Understanding CELMoDs
(cereblon E3 ligase modulatory drugs)
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What you will learn from this booklet
Myeloma is a cancer that is not known to most patients at the time of diagnosis. To play an active role in your own medical care and to make good decisions about your care in partnership with your doctor, it is important and helpful to learn about myeloma, as well as its treatment options and supportive care measures.
If you are a patient with myeloma, we suggest that you read the IMF’s publication, Patient Handbook for Multiple Myeloma, which presents an overview of this disease and its treatments. In addition, the Patient Handbook will direct you to resources that may be relevant in your particular case.
The IMF’s Understanding-series publications address specific drugs, drug classes, combination therapies, and supportive care that may help you manage the symptoms and side effects of myeloma and its treatments.
Words in bold+blue are explained in the IMF’s companion publication, Understanding Myeloma Vocabulary, which you can access directly at glossary.myeloma.org. If you prefer to read any of the IMF’s publications in electronic format, the light blue links will take you to the corresponding resources. All IMF publications are free-of-charge and can be read, downloaded, or requested in printed format at publications.myeloma.org.
This booklet is intended to serve as an introduction to cereblon (CRBN) E3 ligase modulatory drugs (CELMoDs), a new drug class in myeloma that is designed to attack the disease in a novel way. CELMoDs are being studied in several clinical trials.
Myeloma is a cancer of the bone marrow
Myeloma is a cancer of the bone marrow plasma cells, white blood cells (WBC) that make antibodies. Healthy plasma cells are an important part of the immune system. Myeloma cells are malignant plasma cells that do not make functioning antibodies, but instead produce an abnormal monoclonal protein (myeloma protein, M-protein).
At the time of diagnosis, approximately 98% of myeloma patients have measurable M-protein in their blood or urine. Only approximately 1%–2% of patients have true non-secretory myeloma. Myeloma is called “multiple” because it frequently involves multiple areas in the body.
Bone marrow is the soft, spongy tissue in the center of bones that produces white blood cells, red blood cells, and platelets. When myeloma is growing, myeloma cells build up in the bone marrow and the M-protein they produce can lead to organ and tissue damage. For more information, see CRAB criteria as well as SLiM-CRAB criteria and myeloma-defining event (MDE).
Myeloma is a highly treatable disease
Many myeloma patients lead full and productive lives for years, even decades, after diagnosis. Survival and quality of life of myeloma patients are improving steadily. Learning about myeloma and understanding how it is treated can help patients and their loved ones reduce their anxiety and gain a sense of control.
CELMoDs are a new drug class in myeloma
Numerous clinical trials are taking place around the world, adding more promising approaches to the growing range of treatment options for patients with myeloma. However, despite the recent advances in myeloma research, there is a continued need to develop new drugs and new drug classes to treat myeloma.
A drug class is a group of medications that have a similar chemical structure or a similar mechanism of action (MOA), the biochemical interaction or process through which a drug or a molecule induces its effect in the body. CELMoDs are a new drug class in myeloma. The emergence of CELMoDs is built upon the well-established platform of immunomodulatory agents.
An immunomodulatory agent is a drug that can modify, enhance, or suppress the functioning of the immune system. Thalidomide, an oral immunomodulatory agent that has been studied since at least the 1950s, was first used to treat myeloma in a 1997 clinical trial, ushering in the age
of “novel therapies” in myeloma. Although thalidomide is now infrequently used in the U.S., many myeloma patients around the globe have benefited from this therapy.
The experience with the use of thalidomide in myeloma gave rise to a next generation of immunomodulatory agents with increased efficacy and reduced side effects. Revlimid® (lenalidomide) was approved by the FDA in June 2006 and is used to treat myeloma throughout the disease course. Pomalyst® (pomalidomide) was approved by the FDA in February 2013 for the treatment of relapsed and/or refractory multiple myeloma (RRMM).
CELMoDs are oral (taken by mouth) medications that have many similarities to immunomodulatory agents, but CELMoDs are able to be used even in patients who have relapsed after treatment with immunomodulatory agents. Currently, there are two CELMoDs in clinical development, iberdomide and mezigdomide.
