Treatment Update: Multiple Myeloma

Treatment of multiple myeloma is based on the person’s individual circumstances. Research arising from clinical trials has shown that a combination of drugs is usually the most effective way of treating the disease.

Immunomodulatory Drugs

Through a complicated mechanism that was only recently discovered, immunomodulatory drugs lead to the degradation (reduction) of growth signals in myeloma cells. These medications are taken by mouth as capsules, typically in combination with corticosteroids like dexamethasone and frequently in combination with proteasome inhibitors and/or monoclonal antibodies.

Immunomodulatory drugs are an important option for treating multiple myeloma. Lenalidomide (Revlimid) was approved by the U.S. Food and Drug Administration (FDA) in 2006 for relapsed (recurring) multiple myeloma. It was approved for newly-diagnosed patients in 2015 and as a maintenance therapy (continued treatment designed to prevent relapse) in 2017. Pomalidomide (Pomalyst) was approved in 2013 for the treatment of relapsed disease.

Proteasome Inhibitors

Proteasome inhibitors are approved by the FDA for the treatment of multiple myeloma. The proteasome is a complex of proteins inside cells that break down unneeded or damaged proteins in healthy cells and cancer cells. Proteasome inhibitors interfere with this action, resulting in the death of myeloma cells.

• Bortezomib (Velcade) was initially approved in 2003 and is now often given as part of combination therapy for the first-line treatment of multiple myeloma. It is typically given as a shot subcutaneously (under the skin).

• Carfilzomib (Kyprolis) was approved as a single agent in 2012. In 2016, its approval was expanded for use in combination with the immunomodulatory drug lenalidomide and dexamethasone, a corticosteroid. Carfilzomib is given intravenously (through a needle into a vein).

• Ixazomib (Ninlaro) was approved in 2015 to be taken in combination with lenalidomide and dexamethasone. Given in pill form, this combination is usually given after other drugs have been tried.

Monoclonal Antibodies

Monoclonal antibodies are lab-generated proteins that target specific antigens on the surface of the myeloma cell, triggering an immune response. There are three monoclonal antibodies approved by the FDA to treat multiple myeloma.

• Elotuzumab (Empliciti) was approved in 2015, in combination with pomalidomide and dexamethasone, for the treatment of relapsed or refractory (resistant to treatment) myeloma in people who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Elotuzumab had previously been approved in combination with lenalidomide and dexamethasone to treat people with multiple myeloma who had received one to three prior therapies. This drug is given intravenously.

• Daratumumab (Darzalex) was initially approved for people who have received at least three prior treatments for multiple myeloma. It was subsequently approved in combination with lenalidomide plus dexamethasone (or bortezomib plus dexamethasone) in people whose cancer has returned after one prior treatment type. It was subsequently approved for the treatment of newly-diagnosed multiple myeloma, in combination with lenalidomide and dexamethasone in people who are not candidates for a stem cell transplant. This drug is given intravenously or subcutaneously.

• Isatuximab (Sarclisa) was approved in 2020, in combination with pomalidomide and the corticosteroid dexamethasone, for the treatment of people with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. In 2021, the approval was extended for use in combination with carfilzomib and dexamethasone for previously-treated multiple myeloma. This drug is given intravenously.

High Dose Melphalan and Stem Cell Transplant (Bone Marrow Transplant)

In some patients, high dose melphalan (a chemotherapy) and stem cell transplant is recommended as a part of the overall treatment approach. In the procedure, stem cells are harvested (collected) from the patient or from a donor and then stored. The patient is given high doses of chemotherapy to destroy as many myeloma cells as possible. The stem cells are then infused (transplanted) into the body, where they travel to the bones and begin rebuilding bone marrow.

When a person with multiple myeloma receives their own stem cells, the procedure is called an autologous stem cell transplant. If the stem cells are from a donor (either a close relative, such as a brother or sister, or a donor from a registry), the procedure is known as an allogeneic stem cell transplant. In multiple myeloma, autologous stem cell transplant is much more commonly used than allogeneic stem cell transplant.

