Drug Therapy for Multiple Myeloma

Many different types of drugs can be used to treat multiple myeloma.

Chemotherapy

Chemotherapy (chemo) is the use of certain kinds of drugs that destroy or control the growth of cancer cells. These drugs can be taken by mouth or given in a vein or a muscle. They enter the bloodstream and reach almost all areas of the body.

At one time, chemo was often part of the main treatment for multiple myeloma. As newer types of drugs have become available in recent years, chemo has become less important in treating myeloma, although it is still used in some situations.

Chemo drugs that can be used to treat multiple myeloma include:

• Cyclophosphamide (Cytoxan)
• Etoposide (VP-16)
• Doxorubicin (Adriamycin)
• Liposomal doxorubicin (Doxil)
• Melphalan
• Bendamustine (Treanda)

Often one of these drugs is combined with other types of drugs like corticosteroids and immunomodulating drugs (see below). If a stem cell transplant is planned, most doctors avoid using certain chemo drugs, like melphalan, that can damage bone marrow.

Chemo side effects

Chemo drugs kill cancer cells but also can damage normal cells. They are given carefully to avoid or reduce the side effects of chemotherapy. These side effects depend on the type and dose of drugs given and the how long they are taken. Common side effects of chemo include:

• Hair loss
• Mouth sores
• Loss of appetite
• Nausea and vomiting
• Diarrhea or constipation

Chemotherapy often leads to low blood counts, which can cause:

• An increased risk of serious infection (from having too few white blood cells)
• Easy bruising or bleeding (from having too few blood platelets )
• Feeling tired or short of breath (from having too few red blood cells)

Most side effects go away after treatment is finished.

If you have side effects, your cancer care team can suggest steps to ease them. For example, drugs can be given along with the chemo to prevent or reduce nausea and vomiting.

Along with these short-term side effects, some chemo drugs can permanently damage certain organs such as the heart or kidneys. The possible risks of these drugs are carefully balanced against their benefits, and the function of these organs is carefully monitored during treatment. If serious organ damage occurs, the drug that caused it is stopped and sometimes replaced with another.

For more information about chemo and its side effects, see Chemotherapy.

Corticosteroids (steroids)

Corticosteroids, such as dexamethasone and prednisone, are an important part of the treatment of multiple myeloma. They can be used alone or combined with other drugs as a part of treatment. Corticosteroids are also used to help decrease the nausea and vomiting that chemo might cause.

Common side effects of these drugs include:

• High blood sugar
• Increased appetite and weight gain
• Problems sleeping
• Changes in mood (some people become irritable or “hyper”)

When used for a long time, corticosteroids also suppress the immune system. This increases the risk of serious infections. Steroids can also weaken bones.

Most of these side effects go away over time after the drug is stopped.

Immunomodulatory drugs (IMiDs)

The way immunomodulatory drugs (IMiDs) affect the immune system isn’t entirely clear, but these drugs are often helpful in treating multiple myeloma.

These drugs are taken daily as pills, with breaks from treatment on certain days each month.

These drugs might cause severe birth defects when taken during pregnancy, so they can only be obtained through a special program run by the drug company that makes them.

Because these drugs can increase the risk of serious blood clots, they are often given along with aspirin or a blood thinner.

Thalidomide (Thalomid) was first IMiD used to treat multiple myeloma. Side effects of thalidomide can include drowsiness, fatigue, severe constipation, and painful nerve damage (neuropathy). The neuropathy can be severe, and it might not go away after the drug is stopped. There is also an increased risk of serious blood clots that start in the leg and can travel to the lungs.

Lenalidomide (Revlimid) is similar to thalidomide, although it tends to have less severe side effects. This is often the first IMiD used in treating multiple myeloma. The most common side effects of lenalidomide are thrombocytopenia (low blood platelet counts) and low white blood cell counts. It can also cause painful nerve damage. The risk of blood clots is not as high as that seen with thalidomide, but it is still increased.

In people whose myeloma is in remission after either a stem cell transplant or initial treatment, lenalidomide may be given for maintenance therapy to help prolong the remission. 

