In people with multiple myeloma, the myeloma cells multiply uncontrollably and accumulate in bone marrow, solid parts of bone and occasionally in other organs. This accumulation of myeloma cells usually occurs in multiple areas of the bones in the body, giving the disease its name, “multiple myeloma” (see Figure 1).
When the cells collect in bone marrow, they slow down the growth of healthy white blood cells, red blood cells and platelets. These cells collect in solid bone, causing holes called lytic lesions. The majority of people with multiple myeloma have these lesions when their disease is diagnosed.
Multiple myeloma is a type of cancer that may return. Because few people who have it are currently cured, doctors now treat it similarly to a chronic condition. Relapsed multiple myeloma occurs when the disease comes back after initial treatment. Refractory myeloma is when the disease does not respond to treatment or it stops responding to a treatment that previously worked.
Treatment options will vary depending on which hematologic cancer you have and your unique characteristics, such as previous treatments, age and general health. With many types of lymphoma and leukemia, identifying the subtype is crucial for developing an effective treatment strategy. Certain types of immunotherapy treat only certain subtypes, making it important to have a specific diagnosis. Biomarker testing helps doctors determine subtypes and whether a patient is a good candidate for immunotherapy.
Common hematologic cancer treatments include watchful waiting, chemotherapy, targeted therapy, radiation therapy, immunotherapy, stem cell transplantation, corticosteroids, bone-modifying agents and surgery. Although surgery is not commonly used for many blood cancers, it may be used to treat a single plasmacytoma (malignant plasma cell tumor) that can occur with multiple myeloma or as palliative treatment to relieve bone pain caused by cancer that has metastasized (spread) to the bone.
HOW DOES THE IMMUNE SYSTEM WORK?
The immune system is a complex network of cells, molecules, organs and lymph tissues working together to defend the body against germs, cancer cells and other microscopic invaders. The first job of the immune system is to distinguish between what is part of the body (“self”) and what is not (“non-self”). Once the immune system determines that a cell is non-self, or foreign, to the body, it begins a series of reactions to identify, target and eliminate those non-self cells.
Your immune system constantly identifies and eliminates harmful organisms that could negatively affect your health. For example, when you scrape your elbow, harmful substances can easily enter the body (see Figure 1).
A healthy immune system works to destroy viruses and bacteria (non-self antigens) that cause your illness and helps you recover.
A large part of your immune system is the lymphatic system, which is made up of lymph nodes as well as the spleen, thymus, adenoids and tonsils. Lymph nodes are located throughout the body, with large concentrations near the chest, abdomen, groin, pelvis, underarms and neck.
Lymph, a clear fluid, is circulated throughout the body. It collects and filters bacteria, viruses, toxins and chemicals known as antigens, which are circulating in the lymphatic system and bloodstream. Lymph contains lymphocytes, a type of white blood cell that attacks infectious agents. Lymphocytes begin in the bone marrow and develop from lymphoblasts (immature cells found in bone marrow). Lymphoblasts mature into infection-fighting cells. The two main types of lymphocytes are B-lymphocytes (B-cells) and T-lymphocytes (T-cells).
B-cells develop in the bone marrow and mature into either plasma cells or memory cells. Plasma cells make antibodies to fight germs and infection. Memory B-cells help the immune system remember which antigens attacked the body so it can recognize them and respond more quickly if they return.
T-cells also develop in the bone marrow but travel to the thymus to mature into four types, each with its own role in the immune system.
- Helper T-cells identify foreign, or non-self, antigens and communicate with other immune system cells to coordinate with the B-cells or other T-cells for an attack.
- Killer T-cells directly attack and destroy cancer cells or normal body cells infected with a virus by inserting a protein that causes them to enlarge and burst. One type of killer T-cell specifically targets cancer cells.
- Regulatory T-cells slow down the immune system after an immune response is finished.
- Memory T-cells can stay alive for years, continuing to fight the same invading cells. Memory is the basis of immune protection against disease in general and explains why we usually don’t become infected with some diseases, such as chickenpox, more than once.
The normal process for an immune response begins when B-cells and helper T-cells identify a threat (non-self antigen) and tell the rest of the immune system. The body then ramps up its production of T-cells to fight. Killer T-cells are sent to destroy the non-self cells. Regulatory T-cells are sent to slow down the immune system once the non-self cells have been eliminated to prevent the T-cells from attacking healthy parts of the body. As a result, T-cells return to normal levels. The immune system uses the same process to recognize and eliminate cancer cells as it does to remove other non-self cells, but the process is more complicated.
