05 August 2022

A major study of patients with relapsed multiple myeloma has found numerous genetic changes in key cancer pathways, "much more than previously thought".

Researchers at the University of Michigan, USA, reported finding alterations in up to 65% of NF-κB and RAS/MAPK pathways, showing they were more commonly altered than anticipated.

They also show for the first time that these changes are similar to those found in genetic syndromes called RASopathies, they report in Nature Communications.

The team compared genetic changes in 500 patients with relapsed multiple myeloma with those found in patients in untreated disease. This allowed them to describe the drivers of more aggressive disease.

Researcher Dr Arul Chinnaiyan said: “It also led us to discover resistance mechanisms that occur in the patients whose disease relapses and is resistant to treatment.”

“We found that an upwards of a quarter of the patients had developed some sort of resistance mechanism. The genetic alterations that occur in these patients make them resistant to commonly used treatments of multiple myeloma.”

Dr Chinnaiyan added: “We’re developing tools and knowledge to translate these strategies into actual clinical impact for patients.”

Dr Hearn Jay Cho, chief medical officer of the Multiple Myeloma Research Foundation, added: “Treatment of relapsed multiple myeloma can be extremely difficult despite the tremendous progress we have made.

“Uncovering new targets and therapies that act upon them may be helpful in the future for patients who develop resistance to current treatment such as CD38-targeting monoclonal antibodies.”

From knowledge gained through this work, researchers have now initiated a study assigning patients to individual arms of a clinical trial based on their molecular profile. The study will use a comprehensive sequencing-based approach to identify genetic changes in each patient’s individual disease, allowing them to be matched with potential therapies.


Vo JN, Wu YM, Mishler J, Hall S, Mannan R, Wang L, Ning Y, Zhou J, Hopkins AC, Estill JC, Chan WKB, Yesil J, Cao X, Rao A, Tsodikov A, Talpaz M, Cole CE, Ye JC; Multiple Myeloma Research Consortium, Bergsagel PL, Auclair D, Cho HJ, Robinson DR, Chinnaiyan AM. (2022) “The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma.” Nature Communications, 13(1):p3750. doi:10.1038/s41467-022-31430-0

Link: https://www.nature.com/articles/s41467-022-31430-0

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