Pomalidomide (Pomalyst) can also be used to treat multiple myeloma, most often after other treatments have been tried. Some common side effects include low red blood cell counts (anemia) and low white blood cell counts. The risk of nerve damage is not as severe as it is with the other immunomodulating drugs, but it’s also linked to an increased risk of blood clots.

Proteasome inhibitors

Proteasome inhibitors work by stopping enzyme complexes (proteasomes) in cells from breaking down proteins important for controlling cell division. They appear to affect tumor cells more than normal cells, but they are not without side effects.

Bortezomib (Velcade) was the first of this type of drug to be approved, and it’s often used to treat multiple myeloma. It may be especially helpful in treating myeloma patients with kidney problems. It’s injected into a vein (IV) or under the skin, once or twice a week.

Common side effects of this drug include nausea and vomiting, tiredness, diarrhea, constipation, fever, decreased appetite, and lowered blood counts. The platelet count (which can cause easier bruising and bleeding) and the white blood cell count (which can increase the risk of serious infection) are most often affected. Bortezomib can also cause nerve damage (peripheral neuropathy) that can lead to problems with numbness, tingling, or even pain in the hands and feet. The risk of nerve damage is less when the drug is given under the skin. Some patients develop shingles (herpes zoster) while taking this drug. To help prevent this, your doctor may have you take an anti-viral medicine (like acyclovir) while you take bortezomib.

In patients where the myeloma was put into remission after either a stem cell transplant or initial treatment, bortezomib may also be given for maintenance therapy to prolong the remission. 

Carfilzomib (Kyprolis) is a newer proteasome inhibitor that can be used to treat multiple myeloma in patients who have already been treated with other drugs that didn't work. It’s given as an injection into a vein (IV), often in a 4-week cycle. To prevent problems like allergic reactions during the infusion, the steroid drug dexamethasone is often given before each dose in the first cycle.

Common side effects include tiredness, nausea and vomiting, diarrhea, shortness of breath, fever, and low blood counts. The blood counts most often affected are the platelet counts (which can cause easier bruising and bleeding) and the red blood cell count (which can lead to tiredness, shortness of breath, and being pale). People on this drug can also have more serious problems, such as pneumonia, heart problems, and kidney or liver failure.

Ixazomib (Ninlaro) is a proteasome inhibitor that is a capsule taken by mouth, typically once a week for 3 weeks, followed by a week off. This drug is usually given after other drugs have been tried.

Common side effects of this drug include nausea and vomiting, diarrhea, constipation, swelling in the hands or feet, back pain, and a lowered blood platelet count (which can cause easier bruising and bleeding). This drug can also cause nerve damage (peripheral neuropathy) that can lead to problems with numbness, tingling, or even pain in the hands and feet.

Monoclonal antibodies

Antibodies are proteins made by the body’s immune system to help fight infections. Man-made versions (monoclonal antibodies) can be designed to attack a specific target, such as proteins on the surface of myeloma cells.

Antibodies against CD38

Daratumumab (Darzalex) is a monoclonal antibody that attaches to the CD38 protein, which is found on myeloma cells. This is thought to both kill the cancer cells directly and to help the immune system attack them. This drug is used mainly in combination with other types of drugs, although it can also be used by itself in patients who have already had several other treatments for their myeloma.

This drug is often given as an infusion into a vein (IV). A newer form of the drug, known as daratumumab and hyaluronidase (Darzalex Faspro), can be given as a subcutaneous (under the skin) injection, typically in the belly area over a few minutes.

Either form of this drug can cause a reaction in some people while it is being given or within several hours afterward, which can sometimes be severe. Symptoms can include coughing, wheezing, trouble breathing, tightness in the throat, a runny or stuffy nose, feeling dizzy or lightheaded, headache, rash, and nausea.

Other side effects can include fatigue, nausea, back pain, fever, and cough. This drug can also lower blood cell counts, which can increase the risk of infections and bleeding or bruising. Darzalex Faspro can also cause reactions at the injection site, such as swelling, itching, and redness.

