Treatment of Stage III Multiple Myeloma

If you have stage III multiple myeloma, you are experiencing symptoms. Your medical test results also show that the disease is progressing. Your doctor has found evidence of bone disease, and you may be having problems with kidney function.

Stage III multiple myeloma requires treatment. There are many different options for treating the disease. A key first step is for you and your doctor to decide whether or not you are a good candidate for stem cell transplantation. Research studies have shown that a stem cell transplant is the best way to control multiple myeloma and extend survival.

Whether or not you are a good candidate can depend on a number of factors, including: your age; your overall health; other medical conditions you have; and how well key organs, such as your kidneys, heart, and lungs are working. It also can depend on personal preference. Stem cell transplantation is a rigorous treatment that requires you to spend time in the hospital. So, you may wish to consider the pros and cons of this and other options before you make your decision.

Your course of treatment will depend on whether or not you are a candidate for a stem cell transplant. Whatever treatment you and your doctor choose, he or she will check on how well your disease responds by measuring the levels of M protein in your blood and urine. You may hear your doctor use the following terms:

• Complete response - No evidence of M protein.
• Very good partial response - A greater than 90 percent decrease in the level of M protein.
• Partial response (PR) - Greater than 50 percent decrease in M protein.
• Minimal response (or minor response) - Less than 50 percent decrease in M protein.

Other tests may include bone x-rays and bone marrow biopsy. Biopsy involves taking a small sample of tissue and examining it for the presence of abnormal cells. Supportive therapy also will be given to treat the symptoms of your myeloma, such as bone damage and pain.

For Patients Having Stem Cell Transplant

Initial Therapy

Patients who will undergo stem cell transplantation first have a course of initial therapy. This is done to help bring the disease under control. High-dose dexamethasone plus the targeted therapy Thalomid^® (thalidomide) is the most commonly used initial therapy. Chemotherapy may be used as well. Possible combinations include:

• The steroid medication dexamethasone, with or without thalidomide - The combination treatment is called Thal-Dex. Thalomid^® is an oral medication that appears to block some of the ways that myeloma cells grow and reproduce. It stops the formation of new blood vessels and proteins called growth factors, which enable the cells to thrive. It also may help to stimulate the body’s immune system. Usually, doctors start patients on a lower dose, gradually increasing it over a few weeks. It may take a few months for the medication to take effect. Patients usually stay on the drug as long as it is working and they can tolerate the side effects.
  
  Although Thalomid® promotes myeloma cell death, it also can cause side effects, such as rash, low heart rate, and deep vein thrombosis (DVT). DVT is the formation of blood clots in the veins. Therefore, doctors may also prescribe a medication that prevents blood clotting, such as Coumadin^® (warfarin) or Lovenox^® (heparin), or recommend taking aspirin.

• Velcade^® (bortezomib)-based treatments - Bortezomib is a type of medication called a proteasome inhibitor. It appears to work by interfering with the growth and survival of myeloma cells. It also causes cell death. Often it is used in combination with other treatments, such as dexamethasone, thalidomide, and/or liposomal doxorubicin. Like lenalidomide, it is typically given after a patient has received at least one prior therapy. However, it is now being investigated as a possible first treatment for myeloma.
  
  Bortezomib is given intravenously (into a vein) on a monthly cycle. A typical schedule might have a patient receiving the drug twice per week for 2 weeks, followed by a 10-day rest period. However, the schedule can vary from person to person, depending on his or her needs and the side effects that develop.

• Dexamethasone with Revlimid^® (lenalidomide) - Typically, lenalidomide has been used as a second-line therapy for multiple myeloma, usually in combination with dexamethasone. “Second-line” means that it is given after a prior therapy stops working. However, it is now being investigated as a possible first treatment for myeloma.
  
