Understanding CELMoDs
(cereblon E3 ligase modulatory drugs)
Founded in 1990, the International Myeloma Foundation (IMF) is the first and largest organization focusing specifically on myeloma. The IMF’s reach extends to more than 525,000 members in 140 countries. The IMF is dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure through our four founding pillars: Research, Education, Support, and Advocacy.
RESEARCH
The IMF is dedicated to finding a cure for myeloma, and we have a range of initiatives to make this happen. The International Myeloma Working Group, which emerged from the IMF’s Scientific Advisory Board established in 1995, is the most prestigious organization with 319 myeloma researchers conducting collaborative research to improve outcomes for patients while providing critically appraised consensus guidelines that are followed around the world. Our Black Swan Research Initiative® is bridging the gap from long-term remission to cure. Our annual Brian D. Novis Research Grant Program is supporting the most promising projects by junior and senior investigators. Our Nurse Leadership Board, comprised of nurses from leading myeloma treatment centers, develops recommendations for the nursing care of myeloma patients.
EDUCATION
The IMF’s webinars, seminars, and workshops provide up-to-date information presented by leading myeloma scientists and clinicians directly to patients and their families. We have a library of more than 100 publications for patients, care partners, and healthcare professionals. IMF publications are always free-of-charge, and available in English and select other languages.
SUPPORT The IMF InfoLine responds to your myeloma-related questions and concerns via phone and email, providing the most accurate information in a caring and compassionate manner. We also sustain a network of myeloma support groups, training hundreds of dedicated patients, care partners, and nurses who volunteer to lead these groups in their communities.
ADVOCACY
We empower thousands of individuals who make a positive impact each year on issues critical to the myeloma community. In the U.S., we lead coalitions to represent the interests of the myeloma community at both federal and state levels. Outside the U.S., the IMF’s Global Myeloma Action Network works to help patients gain access to treatment.
Learn more about the ways the IMF is helping to improve the quality of life of myeloma patients while working toward prevention and a cure. Call us at
, or visit myeloma.org .
You are not alone
The International Myeloma Foundation (IMF) is here to help you. The IMF is committed to providing information and support for patients with multiple myeloma (which we refer to simply as “myeloma”) and their care partners, friends, and family members.
We achieve this through a broad range of resources available on our website myeloma.org, and through numerous programs and services such as seminars, webinars, workshops, and the IMF InfoLine, which consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.
What you will learn from this booklet
Myeloma is a cancer that is not known to most patients at the time of diagnosis. If you have myeloma, it is important and helpful for you to learn about your disease, its treatment options, and supportive care measures in order to play an active role in your own medical care and to make good decisions about your care in partnership with your doctor.
If you are a patient with myeloma, we suggest that you read the IMF’s publication, Patient Handbook for Multiple Myeloma, which will help you to better understand this disease. In addition, this booklet will direct you to resources that may be relevant in your particular case. All IMF publications are free-of-charge and can be read, downloaded, or requested in printed format at publications.myeloma.org.
The IMF’s Understanding-series publications address specific drugs, drug classes, and combination therapies used to treat myeloma. These booklets also discuss supportive care measures that may help manage the symptoms and side effects of myeloma and its treatments. The IMF’s publication, Understanding Your Test Results, explains how myeloma is diagnosed, monitored, and assessed throughout the disease course.
Words in bold+blue type are explained in the IMF’s companion publication, Understanding Myeloma Vocabulary, a comprehensive glossary that also can be helpful in discussions with your doctor. Myeloma is complicated, but the language that describes it doesn’t have to be hard to understand.
If you are reading this booklet in electronic format, the light blue links will take you to the corresponding resources.
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.
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.
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.
immune modulation myeloma cells proliferation apoptosis
CUL4: cullen-4
DDB1: damaged DNA binding protein 1
ROC1: regulator of cullins-1
Ub: ubiquitination
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
CELMoD agents are being studied in many clinical trials with different drug combinations and in different myeloma patient populations. Iberdomide
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
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 effective treatment with good quality of life, you must play an active role in your own medical care.
We encourage you to visit myeloma.org for more information about myeloma and to contact the IMF InfoLine with your myeloma-related questions and concerns. The IMF InfoLine consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.
INTERACTIVE RESOURCES AT A GLANCE
