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HERE'S WHAT YOU SHOULD KNOW

Autologous Bone Marrow and Stem Cell Transplantation

Introduction: You've just been told by your physician that you have cancer... Multiple myeloma in fact. You may have never heard of this particular disease, but, from this moment on, it will take center stage in your life.

Multiple Myeloma (MM) is a malignancy of plasma cells. Plasma cells are antibody producing cells normally present in the blood and throughout the body. Myeloma is usually called multiple myeloma because the malignant plasma cells, or myeloma cells, accumulate and produce areas of involvement in multiple areas of the bone marrow.

How you gather information, learn about the different options and deal with your diagnosis will be important in the management of your treatment.

The International Myeloma Foundation (IMF) is a non profit foundation whose mission is to improve the quality of life of myeloma patients while working toward prevention and a cure. The IMF believes that knowledge about your disease is critical. Obtaining the latest information on the treatment and management of myeloma will help you take responsibility for managing your treatment. Patients who learn about myeloma, understand their treatment options, and form partnerships with their doctors do better in managing their disease and outcome. Most general information regarding myeloma can be found in our sister publication, "The IMF Patient Handbook". An excellent source of technical information can be found in, "The IMF: A Concise Review of the Disease and Treatment Options" prepared by Dr. Brian G. M. Durie. Both of these booklets are available through the IMF free of charge. Another important source of information is the IMF's web page www.myeloma.org.

Once you have done your homework and become familiar with the different treatment options, you may be considering an autologous peripheral blood stem cell transplant (PBSCT) as treatment for your disease. The preferred treatment by many doctors is the peripheral blood stem cell transplant (PBSCT), as it allows for a faster recovery. In this brochure we discuss what autologous transplantation is and answer some commonly asked questions regarding this procedure. Many of the discussions in this brochure were provided by myeloma patients like you who have had experience with autologous transplantation. Without them this patient guide would not have been possible. We would like to thank all the myeloma patients who have either had or are considering an autologous transplant who shared their insight with us.

Am I a Candidate for an Autologous Transplant?

An autologous transplant is a treatment option for myeloma patients, however it is not a cure. It can improve the duration of remission and provide a better quality of life for some patients. A goal of transplantation is to provide you with the longest remission time as possible. Not all patients diagnosed with myeloma are candidates for an autologous transplant. Many factors must be taken into consideration. For example, the type of myeloma, its progression, aggressiveness and the responsiveness of the disease to treatment are all important. We cannot stress enough that myeloma is a highly individualized disease. While there are similarities between patients, each case has its own distinct characteristics. Therefore, general statements regarding patient outcomes both during the transplant procedure and post transplant are inappropriate.

There are several things to consider when deciding if a transplant is the right treatment option for you. For example, there are prognostic factors, including your overall health and age, that your doctor will take into consideration before recommending a transplant. There will be emphasis on kidney and liver function. There will be testing to determine how much myeloma there is in your body and how aggressive it is. All of these variables will be weighed before determining whether a transplant is appropriate for you.

When to transplant is also an important consideration. There is no clear cut clinical data to suggest that transplantation earlier in your treatment regimen is better than waiting until later. Remember, in most cases, unlike a heart attack, you do have the luxury of time to do your homework and to gather all the information and make an informed decision about what's right for you. For example, you could harvest your stem cells and save them for a later treatment. This leaves you open to other more immediate treatment options. These are all things to discuss with your doctor. It's important to remember that even if you are a good transplant candidate, the ultimate decision on whether or not to have a transplant is yours.

What Is an Autologous Transplant?

An autologous peripheral blood stem cell transplant is a procedure that replenishes the supply of normal cells that are destroyed by high dose chemotherapy and/or radiation therapy. In autologous transplantation, patients receive cells collected from their bone marrow or blood prior to receiving chemotherapy or radiation treatment. The word autologous means that the blood is collected from the patient, not from a relative or a volunteer donor.

With high dose chemotherapy, patients receive large doses of anticancer drugs in order to destroy as many cancer cells as possible.

Although high dose chemotherapy is often very effective, this treatment also destroys normal cells in your blood and bone marrow. Autologous transplantation provides replacement of normal cells and "rescues" the patient's immune system from the effect of high dose chemotherapy or radiation treatment.

Prior to administration of high dose chemotherapy, the patient's blood or bone marrow is harvested or collected so that their stem cells can be re-infused after receiving chemotherapy. A stem cell is the "mother cell" that leads to the production of all the various types of cells in the blood. New blood cells are produced in the bone marrow.

Stem cells are very rare and powerful cells that reside in the bone marrow and at lower levels in peripheral blood, constituting only a small fraction (less than 1%) of all the cells in the marrow. Stem cells divide and grow to produce three main types of mature cells found in your blood:

Stem Cell
Red Blood Cells
Platelets
White Blood Cells
Red blood cells, which carry energy giving oxygen from the lungs to the entire body,
White blood cells, which play an important role in fighting bacteria and viruses that cause infections; and
Platelets, which help blood to clot when bleeding occurs.