  Lenalidomide is similar to thalidomide, but it appears to be more potent and causes different side effects. Researchers do not yet fully understand how it works. It appears to stop myeloma cells from growing and dividing. It also seems to play a role in keeping the cells from developing the new blood vessels they need to thrive.
  
  Like thalidomide, it is an oral medication, and the dose is usually adjusted based on how the disease responds and whether the patient experiences side effects. It also can increase the risk of blood clots, or DVT. Doctors may prescribe a medication that prevents blood clotting, such as warfarin or heparin, or recommend taking aspirin.
• Dexamethasone plus the chemotherapy drugs vincristine and Adriamycin^® (doxorubicin hydrochloride), or VAD - These medications are given intravenously (directly into a vein) in the hospital. Chemotherapy is typically given in cycles, with treatments spaced out every few weeks.
• Dexamethasone plus the chemotherapy drugs vincristine and Doxil^® (liposomal doxorubicin), or DVD - These medications are given intravenously (directly into a vein) in the hospital. Chemotherapy is typically given in cycles, with treatments spaced out every few weeks.

Stem Cell Transplantation

Stem cell transplantation follows initial therapy. It involves a three-step process:

• Collection of blood stem cells from the patient or a donor - Stem cells are the cells that develop into white blood cells, red blood cells, and platelets. They can be removed from the bloodstream through a special process. The stem cells are then processed in the laboratory, frozen, and stored until needed.
• High-dose chemotherapy, usually with Alkeran^® (melphalan) - The patient receives high doses of chemotherapyaimed at destroying the myeloma cells. Because the doses are so high, healthy bone marrow cells are destroyed in the process.
• Transplantation of stem cells - The stem cells are thawed and infused into the patient through a flexible tube placed in a large vein in the neck or chest area. The transplanted stem cells begin to produce new blood cells. For the first 2 to 4 weeks, patients are vulnerable to life-threatening infections. That risk lessens as the transplanted cells begin to make enough new disease-fighting cells.

The type of transplant depends on where the stem cells come from:

• Autologous stem cell transplantation - This type of transplant uses your own stem cells. After you receive high-dose chemotherapy, the stored stem cells are thawed and returned to the bloodstream. It is the most common type of stem cell transplant performed for multiple myeloma.
  
  Some people choose to go ahead with the procedure as soon as their stem cells are “harvested” and stored. Others choose to wait a while and continue with initial therapy as long as it is working well.
  
  Researchers continue to conduct clinical trials of the best ways to use stem cell transplantation. Some are looking at whether two transplants performed within 6 months of each other—called “tandem” or double transplants—are better that a single transplant. Others are looking at whether a second round of high-dose therapy and stem cell transplantation can benefit patients who do not get enough benefit from the first procedure.
• Allogeneic stem cell transplantation - An allogeneic stem cell transplant is similar to an autologous transplant, except that it involves stem cells collected from a donor. Often the donor is a close relative, but a genetically matched non relative may also be the donor.
  
  This type of transplant has a high risk of a complication known as graft-versus-host disease. This occurs when the donor’s immune cells attack the body of the transplant patient because they do not recognize it as their own. Because of this risk, allogeneic stem cell transplants are not performed frequently for people with multiple myeloma. However, some patients who have this type of transplant can achieve long-term, disease-free survival. This is because the donor cells bring strong immunity against the recipient’s myeloma.
  
  Clinical trials are researching new ways of using allogeneic stem cell transplants to treat multiple myeloma. One possibility involves using lower doses of chemotherapy before the transplant. This is called a nonmyeloablative or “mini-allogeneic” transplant.
• Syngeneic stem cell transplantation - This type of transplant uses stem cells from the patient’s healthy identical twin.

  Maintenance therapy is ongoing treatment given in the hope of making sure the disease does not return. It is not standard for people with multiple myeloma after a stem cell transplant. However, this strategy is under investigation in clinical trials. For example, studies are looking at whether continued treatment with Thalomid® (thalidomide) Velcade^® (bortezomib), or Revlimid^® (lenalidomide) can offer any benefit.