IMMUNOTHERAPY FOR HEMATOLOGIC CANCERS
Blood cancer treatment has been revolutionized by various types of immunotherapy. Training the immune system to respond to cancer has the potential for a more lasting response that can extend beyond the end of treatment.
Immunotherapy is not effective for every person, even if it is approved for that person’s cancer type. Research is ongoing to find new tests that will help guide doctors to recommend immunotherapy only to patients who are most likely to respond to it.
Different types of immunotherapy may be used alone or in combination with other therapies to treat certain blood cancers.
Adoptive Cellular Therapy (T-Cell Therapy)
There are two main approaches to adoptive cellular therapy, a treatment that enhances or changes the body’s own immune cells to be able to fight cancer. In one strategy, the doctor isolates T-cells that have attached to a patient’s tumor (tumor-infiltrating lymphocytes, or TILs), helps the T-cells multiply outside of the body and then administers them back to the patient.
In the second strategy, a patient’s T-cells are collected from a blood sample and chimeric antigen receptors (CARs) are added that enable the T-cells to recognize specific proteins on the surface of cancer cells. These engineered T-cells are called CAR T-cells (see Figure 2). They are multiplied in a laboratory and then infused back into the patient. The goal is for the T-cells to multiply, seek and destroy the cancer cells that carry those specific antigens.
Two CAR T-cell therapies are approved to treat certain blood cancers. These breakthrough therapies are giving hope to people with B-cell lymphoma and B-cell acute lymphoblastic leukemia. Clinical trials are evaluating applications for other types of leukemia as well as for lymphoma and multiple myeloma.
The benefits of CAR T-cell therapy include a high response rate, the possibility of long-term remission, the need for only one infusion (in most cases) and the long-term effectiveness of CAR T-cells, which are designed to work for many years in the bloodstream. Drawbacks include the high cost of the treatment and the risk of dangerous side effects, such as cytokine release syndrome (CRS), neurologic toxicities, B-cell aplasia, tumor lysis syndrome (TLS) and anaphylaxis. Most side effects are reversible, but they should be taken seriously.
Cytokines are proteins released by immune cells that communicate with other immune cells. Cytokine immunotherapy aids in communication among immune cells and plays a big role in the full activation of an immune response. This type of immunotherapy works by introducing large amounts of the following laboratory-made cytokines to the immune system to promote specific immune responses.
- Interleukins help regulate the activation of certain immune cells.
- Interferons boost the ability of certain immune cells to eliminate viral infections and attack cancer cells.
- Granulocyte-macrophage colony stimulating factors (GM-CSFs) stimulate the bone marrow, promoting the growth of immune and blood cells and the development of dendritic cells, which become antigen-presenting cells (cells that show the antigens to T-cells).
Immune Checkpoint Inhibitors
The immune system must regulate itself, and it only makes enough white blood cells to identify a single germ or abnormal cell present in the body.
Once a target is identified for destruction by the immune system, killer cells are activated and increase in number to provide an immune response. After an attack, however, the immune system must slow down. It does this through the use of checkpoints.
Checkpoints keep the immune system “in check,” preventing an attack on normal cells by using regulatory T-cells. When the correct proteins and cell receptors connect, a series of signals is sent to the immune system to slow down once an immune response is finished, such as when a virus is completely eliminated (see Figure 3). Three checkpoint receptors that slow down the immune system are identified for their roles in cancer treatment.
- CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a receptor that binds with certain molecules to tell the immune system to slow down.
- PD-1 (programmed cell death protein 1) is a receptor involved with telling T-cells to die and to reduce the death of regulatory
T-cells (suppressor T-cells). Both slow down an immune response. PD-1 can tell the immune system to slow down only if it connects with PD-L1.
- PD-L1 (programmed death-ligand 1) is a protein that, when combined with PD-1, sends a signal to reduce the production of T-cells and enables more T-cells to die.
Checkpoint-inhibiting drugs prevent connections between checkpoints. This prevents the immune response from slowing down, which allows the immune cells to continue fighting the cancer. Along with keeping the immune response from slowing down, it also helps the immune system recognize cancer cells as foreign cells.
Immunomodulatory agents may stimulate or slow down the immune system in indirect ways. They may boost the immune system and the effects of other therapies on the tumor and the tumor microenvironment, slow or stop the growth of the tumor and its blood vessel formation, improve the bone marrow microenvironment and have an anti-inflammatory effect, slowing the growth of the cancer.
