Understanding The Immune System in Myeloma
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 discusses the basics of the human immune system as they relate to myeloma. It aims to help patients with myeloma to better understand their compromised immunity and how immunotherapies may leverage their immune system to treat their myeloma.
Myeloma and the immune system
The human immune system is comprised of a complex network of cells, tissues, organs, and the substances they make. The immune system helps the body defend itself from external threats such as bacteria, viruses, and toxins, and from internal threats such as cancer by destroying infected and diseased cells. The immune system helps remove cellular debris and protects healthy cells.
The immune system can be likened to a fine Swiss watch, with many tiny moving parts working together seamlessly. A change or malfunction in even one of those tiny parts can affect all the others.
Myeloma is a cancer of the bone marrow plasma cells, white blood cells that make antibodies. Myeloma cells are unable to produce functioning antibodies that would fight infection, and the reduced function of immune cells means that they are less capable of controlling or attacking the myeloma cells.
Myeloma cells are cancerous plasma cells that produce monoclonal protein (myeloma protein, M-protein), an abnormal protein that accumulates in and damages bone and bone marrow. M-protein can also lead to organ and tissue damage (e.g., anemia, kidney damage, nerve damage).
How myeloma evolves and grows
In a normal immune response, an antigen triggers B cells, which in turn develop into plasma cells that secrete antibodies specifically targeted to attack the triggering antigen. When myeloma develops, the plasma cells secrete proteins that are not functional as antibodies. That is why M-protein is used as a marker of the amount and the activity of myeloma cells.
Myeloma evolves from a single clone. During the course of the disease, many clones are developed. As myeloma treatments successfully eliminate the dominant clones, smaller sub-clones that are resistant to the treatment can survive and become dominant.
The growth of myeloma cells suppresses the immune response as a whole, reducing the number of normal antibodies and affecting all the cells that would patrol for and attack abnormal cells. Regulatory T cells, natural killer (NK) cells, and macrophages can no longer perform their functions. Some of the cytokines that are secreted to trigger an immune response may instead stimulate the growth of myeloma cells.
Successful treatment of myeloma helps restore the number and function of immune system cells.
Blood cells play a key role in immunity
All blood cells derive from blood stem cells (hematopoietic stem cells) in the bone marrow. Depending upon the body’s needs, these stem cells can make white blood cells, red blood cells, or platelets.
White blood cells (WBC)
The immune system is made up of various types of white blood cells (WBC) that circulate in the bloodstream and in the lymphatic system (also called lymphoid system), a subsystem of the circulatory system that includes our lymph nodes and the channels that connect them. One of the main functions of the lymphatic system is the production and circulation of immune cells. Lymphoid organs include the bone marrow and the thymus.
WBC is a general term for a variety of leukocytes responsible for fighting invading germs, infections, and allergy-causing agents. These cells begin their development in bone marrow and then travel to other parts of the body. Specific white blood cells include neutrophils, basophils, eosinophils, lymphocytes, and monocytes. Each type has a different function in the immune system:
¡ Neutrophils constitute about 60% of white blood cells. Neutrophils are necessary to combat bacteria and fungi. A reduced level of neutrophils is called neutropenia. Having too few neutrophils can lead to infection.
¡ Eosinophils can signal the presence of parasites, allergies or cancer. Eosinophils can also regulate allergic response.
¡ Basophils help prevent blood from clotting and release histamine, a signaling compound, during allergic reactions.
¡ Monocytes migrate from the bloodstream to other tissues. Monocytes present in tissue are also called a macrophages. They engulf and devour any cell (including a cancer cell) that does not have proteins on its surface to identify it as a healthy body cell.
¡ Lymphocytes (B cells, T cells, and NK cells) constitute 30% of WBCs.
B cells (B lymphocytes)
B cells are white blood cells that originate and mature in the bone marrow. When activated by a specific antigen, some B cells develop into plasma cells and make antibodies to that specific antigen.
Other B cells multiply and become memory B cells that remain in the body and carry long-term memory of an antigen. Memory B cells help protect us from infectious agents after we have had a disease or have been immunized against one.
T cells (T lymphocytes)
T cells are reduced in number and function in patients with myeloma, contributing to the immune suppression that is characteristic of the disease.
T cells originate in the bone marrow but mature in the thymus, a gland beneath the breastbone (sternum). T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on the cell surface. T cells can recognize specific antigens and bind to them in order to surround and disable pathogens (infectious agents that cause disease). T cells can become memory cells that provide long-lasting immunity.
There are three types of T cells:
1. Cytotoxic (cell-killing) T cells (Tc) are activated by various cytokines, bind to specific antigens on infected cells and cancer cells, then kill them. Myeloma patients may have a lack of specific cytotoxic T cells.
