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Treatment Options - High-dose Chemotherapy with Stem Cell Transplantation


High-Dose Chemotherapy and Stem Cell Transplantation

What is high-dose chemotherapy and stem cell transplantation?

High-dose chemotherapy and stem cell transplantation is a treatment option for some patients with multiple myeloma. With this treatment, high doses of chemotherapy are given in order to destroy more myeloma cells than would be possible with conventional (standard dose) chemotherapy. High-dose chemotherapy also destroys important cells in the bone marrow, called hematopoietic stem cells, which are responsible for the production of blood cells. Without these stem cells, blood cell production would cease. These stem cells must be replaced in order to restore blood cell production after high-dose chemotherapy. The procedure that restores the stem cells is called stem cell transplantation.

Historically, high-dose chemotherapy and hematopoietic stem cell transplantation has been considered to provide patients with a better chance for longer survival than other therapies. However, the newer, novel agents (e.g., Revlimid®, Velcade®, Thalomid®) are providing high response rates, with significantly prolonged survival as well. Thus, the role of high-dose chemotherapy and stem cell transplantation in the treatment of multiple myeloma is evolving.

Approximately 5000 patients with multiple myeloma receive high-dose chemotherapy and stem cell transplant each year in North America.

What are hematopoietic stem cells and why are they so important?

Hematopoietic stem cells are remarkable types of cells that can divide and develop into any of the three main types of cells found in the blood:

  • Red blood cells, which carry energy-giving oxygen from the lungs to the entire body

  • White blood cells, which are important immune cells that play an important role in fighting bacteria and viruses that cause infection

  • Platelets, which help blood to clot when bleeding occurs



Hematopoietic stem cells are found in the bone marrow, an organ which is found inside almost all the bones of the body, and in the circulating blood (also called peripheral blood). Stem cells constitute only a small fraction (less than 1%) of all cells in the bone marrow and an even smaller percentage of cells in the peripheral blood.

How do hematopoietic stem cells differ from other types of stem cells?

Hematopoietic stem cells are entirely different from embryonic stem cells, which have received much attention in the media over the last few years.

Embryonic stem cells are immature cells that come from human embryos. They are not yet specialized to perform any particular function in the body so they can grow and develop into many types of tissues. They are being studied as possible cures for many types of chronic diseases.

In contrast, hematopoietic stem cells are specialized and can only produce blood cells. Only hematopoietic stem cells are used in the transplantation procedure for multiple myeloma.

For the remainder of this discussion hematopoietic stem cell transplantation will be referred to simply as stem cell transplantation.

Who is a candidate for high-dose chemotherapy and stem cell transplantation?

Many factors must be considered to determine whether a patient is a candidate for high-dose chemotherapy and stem cell transplant. These include:

  • The type of myeloma

  • The stage of disease and how aggressive it is

  • How the cancer responded to prior treatment

  • Age and general physical condition

In the past, transplants were limited to younger patients in good physical condition. However, they are now performed in a more diverse group of patients. In general, patients in overall good physical condition with adequate kidney, lung, and heart function are eligible.

In addition, recent studies have shown that high-dose chemotherapy and stem cell transplant may even be possible in patients who have reduced kidney function or kidney failure, with proper precautions and somewhat lower doses of chemotherapy.

Transplant may not be feasible in patients who have received:

  • Certain types of chemotherapy, especially melphalan

  • Radiation therapy to the spine or pelvis

These treatments may impact the ability to obtain the stem cells needed for the transplantation.

Although it seems counter-intuitive, some experts do not recommend high-dose chemotherapy and stem cell transplant for patients who have some types of high risk disease, which accounts for approximately 25% of myeloma patients. High-risk patients include those with certain types of DNA abnormalities (e.g. chromosome 13 deletion, chromosome 17 translocation). These patients tend to have shorter periods of remission. Further, one study showed there may actually be poorer survival.

You and your doctor will determine if high-dose chemotherapy and stem cell transplant is right for you.

What are the different types of stem cell transplants?

Stem cell transplants are classified in several different ways.

  • By the type of donor (individual providing stem cells):

    • Autologous: from the patient

    • Allogeneic: from another individual who is genetically similar or matched to the patient.

      • The donor’s cells must match the patient’s, similar to the matching process used for kidney or other organ transplantation. In many cases, the stem cell donor is related to the recipient, typically a brother or sister.

      • Stem cells from unrelated donors can also be used if there is a match. It may also be possible to use cells from banked cord blood.

