy white blood cells.

In the patient treated with the highest dose, the cancer stopped progressing for more than three months, measured by a reduction in serum free light‐chain and paraprotein levels. This patient was maintained on DTP3 therapy for three treatment cycles before the disease progressed. 

One of the important findings was that DTP3 therapy was well-tolerated and had no adverse effects or signs of significant toxicity.

Researchers believe the therapy’s lack of effect in the third patient may have been because not all myelomas have the GADD45b gene “switched on” and driving the production of GADD45B protein.

Therefore, the team proposes that the activity of the GADD45B gene could be used in the future as a biomarker to help predict which patients will likely respond to DTP3 treatment.

“While the findings of this pilot study must be interpreted with caution at such an early stage of clinical testing, they are nevertheless highly encouraging and strongly support the further development of this approach,” Auner concluded.