For Patients Not Having Stem Cell Transplant

Patients who are not planning to have stem cell transplantation are usually treated with the chemotherapy agent Alkeran^® (melphalan) and prednisone tablets either 4 or 7 days monthly. Prednisone is a type of steroid medication. (Melphalan cannot be used as initial therapy for those undergoing stem cell transplant. Its effects can make it difficult to harvest enough stem cells for later treatment.)

Often, doctors will combine the melphalan and prednisone with some of the newer targeted therapies for myeloma, such as such as Thalomid^® (thalidomide), Revlimid^® (lenalidomide), and Velcade^® (bortezomib). Research suggests that these combinations may produce better results.

In addition, these patients are candidates for the same treatments that are used as initial therapy in people who do plan to have stem cell transplantation:

• The steroid medication dexamethasone, with or without thalidomide or lenalidomide - Thalidomide is an oral medication that appears to block some of the ways that myeloma cells grow and reproduce. It stops the formation of new blood vessels and proteins called growth factors, which enable the cells to thrive. It also may help to stimulate the body’s immune system. Usually, doctors start patients on a lower dose, gradually increasing it over a few weeks. It may take a few months for the medication to take effect. Patients usually stay on the drug as long as it is working and they can tolerate the side effects.
  
  Although thalidomide promotes myeloma cell death, it also can produce more side effects, such as a rash, low heart rate, and deep vein thrombosis (DVT). DVT is the formation of blood clots in the veins. Therefore, doctors may also prescribe a medication that prevents blood clotting, such as Coumadin^® (warfarin) or Lovenox^® (heparin), or recommend taking aspirin.
  
  Another option with dexamethasone is lenalidomide, which is similar to thalidomide, but it appears to be more potent and causes different side effects. Researchers do not yet fully understand how it works. It appears to stop myeloma cells from growing and dividing. It also seems to play a role in keeping the cells from developing the new blood vessels they need to thrive.
  
  Typically, lenalidomide has been used as a second-line therapy for multiple myeloma, usually in combination with dexamethasone. “Second-line” means that it is given after a prior therapy stops working. However, it is now being investigated as a possible first treatment for myeloma.
  
  Like thalidomide, it is an oral medication, and the dose is usually adjusted based on how the disease responds and whether the patient experiences side effects. It also can increase the risk of blood clots, or DVT. Doctors may prescribe a medication that prevents blood clotting, such as warfarin or heparin, or recommend taking aspirin.
  
  
• Velcade^® (bortezomib)-based treatments - Bortezomib is a type of medication called a proteasome inhibitor. It appears to work by interfering with the growth and survival of myeloma cells. It also causes cell death. Often it is used in combination with other treatments, such as dexamethasone, thalidomide, and/or liposomal doxorubicin. Like lenalidomide, it is typically given after a patient has received at least one prior therapy. However, it is now being investigated as a possible first treatment for myeloma.
  
  Bortezomib is given intravenously (into a vein) on a monthly cycle. A typical schedule might have a patient receiving the drug twice per week for 2 weeks, followed by a 10-day rest period. However, the schedule can vary from person to person, depending on his or her needs and the side effects that develop.
• Dexamethasone plus the chemotherapy drugs vincristine and Adriamycin^® (doxorubicin hydrochloride), or VAD - These medications are given intravenously (directly into a vein) in the hospital. Chemotherapy is typically given in cycles, with treatments spaced out every few weeks.
• Dexamethasone plus the chemotherapy drugs vincristine and Doxil^® (liposomal doxorubicin), or DVD - These medications are given intravenously (directly into a vein) in the hospital. Chemotherapy is typically given in cycles, with treatments spaced out every few weeks.

Nontransplant candidates typically continue initial therapy for about a year, or until their disease stops responding. At that time they may receive some form of maintenance therapyand continue to receive treatment for their symptoms as needed.