High dose chemotherapy destroys not only the tumor cells, but also stem cells in the bone marrow and mature cells in the blood. The reduced supply of blood cells can cause several problems, including:

Infection from lack of white blood cells that attack invading germs
Bleeding from lack of platelets that help the blood to clot; and
Fatigue and difficulty breathing from lack of red blood cells that carry oxygen throughout the body. Fortunately, autologous transplantation makes it possible to replenish the supply of normal stem cells and blood cells lost during high dose chemotherapy. Physicians re-infuse stem cells harvested prior to the administration of high dose chemotherapy or radiation, to restore the blood production and immune systems of patients whose bone marrow has been extensively damaged from chemotherapy.

Autologous transplantation is a complex process that can take weeks to months to complete. The diagram above and the discussions that follow illustrate the major steps involved in the autologous transplant process. Many of these steps will be performed as an outpatient while other components of the transplant will require hospitalization.

Autologous Transplant Process

COLLECTION

Blood is harvested from the patient to collect stem cells. Recent medical advances now make it possible to collect stem cells from circulating blood as well. Your doctor will explain which method of stem cell collection- bone marrow or peripheral blood- is best for you.

o Collecting stem cells from bone marrow

Collecting or harvesting bone marrow is usually done in a hospital operating room under general anesthesia. Using a hollow needle, a surgeon will take bone marrow from several different areas of the hipbones. The bone marrow is then frozen and stored until high dose chemotherapy is completed. In the majority of cases, the only side effect of the procedure is some soreness in the hip area for a few days.

o Collecting stem cells from peripheral blood

Harvesting stem cells from the patient's blood, often referred to as peripheral blood stem cells or peripheral blood progenitor cells (PBPC) has certain advantages over collecting stem cells from bone marrow. No general anesthesia is needed for this collection method, and it is done in an outpatient setting so no overnight hospitalization is necessary. Because most stem cells reside in the bone marrow, it is necessary to move stem cells from the bone marrow to the bloodstream. This procedure is called mobilization. Prior to peripheral blood stem cell collection, your physician may administer cytokines or colony stimulating growth factors. These drugs are given to mobilize or move stem cells from the bone marrow to the circulating blood thereby allowing for a greater harvest of stem cells. Once a sufficient number of stem cells are mobilized from the bone marrow into the bloodstream, the patient's blood is collected using a process called apheresis. Prior to starting apheresis, a thin flexible plastic tube called a catheter is inserted through the skin and into a vein so that blood can be taken out. The catheter is usually inserted into the chest just below the collarbone. Insertion of the catheter is usually done as an outpatient procedure, and only a local anesthetic is needed. The site where the catheter enters the skin may be sore for a few days, which can be relieved with medications like acetaminophen (Tylenol). The catheter may be kept in place for several weeks, because it can be used to give chemotherapy after stem cells have been collected.

Once the catheter is in place, the patient, while lying down, is connected to the apheresis machine through the catheter. Blood is circulated through the apheresis machine, which removes a fraction of the blood containing the mobilized stem cells and returns other blood cells back to the patient. Patients usually do not need to be hospitalized for apheresis, but most come in for one or two sessions, lasting two to four hours each, in order to ensure that enough stem cells are collected. The most common side effects experienced during apheresis are slight dizziness and tingling sensations in the hands and feet. Less common side effects include chills, tremors, and muscle cramps. These side effects are temporary and are caused by changes in the volume of the patient's blood as it circulates in and out of the apheresis machine, as well as by blood thinners added to keep the blood from clotting during apheresis.

PROCESSING STEM CELLS

After collection, the bone marrow or peripheral blood is taken to the processing laboratory, which is usually located within the hospital or local blood bank. In the processing laboratory, the bone marrow or blood cells are prepared for freezing (cryopreservation). The processing laboratory may also use additional procedures to select stem cells and remove tumor cells. 11 Stem Cell Concentration Harvested Blood or Bone Marrow (1-2% Stem Cells) Concentrated Stem Cells Non-target Cells The purification process used to concentrate stem cells cannot recognize tumor cells and therefore does not include them in the concentrated product.

STEM CELL SELECTION Autologous bone marrow and peripheral blood stem cell transplantation often carries the risk that some tumor cells will be re-infused back into the patient following high dose chemotherapy. With the advent of highly sensitive detection methods, the presence of contaminating tumor cells in bone marrow and mobilized peripheral blood is well documented. In an attempt to minimize tumor contamination in autologous transplants, investigators have pursued a number of methods for eradicating or purging tumor cells from bone marrow and blood. Stem cell selection is one method used for purging tumor cells. Recent clinical studies have demonstrated that stem cell selection reduces the tumor contamination found in mobilized blood. This is possible because stem cells have unique properties not shared by tumor cells. The long term clinical benefit of eliminating tumor contamination has not been determined in randomized clinical trials. However, preliminary evidence suggests that eliminating tumor contamination may be beneficial. Gertz, et. al. demonstrated that contaminating tumor cells in peripheral blood collected from patients with multiple myeloma are associated with shortened relapse-free survival after transplantation. However, this may not be a direct effect of the contaminating myeloma cells, but more related to the aggressive nature of the underlying myeloma in such patients. Many experts believe that tumor purging alone may not improve patient outcomes, but when combined with other therapies, both pre and post transplant, it may contribute to increased disease free survival.