Also referred to as mAbs, these laboratory-made antibodies are designed to target specific tumor antigens (foreign substances). They can work in different ways, such as flagging targeted cancer cells for destruction, blocking growth signals and receptors, and delivering other therapeutic agents directly to targeted cancer cells. They can also be created to carry cancer drugs, radiation particles or laboratory-made cytokines (proteins that enable cells to send messages to each other) directly to cancer cells.
When a mAb is combined with a toxin, such as a chemotherapy drug, it travels through the system until it reaches the targeted
cancer cell. Then it attaches to the surface, is swallowed by the tumor cell and breaks down inside the cell, releasing the toxin and causing cell death. Combining mAbs with radiation particles, a treatment known as
radioimmunotherapy, allows radiation to be delivered in lower doses over a longer period of time. This direct form of radiation delivery typically damages only the targeted cells.
- Naked mAbs work by themselves. No drugs or radioactive particles are attached.
- Conjugated mAbs have a chemotherapy drug or a radioactive particle attached to them. They are used to deliver treatment to the cancer cells. These also are referred to as tagged, labeled or loaded antibodies.
- Bispecific mAbs are made up of two different mAbs and can attach to two different proteins at the same time. In some cases, the two proteins may both be on a cancer cell. In other cases, one protein may be on a cancer cell and one on a T-cell, thereby connecting the T-cell to a cancer cell.
Different types of mAbs are used in cancer treatment, but they should not be confused with monoclonal antibodies that directly attack certain components in or on cancer cells. This type of treatment is known as targeted therapy.
During photopheresis, blood is removed from the body and separated into red blood cells, white blood cells and platelets. The white blood cells are treated with ultraviolet light and drugs. The blood is then returned to the body, and the treated white blood cells boost the immune system in their attack on cancer cells.
Illustration: Figure 1 Normal Immune Response (filename: About Blood Cancers Fig 1)
Illustration: Figure 2 CAR T-cell Therapy (filename: About Blood Cancers Fig 2)
Illustration: Figure 3 Immune Checkpoint Inhibitors (filename: About Blood Cancers Fig 3)
SIDEBAR: HOW THE IMMUNE SYSTEM REMEMBERS
Although cancer cells can be clever, the immune system has a long memory when it comes to battling dangerous cells. When your immune system encounters a virus, such as chickenpox, the memory T-cells check to see if that virus has any characteristics of cells they have attacked in the past. If so, your memory T-cells offer you immunity from that virus, and most of the time, you don’t get the chickenpox again. The memory T-cells alert the rest of the immune system and tell it to make more immune cells to attack the virus and keep you from getting the disease again. Memory T-cells stay alive and store this information for a long time, remaining effective long after treatment ends. Investigators believe that effective immunotherapy can result in cancer-specific memory cells that provide long-term protection against cancer.
IMMUNOTHERAPY FOR MULTIPLE MYELOMA
Recent treatment advances, including those using immunotherapy, are helping make it possible for some people to manage their disease and live longer with a better quality of life. Types of immunotherapy approved to treat multiple myeloma include immunomodulatory agents and monoclonal antibodies (mAbs).
To treat multiple myeloma, immunomodulatory agents are often combined with antiangiogenic agents, which may prevent the growth of new blood vessels that tumors need to grow. They are also often combined with a corticosteroid. Immunomodulatory agents are most often used along with other treatments to improve initial response, stimulate the immune system and/or stop disease progression. These drugs can be effective in treating newly diagnosed multiple myeloma and relapsed or refractory disease.
Additionally, mAbs are a treatment option that may be used alone or in combination with other systemic therapies, such as a corticosteroid or an immunomodulatory agent.
These and other types of immunotherapy are also currently in clinical trials, so be sure to discuss this potential treatment option with your health care team.
Illustration: Figure 1 Uncontrollable Myeloma Cell Growth (filename: Multiple Myeloma Fig 1)
FDA-APPROVED CANCER IMMUNOTHERAPIES FOR MULTIPLE MYELOMA*
- daratumumab (Darzalex)
- elotuzumab (Empliciti)
- lenalidomide (Revlimid)
- pomalidomide (Pomalyst)
- thalidomide (Thalomid)
*Each therapy is prescribed based on specific criteria. Discuss your options with your doctor.
As of 3/14/19
SIDEBAR: QUESTIONS TO ASK YOUR DOCTOR
- Have you had success treating multiple myeloma with immunotherapy?
- How long will I be on treatment?
- What short-term and long-term side effects can I expect, and how serious could they be?