A stem cell transplant is an intensive treatment. To determine if stem cell transplant is the right treatment approach, doctors weigh a number of factors, including the person’s age and general physical health.

Chimeric Antigen Receptor T-cell (CAR T-cell) Therapy

CAR T-cell therapy is an approach where T-cells, a type of white blood cell, are collected from the patient (in a process similar to donating blood) and genetically modified so that they target a particular protein found on cancer cells. These reprogrammed T-cells are infused back into the patient to attack the myeloma cells.

There are two CAR T-cell therapies approved for the treatment of multiple myeloma. In 2021, the FDA approved idecabtagene vicleucel (Abecma) for the treatment of relapsed or refractory multiple myeloma after four or more prior therapies. Ciltacabtagene autoleucel (Carvykti) was approved in 2022 for a similar patient population. In 2024, the approvals were updated as treatment options after fewer prior therapies.

Bispecific antibodies

Bispecific antibodies, a type of immunotherapy, are antibodies that bind to two proteins at the same time. In multiple myeloma, the bispecific antibodies bind to both a protein on myeloma cells and a protein on T-cells (a type of white blood cell). By bringing the

T-cells to the myeloma cells, bispecific antibodies enable the immune system to attack the myeloma cells more effectively. There are three bispecific antibodies currently approved in multiple myeloma:

• Teclistamab (Tecyvayli) was approved in October 2022 for the treatment of relapsed or refractory multiple myeloma after at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

• Elranatamab (Elrexfio) was approved in August 2023 for the same patient population as teclistamab. Both elranatamab and teclistamab bind to BCMA (B-cell maturation antigen), a protein on the surface of myeloma cells.

• Talquetamab (Talvey) binds to GPRC5D, another protein on the surface of myeloma cells. Talquetamab was approved in August 2023, for the same patient population as teclistamab and elranatamab.

Other Treatment Options for Multiple Myeloma

Corticosteroids, such as prednisone and dexamethasone, control inflammation in the body and can also fight myeloma cells. Corticosteroids can be taken in pill form or given intravenously. In combination with other drugs, corticosteroids are often used throughout the course of multiple myeloma treatment.

Chemotherapy drugs, given intravenously or in pill form, can destroy myeloma cells but can affect healthy cells as well. The types of chemotherapy most often given to treat multiple myeloma are:

• Melphalan (Alkeran). Given in high doses, melphalan is used in association with a stem cell transplant.

• Cyclophosphamide (Cytoxan). Cyclophosphamide is given in combination with other multiple myeloma treatments.

Selective Inhibitor of Nuclear Export (SINE) compounds work by inhibiting the action of proteins involved in cancer cell growth. Selinexor (Xpovio), a type of SINE called an XPO1 inhibitor, was approved in 2019 for people with relapsed or refractory multiple myeloma who have received at least four prior therapies. Initially approved for use in combination with dexamethasone, it may be combined with proteasome inhibitors for the treatment of multiple myeloma. Selinexor is given orally.

Radiation therapy is often used to shrink myeloma cells in a specific area, such as a plasmacytoma (a collection of myeloma cells that create a bone tumor). The course of treatment can last several weeks.

All cancer treatments can cause side effects. It’s important that you report any side effects that you experience to your health care team so they can help you manage them. Report them right away—don’t wait for your next appointment. Doing so will improve your quality of life and allow you to stick with your treatment plan. It’s important to remember that not all patients experience all side effects, and patients may experience side effects not listed here.

People with multiple myeloma have an increased risk of infection, both from the disease itself and its treatment. When white blood cells are abnormally low (a condition called neutropenia), an infection may progress rapidly and become serious. For this reason, it’s important that people being treated for multiple myeloma immediately report fevers or other signs of infection to their health care team.

Side Effects of Immunomodulatory Options, Proteasome Inhibitors and Bispecific Antibodies

Common side effects of immunomodulatory options include fatigue, blood clots, diarrhea and rash. Proteasome inhibitors approaches can result in peripheral neuropathy (numbness or tingling in hands and feet), an increased risk of shingles and an increased risk of cardiovascular disease or pulmonary side effects. Bispecific antibodies carry a risk of low white blood cell counts and low levels of immunoglobins, increasing the risk of infections and other illnesses.

