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First-in-Class Agent Targets NF-kB Signaling in Multiple Myeloma

By: Celeste L. Dixon
Posted: Friday, January 4, 2019

The initial successes of a first-in-class nuclear factor (NF)‐kB–targeting therapeutic for multiple myeloma with a novel mode of action has been described in the British Journal of Haematology. Laura Tornatore, PhD, of the Imperial College London in the United Kingdom, and colleagues call the agent DTP3.

According to the investigators, DTP3 represents a “significant opportunity” for managing patients with multiple myeloma due to this mode of action. It is a “GADD45β/MKK7 inhibitor…which selectively kills multiple myeloma cells by inducing MKK7/JNK‐dependent apoptosis, ex vivo and in vivo, without toxicity to normal tissues…and none of the preclusive toxicities of conventional IKKβ/NF‐kB–targeting agents.” GADD45β is an NF‐kB–regulated antiapoptotic factor, whereas MKK7 is a JNK‐activating kinase.

Although the NF‐kB pathway is almost always abnormally activated in multiple myeloma, enhancing tumor cell survival, no specific NF‐kB inhibitor has earned clinical approval in 30 years. “Agents indicated in multiple myeloma, such as proteasome inhibitors and immunomodulatory drugs, inhibit NF‐kB but also many other pathways, and neither specifically target cancer cells nor afford their clinical benefit through NF‐kB inhibition,” the authors pointed out.

Encouraged by DTP3’s preclinical proof-of-concept results, Dr. Tornatore and colleagues initiated its first‐in‐human phase‐I/IIa trial to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with relapsed or refractory multiple myeloma. To date, 3 patients with progressive disease have participated; the dose levels under study are 0.5, 1, and 2 mg/kg, administered intravenously 3 times a week. All of the patients completed at least a single 28‐day treatment cycle without complications or serious adverse effects.

Disclosure: The study authors’ disclosure information may be found at the BJH.



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