Studies are ongoing to evaluate the benefit of removing tumor cells from the collected stem cells prior to infusion in the patient.

CRYOPRESERVATION

After collection, the blood is cryopreserved (frozen). The blood must be preserved to keep the stem cells alive until it is time to re-infuse them back into the patient's bloodstream. The cells are frozen and stored in liquid nitrogen. They can be stored frozen for as long as necessary. There is some deterioration with time, but excellent function of stem cells is retained for at least 10 years.

ADMINISTERING HIGH DOSE CHEMOTHERAPY OR RADIATION THERAPY

After the stem cells are frozen and stored, the patient is ready to receive high dose chemotherapy. Sometimes called dose intensive chemotherapy, this treatment is designed to destroy cancer cells more effectively than standard chemotherapy. The purpose of high dose chemotherapy is to kill tumor cells inside the patient's body. Depending on the type of cancer and other factors, some patients may receive one or more cycles of chemotherapy, possibly in combination with radiation therapy, over a period of several days.

The kind of high dose chemotherapy or radiation treatment a patient receives depends on a number of factors, such as the type of cancer and how far advanced it is. Some patients may need only one cycle of treatment, while others may require several cycles with rest periods in between.

High dose chemotherapy can cause severe side effects, which may require that some patients be admitted to the hospital for treatment. Shortly before starting chemotherapy, patients usually are given large amounts of fluid to prevent dehydration and kidney damage from the chemotherapy. Medications designed to prevent or lessen some of the expected side effects of treatment are also given.

Some of the more common side effects of chemotherapy include nausea, vomiting, diarrhea, mouth sores, skin rashes, hair loss, fever or chills and infection. Patients are very closely monitored during the high dose chemotherapy administration. Monitoring includes daily weight measurement, as well as frequent measurements of blood pressure, heart rate, and temperature. During this period patients will feel helpless and very fatigued. Having a family support network is very important during this period.

RE-INFUSION

After chemotherapy is administered, the patient's stem cells are thawed and given back to them. This procedure is often referred to as the transplant. Within a few days after completing the high dose chemotherapy, the stored stem cells are transplanted, or re-infused into the patient's bloodstream. The re-infusion process is similar to a blood transfusion and takes place in the patient's room: it is not a surgical procedure. The frozen bags of bone marrow or blood cells are thawed in a warm water bath, and then injected into the bloodstream through the catheter. It usually takes 2-4 hours for the infusion. Infused stem cells travel through the bloodstream, and eventually, to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets.

ENGRAFTMENT AND RECOVERY

During the first 2 - 3 weeks after transplantation, the re-infused stem cells migrate to the bone marrow and begin the process of producing replacement blood cells, a process called engraftment. Until engraftment is complete, the patient is susceptible to infection and bleeding caused by low blood cell counts. Therefore, special precautions are necessary during recovery. Since the patient's immune system is very weak, patients will remain in the hospital for at least several days to a week until platelet and white blood cell counts are improving to a safe level for the patient to be discharged. With close monitoring the patient can be out of the hospital during the recovery period.

The long weeks of waiting for the transplanted stem cells to engraft, for blood counts to return to safe levels and for side effects to disappear increase the emotional trauma felt by a patient. Recovery can be like a roller coaster ride: one day a patient may feel much better, only to awake the next day feeling as sick as ever. It is important during this period to take things one day at a time.

After being discharged from the hospital, a patient continues recovery at home for two to four months. Patients usually cannot return to fulltime work for up to six months after the transplant. Although patients may be well enough to leave the hospital, their recovery will be far from over. For the first several weeks the patient may be too weak to do much more than sleep, sit up and walk a little around the house. Frequent visits to the hospital will be required to monitor the patient's progress. It can take six months or more before a patient is ready to fully resume normal activities.

Until engraftment of the stem cells takes place, patients are very susceptible to developing infections. Even a minor infection like the common cold, can lead to serious problems because the body's immune system is so weakened by the effects of the high dose chemotherapy and the loss of blood cells.

PREVENTING INFECTION

Patients may be given red blood cell and platelet transfusions during the recovery period to help prevent anemia and bleeding.

Antibiotics are often prescribed to help prevent infection.

Visitors may be asked to wear masks and gloves to minimize contact with the patient. Fresh fruits, vegetables and flowers may be prohibited from the patient's room as these can carry bacteria and fungi.

If infection and fever occur, the patient may be admitted to the hospital and given intravenous antibiotics.

Each medical center has its own specific guidelines for patient care, including removal of the catheter, during recovery. The health care team will explain these guidelines to patients and family members.

SUMMARY

High dose chemotherapy and autologous transplantation can place an enormous stress on patients and families. Physical, psychological, emotional and financial stresses can be overwhelming. Patients and families may experience feelings of anger, depression, and anxiety over an unknown future and a lack of control. Support services offered through the hospital and many other organizations are very important during this time.