  • By the way in which stem cells are obtained or collected:

    • Peripheral blood: from the bloodstream

    • Bone marrow

The vast majority of stem cell transplants performed in multiple myeloma patients are autologous peripheral blood stem cell (PBSC) transplants. Bone marrow transplants are rarely performed today in myeloma. Historically, these were the first type of stem cell transplants performed, however peripheral blood stem cell transplants put less strain on the body and stem cells are easier to collect. Occasionally, bone marrow transplants may be used if of the number of stem cells that can be obtained from the peripheral blood are insufficient.

Autologous stem cell transplants have several advantages over other types of transplants:

  • The patient serves as his or her own source of stem cells. There is no need to find a donor and there is no risk of incompatibility (i.e., a mismatch).

  • In many instances, much of the procedure can be done on an outpatient basis.

  • They are relatively safe procedures, with low rates of complications and infections compared with allogeneic transplants. Deaths due to the transplant itself are approximately 2% to 3% in patients with newly diagnosed myeloma.

In theory, one disadvantage of autologous stem cell transplants is that the transplant could be potentially contaminated with tumor cells when a patient’s stem cells are used. However, recent studies indicate that this is not a significant problem and is not a major cause of myeloma relapse.

High-dose chemotherapy followed by an allogeneic transplant has the potential to possibly provide better long-term control of myeloma (with longer time without disease progression) than autologous transplants. However, this is a risky procedure with a high death rate due to the procedure itself (20-50%). As a result, this type of transplant is rarely performed.

A safer type of allogeneic transplant is much more common. This type of transplant is called a mini-allogeneic transplant (also called a reduced intensity or non-myeloablative allogeneic transplant). A "mini-transplant" uses lower doses of chemotherapy prior to transplant and as a result the rate of death due to the procedure is very low, similar to that of an autologous transplant.

Types of Stem Cell Transplants

Source of Stem Cells Frequency of Use
Peripheral Blood (bloodstream) More than 95% of transplants
Bone marrow Occasional; only if the number of stem cells obtained from the peripheral blood is too low
Cord blood (umbilical cord) Rare: Due to limited numbers of stem cells that can be collected from each umbilical cord. New research has shown the feasibility of using multiple cord blood units from more than one donor.


Type of Donor Frequency of Use
Autologous (autografts): Patient Majority
Allogeneic: Siblings, rarely children or parents or an unrelated individual (matched for genetic similarity) Unusual, mostly in clinical trials
Syngeneic: Identical twin Rare


Other Types of Stem Cell Transplantation

Type Description
Tandem autologous transplant 2 transplants within 6 months
Mini (non-myeloablative) allogeneic transplant Uses lower doses of chemotherapy (compared to standard high-dose chemotherapy). Often performed as a tandem transplant after one autologous transplant


What are the steps in the process of high-dose chemotherapy and stem cell transplantation?

High-dose chemotherapy and stem cell transplantation is a complex process that involves several steps.

Induction Therapy (initial treatment)Several months of myeloma treatment is given first to reduce the amount of tumor present, in order to increase the chance of a successful transplant. These treatments may be the same as those given to patients who are not planning to undergo a transplant.
 
Stem Cell CollectionFollowing induction therapy, stem cells are obtained or harvested from a patient or donor. In most cases, patients’ own stem cells are used (autologous transplant).
 
Freezing and StorageWhen a patient’s own stem cells are used, they are frozen and stored until needed.
 
High-Dose ChemotherapyHigh doses of chemotherapy are given in order to eliminate as much disease as possible. High-dose chemotherapy can be given either immediately following stem cell collection or at a later date.
 
Consider Second Transplant or Consolidation Therapy, if M Protein Level greater than 90 % (Under Investigation)After the completion of high-dose chemotherapy, the stem cells are injected into the patient’s bloodstream. The stem cells travel to the bone marrow and begin to produce new blood cells, replacing the normal cells lost during high-dose chemotherapy.
  
Maintenance TherapyPatients who do have a less than ideal response (less than a very good partial response) after high- dose chemotherapy and transplant may be considered for a second transplant or additional myeloma treatments (known as consolidation therapy) in order to further reduce the amount of tumor present.

Ongoing treatment with a myeloma drug may be considered, even for patients who are in complete remission, following the completion of high-dose chemotherapy and stem cell transplant, with the goal of further reducing the chance of a relapse.
  


Reviewed by:
William I. Bensinger, MD
Director,
Autologous Marrow Transplant Program,
Seattle Cancer Care Alliance
Professor of Medicine,
University of Washington School of Medicine
Seattle, WA