Isatuximab (Sarclisa) is another monoclonal antibody that attaches to the CD38 protein on myeloma cells. This is thought to both kill the cancer cells directly and to help the immune system attack them. This drug is used along with other types of myeloma drugs, typically after at least 2 other treatments have been tried. It’s given as an infusion into a vein (IV).

This drug can cause a reaction in some people while it is being given or within a few hours afterward, which can sometimes be severe. Symptoms can include coughing, wheezing, trouble breathing, tightness in the throat, chills, feeling dizzy or lightheaded, headache, rash, and nausea.

The most common side effects of this drug include respiratory infections (such as colds or pneumonia) and diarrhea. This drug can also lower blood cell counts: 

• Having too few white blood cells can increase your risk for infections.
• Having too few red blood cells (anemia) can make you feel tired and weak.
• Having too few blood platelets can increase your risk of bleeding and bruising easily. 

This drug might also increase your risk of developing a second cancer.

Antibodies against SLAMF7

Elotuzumab (Empliciti) is a monoclonal antibody that attaches to the SLAMF7 protein, which is found on myeloma cells. This is thought to help the immune system attack the cancer cells. This drug is used mainly in patients who have already had other treatments for their myeloma. It’s given as an infusion into a vein (IV).

This drug can cause a reaction in some people while it is being given or within several hours afterward, which can sometimes be severe. Symptoms can include fever, chills, feeling dizzy or lightheaded, rash, wheezing, trouble breathing, tightness in the throat, or a runny or stuffy nose.

Other common side effects with this drug include fatigue, fever, loss of appetite, diarrhea, constipation, cough, nerve damage resulting in weakness or numbness in the hands and feet (peripheral neuropathy), upper respiratory tract infections, and pneumonia.

Bispecific T cell engagers (BiTEs)

Some newer man-made antibodies are designed to attach to two different targets. These are known as bispecific antibodies.

An example are bispecific T-cell engagers (BiTEs). Once in the body, one part of these antibodies attaches to the CD3 protein on immune cells called T cells. Another part attaches to a specific protein on myeloma cells. This brings the two cells together, which helps the immune system attack the cancer cells.

These medicines can be an option to treat multiple myeloma, typically after several other types of drugs have been tried.

Several BiTEs can be used to treat multiple myeloma:

Teclistamab (Tecvayli) attaches to the BCMA protein on myeloma cells. This drug is given as an injection under the skin (subcutaneously), typically once every few days for the first week, then once a week. After several months, it can also be given once every 2 weeks.

Elrenatamab (Elrexfio) also attaches to the BCMA protein. This drug is given as an injection under the skin (subcutaneously), typically once every few days for the first week, then once a week for several months, and then once every 2 weeks.

Talquetamab (Talvey) attaches to the GPRC5D protein on myeloma cells (and some other cells). This drug is given as an injection under the skin (subcutaneously), typically once every few days for the first week, then either once a week or once every other week.

Because these medicines can cause serious side effects when you first get them (see below), you will be started on a low dose, and you might be given other medicines to help lower the risk of side effects. You might need to stay in the hospital for a day or two after the first few doses.

Common side effects of these medicines include:

• Fever
• Feeling very tired
• Headache
• Nausea 
• Diarrhea
• Muscle and joint pain 
• Respiratory infections (including pneumonia)
• Low blood cell counts
• Skin rash
• Liver problems

These drugs can also cause more serious side effects, including:

Cytokine release syndrome (CRS): This is a serious side effect in which T cells in the body release chemicals (cytokines) that ramp up the immune system. This happens most often within the first day after treatment, and it can be life-threatening. Symptoms can include high fever and chills, feeling dizzy or lightheaded, trouble breathing, low blood pressure, headache, and a very fast heartbeat.

Nervous system problems: These drugs might affect the nervous system, which could lead to symptoms such as headaches, numbness or tingling in the hands or feet, feeling dizzy or confused, trouble speaking or understanding things, memory loss, abnormal sleep patterns, tremors, or seizures.

Your health care team will watch you closely for possible signs of CRS and nervous system problems, especially during and after the first few treatments. Be sure to contact your health care team right away if you have any of the symptoms above. 

These drugs might also cause other symptoms. Ask your health care team what you should look out for.

