Is It Possible To Be Resistant to Lenalidomide (Revlimid)?

The immunomodulatory agent (IMiD), lenalidomide (Revlimid) and several of its analogues (Pomalyst/pomalidomide and Thalomid/thalidomide) have been, and are, a mainstay of treatment in myeloma, combined with a range of standard and novel therapies, at all disease stages.

Besides these well-known treatments, there are a couple of newcomers: specifically, iberdomide and mezigdomide (both still in clinical development). These days, this drug group is also referred to as 'Cereblon modulators'. They work by targeting a protein called cereblon (CRBN), which causes the degradation of specific target proteins. Cereblon modulators work like other IMiDs and have various effects, including anti-myeloma effects and immunomodulatory activity. 

Why Resistance to IMiDs Matters

Resistance to therapies like lenalidomide is a serious challenge. While researchers know that changes in cereblon or related genes can lead to resistance, these changes only explain about 20–30% of cases. In most patients, the reasons for resistance are still unknown.

Moreover, specific genetic abnormalities such as gain/amplification of 1q (gain/amp1q), deletion of 17p (del17p), and other complex genetic events (double-hit) may also contribute to therapeutic resistance. Pomalidomide, which is often used after lenalidomide stops working, helps 30–40% of patients. This means that 60–70% of people do not respond, leaving limited options for them.

New Clues from Singapore: The ADAR1 Gene

A press release by the National University of Singapore titled “1 Gene Is Key to Drug Resistance in Multiple Myeloma” caught my eye. This is a brand new development in understanding myeloma and why drugs work, not work, or may stop working for the patient. This press release is backed up by a recent article in the journal Blood, a peer-reviewed publication by the American Society of Hematology (ASH). 

The paper presents in detail, an interesting research that has been going on for several years. Past research indicated that lenalidomide sensitivity was due to the CRBN-IKZF1/IKZF3 degradation pathway. The thinking is that lenalidomide interferes with how the cereblon proteins work in the body and damage the proteins called IKZF’s to inhibit and kill myeloma cells. The research from the Singapore team suggests that lenalidomide sensitivity occurs independently of the CRBN-IKZF1/IKZF3 degradation pathway and that ADAR1 may play a role in lenalidomide resistance.

One cannot do justice in trying to summarize the chain of scientific efforts to led to the key conclusions (and the new development of learning how IMiD’s drugs work), but here are some important statements of this groundbreaking findings:

• “We identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of lenalidomide resistance in multiple myeloma.” 

• “Mechanistically, ADAR1 loss increased lenalidomide sensitivity through endogenous dsRNA accumulation … Conversely, ADAR1 overexpression reduced lenalidomide sensitivity … “

• “Several promising anti-ADAR1 compounds, including ZYS-1 and Rebecsinib, are currently in preclinical development.”

What Could This Mean for Future Treatment Options?

Understanding a gene responsible of becoming resistant to one medication helps identify a more precise and effective treatment plan. And for researchers, it opens the possibility of developing new treatment options that tailor to every patient's needs. 

Rebecsinib is an experimental anticancer medication, under development by Aspera Biomedicines.  It is derived from Pladienolide B natural product extracted from bacteria, which acts as an inhibitor of ADAR1. 

ZYS-1 is a small molecule developed by a Chinese group of researchers, though a more recent publication raised concerns regarding the validation of ZYS-1 as an ADAR1 inhibitor. The primary concern relates to how well it actually works, pointing to issues with the testing method used.

Rebecsinib may have the head start in this race for a new myeloma (and Leukemia) treatment, but we are not even at the stage of human clinical trials. Ergo, we are still several years away from seeing the results of the first clinicals.

Why This Discovery Matters for Patients

Identifying a gene like ADAR1 that plays a role in resistance helps researchers understand why therapies stop working. This opens the door to developing more personalized and effective treatment plans. It may also lead to entirely new therapy options that address each patient’s specific biology.

By learning more about the underlying causes of resistance, both patients and doctors gain better tools for managing myeloma more effectively in the future.

Keep reading articles like this, and stay tuned for our upcoming coverage at the American Society of Clinical Oncology conferences. Click the button below to visit the HealthTree News site and explore more articles!

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Sources: 

• Read more on mezigdomide here. 
• What are IMiDs and CELMoDs in Multiple Myeloma?
• Small Molecule Drug Reverses ADAR1-induced Cancer Stem Cell Cloning Capacity