CUL4: cullen-4
DDB1: damaged DNA binding protein 1
ROC1: regulator of cullins-1 Ub: ubiquitination
CELMoD mechanism of action
There is still a lot to be learned about the MOA of immunomodulatory agents, but we do know they act on the cereblon molecules in myeloma cells. Most patients treated with immunomodulatory agents will eventually become resistant to them.
CELMoDs work in a similar way to immunomodulatory agents in that they act on the cereblon molecules, but CELMoDs are able to overcome resistance to immunomodulatory agents. Indeed, they have a higher binding affinity for cereblon.
CELMoDs also have an effect on the proteasome and engage other elements of the immune system. Specifically, CELMoDs engage with the cereblon E3 ligase complex and, in a targeted fashion, rapidly degrade Ikaros and Aiolos proteins with impact on the pathobiology of myeloma, not only directly on killing myeloma cells but also by enhancing other immune cells.
CELMoD molecules are also bigger molecules than immunomodulatory agents. CELMoDs can synergize with other myeloma agents such as proteasome inhibitors and monoclonal antibodies.
Clinical trials with CELMoDs
A clinical trial is a medical research study with people who volunteer to test scientific approaches to a new treatment or a new combination therapy. At this time, there are numerous ongoing clinical trials for patients with myeloma. CELMoD agents are being studied in several clinical trials with different drug combinations and in different myeloma patient populations.
If you have an interest in participating in a clinical trial, be sure to discuss with your myeloma doctor all the potential risks and benefits that may apply to your particular case.
To help myeloma patients with personalized support for identifying and exploring clinical trial options, the IMF has partnered with SparkCures. Visit myeloma.org/sparkcures or contact the IMF InfoLine for more information.
The U.S. government maintains clinicaltrials.gov, an online database of research studies. However, the government does not review the safety and science of the studies submitted to this website.
For more information about what’s involved in study participation, read the IMF’s publication Understanding Clinical Trials in Myeloma.
Iberdomide clinical trials
Combination therapy with iberdomide + dexamethasone (also called “IBER-dex”) has shown an overall response rate (ORR) of about 30% to 50% in patients with heavily pretreated myeloma (4 to 6 median prior therapies), namely those who are triple-class refractory to proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies.
In December 2023, the first results of the phase II clinical trial EMN26 of iberdomide maintenance therapy to prolong remission after autologous stem cell transplantation (ASCT) in newly diagnosed patients with myeloma demonstrated a favorable safety profile and response improvement at 6 months when compared to maintenance therapy with Revlimid.
Induction therapy with proteasome inhibitor Kyprolis® (carfilzomib) + iberdomide + the steroid dexamethasone [KID] appears safe and did not interfere with stem cell mobilization in a phase I/II clinical trial of ASCTeligible patients with newly diagnosed multiple myeloma (NDMM).
In May 2024, the Journal of Clinical Oncology published the results of the phase II clinical trial I2D by the Intergroupe Francophone du Myélome (IFM), a cooperative myeloma research group that is composed of 140 medical centers in France and 33 centers in Belgium. The I2D study evaluated the all-oral “triplet” (3-drug) study regimen of iberdomide + the proteasome inhibitor Ninlaro® (ixazomib) + dexamethasone in elderly patients with myeloma at first relapse.
The I2D study demonstrated a favorable efficacy and safety profile, including in patients with myeloma who were refractory to Revlimid and to the monoclonal antibody Darzalex® (daratumumab). The ORR was 65%, including 36% of study patients who achieved either complete response (CR) or very good partial response (VGPR). With a median follow-up of 14 months, the 12-month overall survival (OS) was 86%, the 12-month duration of response (DoR) was 76%, and the 12-month progression-free survival (PFS) was 52%.
Mezigdomide clinical trials
Combination therapy with mezigdomide + dexamethasone (also called “MEZI-dex”) has also shown to be very effective in patients with at least 3 prior lines of therapy, including some patients who have been treated with a B-cell maturation antigen (BCMA) -directed therapy. ORR have been mostly in the 40% to 50% range. A line of therapy is 1 or more complete Cycles of a treatment regimen that can consist of a single agent, a combination of several drugs, or a planned sequential therapy of various regimens.
Mezigdomide has also been tested in combination with other agents earlier in the disease course, especially with proteasome inhibitors in patients who have had at least one prior line of therapy. ORR data were very encouraging, from 60% to 80%.