Nuclear export inhibitor

The nucleus of a cell holds most of the cell’s genetic material (DNA) needed to make the proteins the cell uses to function and stay alive. A protein called XPO1 helps carry other proteins from the nucleus to other parts of the cell.

Selinexor (Xpovio) is a drug known as a nuclear export inhibitor. It works by blocking the XPO1 protein. When the myeloma cell cannot transport proteins from its nucleus, the cell dies.

This drug is used with dexamethasone:

• For people whose myeloma has been treated with and no longer responds to at least several other myeloma drugs, OR
• Along with bortezomib for adults whose myeloma has grown on at least one other drug therapy.

It is a pill that can be taken on the first and third day of each week or weekly.

Common side effects include low platelet counts, low white blood cell counts, diarrhea, nausea, vomiting, not feeling hungry, weight loss, low blood sodium levels, and infections like bronchitis or pneumonia.

Using these drugs together to treat multiple myeloma

Although a single drug may be used to treat multiple myeloma, it is often preferable to use at least 2 or 3 different kinds of drugs in combination, because the cancer tends to respond better. Examples of combinations that might be used include:

• Lenalidomide (or pomalidomide or thalidomide) and dexamethasone
• Carfilzomib (or ixazomib or bortezomib), lenalidomide, and dexamethasone
• Bortezomib (or carfilzomib), cyclophosphamide, and dexamethasone
• Elotuzumab (or daratumumab), lenalidomide, and dexamethasone
• Bortezomib, liposomal doxorubicin, and dexamethasone
• Elotuzumab, bortezomib, and dexamethasone
• Melphalan and prednisone (MP), with or without thalidomide or bortezomib
• Vincristine, doxorubicin (Adriamycin), and dexamethasone (called VAD)
• Dexamethasone, cyclophosphamide, etoposide, and cisplatin (called DCEP)
• Dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide (called DT-PACE), with or without bortezomib
• Selinexor, bortezomib, dexamethasone

The choice and dose of drug therapy depend on many factors, including the stage of the cancer and a person's age, kidney function, and overall health. If a stem cell transplant is planned, most doctors avoid using certain drugs, like melphalan, that can damage the bone marrow.

Bisphosphonates for bone disease

Myeloma cells can weaken and even break bones. Drugs called bisphosphonates can help bones stay strong by slowing down this process. They can also help reduce pain in the weakened bone(s). Sometimes, pain medicines such as NSAIDs or narcotics will be given along with bisphosphonates to help control or lessen the pain. Bone pain can be a difficult symptom to treat during and after treatment for myeloma. 

The drugs used most often for treating bone problems in people with myeloma are the bisphosphonates pamidronate (Aredia) and zoledronic acid (Zometa) and the drug denosumab (Xgeva, Prolia). These drugs are given intravenously (IV or into a vein) or subcutaneously (under the skin). Most patients are treated once a month at first, but they may be able to be treated less often later on if they are doing well. Treatment with one of these drugs helps prevent further bone damage and events related to weakened bones such as fractures, hypercalcemia (high calcium levels), and spinal cord compression in multiple myeloma patients.

These treatments can have a rare but serious side effect called osteonecrosis of the jaw (ONJ). Patients complain of pain and doctors find that part of the jaw bone has died. This can lead to an open sore that doesn’t heal. It can also lead to tooth loss in that area. The jaw bone can also become infected. Doctors aren’t sure why this happens or how best to prevent it, but having jaw surgery or having a tooth removed can trigger this problem. Avoid these procedures while you are taking any of these medicines. One way to avoid these dental procedures is to maintain good oral hygiene by flossing, brushing, making sure that dentures fit properly, and having regular dental checkups. Any tooth or gum infections should be treated right away. (Dental fillings, root canal procedures, and tooth crowns do not seem to lead to ONJ.) If ONJ does occur, the doctor will stop the bone medicine.

Your doctor might recommend that you have a dental checkup before starting treatment. That way, any dental problems can be taken care of before starting the drug. They might also recommend taking calcium and Vitamin D supplements while on the medicine to help your body build bone.