2. Helper T cells (Th) secrete chemical messengers called cytokines, proteins that circulate in the bloodstream, usually in response to infection. Cytokines can stimulate or inhibit the growth or activity in other cells. Myeloma cells may block helper T cells.
3. Regulatory T cells (T reg or Treg) control immune response. Cancer patients generally have an increased supply of Treg cells, suggesting that they may be involved in the suppression of immune response in patients with myeloma. Conversely, Treg cells also contribute to the restored immune function seen in patients who have deep and prolonged response to treatment.
Figure 1. Blood cells that play a role in the immune system
Natural killer (NK) cells
NK cells are lymphocytes responsible for tumor surveillance. They are able to recognize cells that have been transformed by tumors and can induce a strong response against tumors through the release of cytokines. NK cells can do this without the need of a “trigger” antigen on the tumor, which can result in a faster defensive response. In patients with active myeloma, NK cells are reduced both in number and in function.
Dendritic cells
Dendritic cells boost immune response by activating helper T cells and stimulating them to release cytokines. Dendritic cells are one type of antigen-presenting cells (APC) that show antigens on their surface to other immune system cells for recognition and destruction, affecting long-term disease control and treatment outcome.
Macrophages
Macrophages begin life as monocytes, which enter damaged tissue through blood vessels and then undergo a series of changes to become macrophages. Macrophages are present in all tissues. Their function is to engulf and digest anything – including cancer cells – that does not have the types of proteins on its surface that are specific to the surface of healthy body cells. There are two types of macrophages. Depending on the body’s needs, one type can increase inflammation, while the other type decreases it.
Immunotherapies used in the treatment of myeloma
Immunotherapy is treatment that engages the patient’s own immune system to attack their myeloma. This is a vital and growing field of cancer research. Immunotherapies have already been approved for myeloma, and more are being tested in clinical trials, research studies of new treatments that involve patients. Immunotherapies can attack the myeloma and produce deep responses.
Unfortunately, even after achieving excellent deep responses with immunotherapies, myeloma patients remain to some extent immunocompromised. Restoring the immune system to a normal healthy state is a complex and difficult task, and we await further research on this.
Monoclonal antibodies
The first monoclonal antibodies for the treatment of myeloma, Darzalex® (daratumumab) and Empliciti® (elotuzumab), were approved by the U.S. Food and Drug Administration (FDA) in November 2015. Sarclisa® (isatuximab-irfc) was approved by the FDA in March 2020. Darzalex Faspro®
(daratumumab + hyaluronidase-fihj), a newer formulation of Darzalex, received FDA approval in May 2020.
Both Darzalex and Sarclisa target CD38, a specific protein on the surface of myeloma cells. The CD (cluster of differentiation) system is a way to classify more than 200 proteins expressed on the surface of cells (e.g., CD1, CD2, CD3). The protein CD38 is widely expressed on the surface of myeloma cells, but it is expressed at low levels on other cells.
Darzalex binds to the CD38 molecule, while Sarclisa binds to a specific portion of the antigen found on the protein. These anti-CD38 monoclonal antibodies recruit other immune system cells to attack and kill the myeloma cells, as well as cause myeloma cells to undergo apoptosis, a cellular process leading to the death of a cell.
Empliciti targets the cell surface receptor SLAMF7 and does not directly attack the myeloma cells, but rather attaches to and activates NK cells and stimulates them to attack myeloma cells via the SLAMF7 receptor.
For more information, please read the following IMF publications:
¡ Understanding DARZALEX® (daratumumab) intravenous infusion and DARZALEX FASPRO® (daratumumab + hyaluronidase-fihj) subcutaneous injection
¡ Understanding EMPLICITI® (elotuzumab)
¡ Understanding SARCLISA® (isatuximab-irfc)
CAR T cells
One of the most robust lines of research in hematologic cancers is an immunotherapy technique called chimeric antigen receptor (CAR) T-cell therapy. In this approach, a patient’s T cells are collected from the blood and genetically engineered to express receptors specifically directed toward antigens on the patient’s tumor cells, then infused back into the patient to launch an immune attack.
In March 2021, Abecma® (idecabtagene vicleucel or “ide-cel” for short) became the first-in-class BCMA-directed CAR T-cell therapy to be approved by the FDA for the treatment of relapsed or refractory multiple myeloma (RRMM) after at least 4 prior lines of therapy. In April 2024, the FDA expanded the approval of Abecma for use in earlier relapse setting after 2 or more prior lines of therapy. For more information, read the IMF’s publication Understanding ABECMA® (idecabtagene vicleucel).