Results from the CC-92480-MM-002 clinical trial of mezigdomide + dexamethasone in combination with either Darzalex or the monoclonal antibody Empliciti® (elotuzumab) showed promising efficacy and a manageable safety profile in patients with relapsed or refractory myeloma who have had 2 to 4 prior lines of therapy. Improved safety and efficacy may be achieved by schedule and dose adjustments.
Iberdomide and mezigdomide similarities
Both iberdomide and mezigdomide are administered by mouth and can be combined with other myeloma therapies, such as proteasome inhibitors and monoclonal antibodies.
Potential side effects of CELMoDs
The side effect profile of a CELMoD is similar to what is seen with immunomodulatory agents. Key risks include the following:
¡ Low blood counts (especially neutrophils) – this increases the risk of infection.
¡ Blood clots – patients should be given medication to prevent blood clots.
Patients may also experience low-grade fatigue and diarrhea. The risk of neuropathy and cardiac complications is low.
Iberdomide has been shown to be associated with Grade 3 infection and anemia, and Grade 3 or 4 neutropenia.
Mezigdomide has been shown to be associated with cytopenias, including Grade 3 or 4 neutropenia, thrombocytopenia, or anemia. Non-hematologic side effects included infections, Grade 3 insomnia, and Grade 3 gastrointestinal (GI) events such as diarrhea.
In closing
This booklet is not meant to replace the advice of your doctors and nurses who are best able to answer questions about your specific healthcare management plan. The IMF intends only to provide you with information that will guide you in discussions with your healthcare team.
To help ensure a good quality of life through effective treatment, you must play an active role in your own medical care. We encourage you to visit
myeloma.org for more information and to join the Myeloma Knowledge Platform at myprofile.myeloma.org.
To receive the most up-to-date information about myeloma in a caring and compassionate manner, call the IMF InfoLine at 1.818.487.7455, email InfoLine@myeloma.org, or visit mmsm.link/infoline to schedule a convenient time to talk with an IMF InfoLine Coordinator.
To get answers to your questions without having to wait, ask Myelo® anytime 24/7 at myeloma.org. This generative AI assistant is designed to help you find the right resources.
Use the hyperlinks and web addresses included in this publication for quick access to resources from the IMF. Sign up at subscribe.myeloma.org for our quarterly journal Myeloma Today and weekly e-newsletter Myeloma Minute, as well as alerts about IMF news, events, and actions.
The International Myeloma Foundation (IMF) is the global leader in myeloma. Our mission is to improve the quality of life of myeloma patients while working toward prevention and a cure. Since 1990, the IMF has been serving the myeloma community through the following four pillars:
RESEARCH At the IMF, finding a cure for myeloma is our top priority. The IMF Scientific Advisory Board (SAB) of leading myeloma experts identifies key opportunities to drive research forward. The IMF Black Swan Research Initiative® (BSRI®) is pushing the boundaries with early screening for a precursor condition of myeloma as well as cure-focused myeloma clinical trials. The IMF International Myeloma Working Group (IMWG) provides trusted guidelines for diagnosing, treating, and managing myeloma. We also fund innovative research through the IMF Brian D. Novis Research Grants.
EDUCATION Myeloma is a complex and unique journey for each patient. The IMF offers hundreds of videos and free publications in multiple languages to inform and empower patients and care partners to navigate their myeloma journey. All IMF seminars, webinars, and workshops are free-of-charge and designed to directly connect the patient community with expert myeloma clinicians. The IMF Nurse Leadership Board (NLB) provides recommendations for the management of myeloma. The IMF M-Power Project works to break down barriers and ensure health equity in underserved populations.
SUPPORT Studies show that social support can greatly improve the quality of life of people with cancer. The IMF offers more than 160 myeloma support groups across North America, including specialized groups for Spanish-speakers, people with smoldering myeloma, care partners of patients with myeloma, and patients who do not have care partners. The IMF InfoLine answers myeloma-related questions. Myelo®, the IMF’s generative AI assistant, is available 24/7 to help you find the right resources.
ADVOCACY In the U.S., the IMF Advocacy team represents your interests at the federal and state levels. Internationally, the IMF Global Myeloma Action Network (GMAN) works to improve patient access to treatments.