Side Effects of Chemotherapy

The side effects of chemotherapy depend on the type and dose of drugs given and the length of time they are used, and can include:

• Hair loss
• Increased risk of infection (from having too few white blood cells)
• Easy bruising or bleeding
• Changes in memory or thinking
• Peripheral neuropathy
• Edema (swelling)
• Mouth sores

Side Effects of CAR T-Cell Therapy

CAR T-cell therapy has its own specific potential side effects, including:

• Cytokine-Release Syndrome (CRS). The infusion of CAR T-cells into the body results in the production of large numbers of cytokines (molecules that help cells communicate), which can cause the immune system to become excessively active. This can lead to CRS, with symptoms such as high fever and flu-like symptoms. These side effects can be controlled and reversed with cytokine-blocking drugs and steroids.

• B-Cell Aplasia. The FDA-approved CAR T-cell therapies destroy normal as well as cancerous B-cells, which can cause B-cell aplasia (low numbers of B-cells), in which the body is less able to make the antibodies that protect against infection. Immunoglobulin replacement, administered intravenously, can be used to treat or prevent infection.

• Tumor Lysis Syndrome (TLS). When cancer cells break down (are destroyed) very quickly, they release large amounts of potassium, phosphate and uric acid into the blood. This can result in TLS, a group of conditions that can cause neurological, heart or kidney problems. TLS is managed by medicines that decrease potassium and uric acid levels in the blood. Medicines may also be prescribed that help increase urination.

• Changes in cognition. Some changes in cognition (thought processes) ranging from mild to severe can occur within several days of CAR T-cell therapy. The symptoms are often treated with steroids and are almost always reversible.

Because of these possible side effects, people who have undergone CAR T-cell therapy should stay close to their treatment location for at least four weeks, so they can be closely monitored by their healthcare team.

Side Effects of Radiation Therapy

Changes to the skin are the most common side effects of radiation therapy. The changes can include dryness, swelling, peeling, redness and blistering. If a reaction occurs, contact your health care team so the appropriate treatment can be prescribed. It’s especially important to contact your health care team if there is any open skin or painful areas, as this could indicate an infection. Infections can be treated with an oral antibiotic or topical antibiotic cream.

Some side effects may occur across treatment approaches. This section provides tips and guidance on how to manage these side effects should they occur.

Managing Digestive Tract Symptoms

Nausea and vomiting

• Avoid food with strong odors, as well as overly sweet, greasy, fried or highly seasoned food.
• Eat meals cold or at room temperature, which often makes food more easily tolerated.
• Nibble on dry crackers or toast. These bland foods are easy on the stomach.
• Having something in your stomach when you take medication may help ease nausea

Diarrhea

• Drink plenty of water. Ask your doctor about using drinks such as Gatorade, which provide electrolytes as well as liquid.
• Over-the-counter medicines such as loperamide (Imodium A-D and others) and prescription drugs are available for diarrhea but should be used only if necessary and after having a discussion with a member of your health care team.
• Choose fiber-dense foods such as whole grains, fruits and vegetables, all of which help form stools.
• Avoid food high in refined sugar and those sweetened with sugar alcohols such as sorbitol and mannitol.

Loss of appetite

• Eating small meals throughout the day is an easy way to take in more protein and calories, which will help maintain your weight. Try to include protein in every meal.
• To keep from feeling full early, avoid liquids with meals or take only small sips (unless you need liquids to help swallow).
• Keep high-calorie, high-protein snacks on hand such as hard-boiled eggs, peanut butter, cheese, granola bars, liquid nutritional supplements, nuts and canned tuna.
• If you are struggling to maintain your appetite, talk to your health care team about whether appetite-building medication could be right for you.