In February 2022, the FDA approved Carvykti® (ciltacabtagene autoleucel or “cilta-cel” for short) for the treatment of RRMM after 4 or more prior lines of therapy. In April 2024, the FDA expanded the approval of Carvykti for
patients with RRMM who have received at least 1 prior line of therapy. For more information, read the IMF’s publication Understanding CARVYKTI® (ciltacabtagene autoleucel).
Newer CAR T-cell approaches are exploring the use of two binding sites on myeloma cells as well as other modifications of the technology. We await results of numerous clinical trials that hope to identify which patients are best suited for this therapy, how to increase the durability of responses, and how to better manage the immune-mediated side effects of CAR T cells.
Bispecific antibodies
A new class of antibodies has emerged, called bispecific antibodies (“bispecifics”), which can bind at the same time to both the BCMA on the surface of myeloma cells and to a cell surface protein marker on T cells (CD3) or NK cells. In the case of T cells, this double binding brings T cells to the myeloma cells, inducing activation of T cells and cytokine release. The result is destruction of myeloma cells and proliferation of cytotoxic T cells, which release toxic chemicals and/or prompt cancer cells to self-destruct.
Bispecifics perform the same function as CAR T cells but are an off-theshelf therapy manufactured in a lab. There is no need to collect T cells from the patient. This saves weeks of time that it would take to modify and expand the patient’s T cells for re-infusion. Bispecifics may have less cytokine release syndrome (CRS) than CAR T-cell therapy and may be more available to patients who are not eligible for or do not have access to CAR T-cell therapy.
For more information, please read the following IMF publications:
¡ Understanding ELREXFIO™ (elranatamab-bcmm)
¡ Understanding TALVEY® (talquetamab-tgvs)
¡ Understanding TECVAYLI® (teclistamab-cqyv)
Antibody-drug conjugates
All patients with myeloma express B-cell maturation antigen (BCMA), a protein involved in myeloma cell growth and survival, also called tumor necrosis factor receptor superfamily member 17 (TNFRSF17). An antibodydrug conjugate (ADC) works by binding to a receptor on the surface of myeloma cells and then releasing a drug that can kill the myeloma cells.
Several ADCs for myeloma are currently in clinical trials, including Blenrep® (belantamab mafodotin-blmf), which is a combination of a monoclonal antibody and monomethyl auristatin F (MMAF), a drug that can kill myeloma cells. The monoclonal antibody portion of Blenrep is designed to find and attach to BCMA, enabling Blenrep to enter the myeloma cell. Then Blenrep releases MMAF, which leads to cell death.
Checkpoint inhibitors
Checkpoint proteins are a safety mechanism built into our immune system to help keep immune responses in check. Checkpoint proteins include “programmed cell death protein 1” (PD-1) on T cells and “programmed death-ligand 1” (PD-L1) on tumor cells. When PD-1 binds to PD-L1, it helps keep T cells from killing other cells. Cancer cells use the binding of PD-1 to PD-L1 to evade immune attack. Checkpoint inhibitors that block PD-1 therefore reduce the deactivation of T cells and enhance the ability of T cells to kill cancer cells.
Researchers have learned that simply blocking PD-1 is not effective in myeloma, and that combining a checkpoint inhibitor with an immunomodulatory agent is not safe. Current clinical trials with checkpoint inhibitors in myeloma use various combination therapy approaches in an attempt to find a method of treatment that is both safe and effective.
Combination therapies
It is important to note that many of the agents already approved for myeloma have immune effects: immunomodulatory agents enhance the ability of NK cells to kill myeloma cells; proteasome inhibitors increase dendritic cell-activated T-cell cytotoxicity. Using multiple immune system components, rather than a single target or pathway, seems to be the most effective way to attack myeloma.
The impact of successful myeloma treatment
Excellent, deep response to therapy can bring with it robust recovery of the immune system. Studies of long-term survivors – those who have lived 10 years or more without treatment – demonstrate a unique immune signature among these potentially cured patients.
Next steps
The new immunotherapies for myeloma target antigens on the outside of the cancer cell, so they are effective even when there are high-risk chromosomal mutations present in the cell’s nucleus. Immunotherapy appears to be largely independent of such high-risk genetic features as deletion of the short arm of chromosome 17 (del 17p, or 17p–), where an important tumor suppressor gene is located, or translocation of genetic material between chromosomes 4 and 14 [t(4;14)].
As monoclonal antibodies, CAR T cells, ADCs, bispecific antibodies, and other immunotherapies join the arsenal of agents against myeloma, the next challenge will be learning how to combine and sequence these treatments.
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
Dr. Joseph Mikhael
IMF Chief Medical Officer