Managing Fatigue

Fatigue (extreme tiredness not helped by sleep) is one of the most common side effects of many cancer treatments. If you are taking a medication, your doctor may lower the dose of the drug, as long as it does not make the treatment less effective. If you are experiencing fatigue, talk to your doctor about whether taking a smaller dose is right for you

There are a number of other tips for reducing fatigue:

• Take several short naps or breaks during the day.
• Take short walks or do some light exercise, if possible.
• Try easier or shorter versions of the activities you enjoy.
• Ask your family or friends to help you with tasks you find difficult or tiring

Fatigue can be a symptom of other illnesses, such as anemia, diabetes, thyroid problems, heart disease, rheumatoid arthritis and depression. So be sure to ask your doctor if he or she thinks any of these conditions may be contributing to your fatigue.

**Q: I have recently been diagnosed with multiple myeloma. What questions should I ask my oncologist about their recommended treatment approach?

A: Here are some questions you should ask; others will likely arise in the course of your discussions.

• What are the goals of treatment?
• How long will treatment last?
• Do you have any written information about this treatment?
• What medical procedures and expenses does my insurance plan cover?
• What are the side effects of this treatment?
• Are there any ways to help manage side effects?
• How do we know if a side effect is severe enough to call you?
• Are there any other treatment options?
• Are there any clinical trials we should be aware of?
• What is the best way to let you know when we have questions about treatment?

Q: I know that multiple myeloma can cause bone damage and an increased risk of fracture. What information should I be aware of?

A: There are medications that are available to minimize the impact of bone damage (also called bone lesions):

• Bisphosphonates include drugs such as zoledronic acid (Zometa) and pamidronate (Aredia). These drugs slow the process by which bone wears away and breaks down. Bisphosphonates belong to a class of drugs called osteoclast inhibitors, which are also used to treat osteoporosis.

• RANK ligand inhibitors block a factor in bone development known as RANK ligand, which stimulates cells that break down bone. By blocking RANK ligand, drugs such as denosumab (Xgeva) increase bone density and strength.

Should a fracture of the vertebrae occur, there are minimally invasive surgical procedures available:

• Vertebroplasty is a procedure in which a special cement is injected into a fractured vertebra, to relieve spinal pain and restore mobility.

• Kyphoplasty is similar to vertebroplasty, with the additional step of creating space for the special cement by using a balloon-like device.

There are also lifestyle choices that you can make to improve the health (density) of your bones:

• A diet high in calcium and vitamin D. Foods that are high in calcium include dairy products, spinach, kale, okra and certain fish (sardines, salmon, perch and rainbow trout). Foods that provide Vitamin D include fatty fish (tuna, mackerel and salmon), cheese, egg yolks and beef liver. Some other foods come in versions fortified with calcium and/or Vitamin D.

• Exercise. Although high-impact exercise should be avoided, some forms of exercise can be beneficial for bone health, including flexibility, endurance, aerobic and strengthening exercises. Importantly, exercise is also known to have a positive impact on physical function, mood, sleep and overall quality of life.

• Eliminate smoking. Even minimal smoking has a negative effect on bone density.

• Avoid or reduce alcohol consumption. Alcohol intake has been shown to decrease bone density.

It’s important that you consult a member of your health care team before making any changes to your diet or exercise routine.

Q: What is a treatment summary and why is it important?

A: Keeping your own records up-to-date in the form of a treatment summary can be helpful, as it allows you and your family members to have instant access to the specifics of your multiple myeloma diagnosis and treatment. A treatment summary should include:

• Your name and date of birth
• Date of diagnosis
• Prescribed therapy/therapies, including dates started and stopped and dosages when appropriate
• Dates and types of baseline and post-diagnosis testing and the results of these tests
• Other medications and supplements you are taking
• Names, affiliations and contact information of all members of your health care team

Ask the members of your health care team what they suggest be included. Take your personal record with you when you visit any doctor, not just your oncologist.

Q: My sister has multiple myeloma. I want to help with caregiving, but I live far away. What can I do?

A: Even from a distance, you can provide ongoing emotional support to your sister and to her primary caregiver. It is sometimes easier for people to talk about difficult topics over the phone than in person, so be willing to have in-depth and serious conversations. You can also help coordinate medical appointments (and send reminders to your sister and her caregiver about those appointments), provide verbal updates to other family members, and share information on how your sister is feeling (if she agrees) in an on-line journal such as CaringBridge.