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Overview of Treatment Options

Module 2: First-Line Treatment of Multiple Myeloma

Section 1: Overview of Treatment Options


What approaches can be considered for first-line treatment of multiple myeloma?

Dr. Robert Kyle: Fortunately, there are various treatments for patients with multiple myeloma.

The standard treatment for the elderly patient and for those who are younger, but who are not candidates for autologous stem cell transplant, is melphalan and prednisone. These agents are given orally for a period of 4 to 7 days and repeated every 4 to 6 weeks.


Another therapeutic approach is the use of VAD, a three-drug combination consisting of vincristine and doxorubicin, given by continuous infusion for 96 hours, plus dexamethasone 40 mg daily on days 1 to 4, 9 to 12, and 17 to 20. VAD is used for patients who are going to have an autologous stem cell transplant.

Combinations of alkylating agents may also be used. The most common is VBMCP, which consists of vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone. This is administered every 6 weeks and is continued until the patient responds. It is important to note that regimens containing alkylating agents are not appropriate for patients who may become transplant candidates. If alkylating agents are to be used, that should be done only after stem cell collection.

Dr. Brian Durie: Steroids are perhaps the single most helpful group of drugs for the treatment of multiple myeloma. Steroids have the following advantages:

  1. For acute management of the disease, they can be used to shrink plasmacytomas, reduce neurologic pressure, reduce hypercalcemia, and achieve overall control of the disease.
  2. In patients with renal failure, they can be used without dose adjustment.
  3. In patients who have low blood counts, they can be used without fear of further
    reduction in counts.

An additional advantage of steroids is that they are perhaps the best agents for maintenance therapy.

Oral Prednisone News

The problem with steroids is that their efficacy needs to be balanced against their potential side effects: particularly, short- and long-term toxicity. These side effects can be substantial, especially with high doses of dexamethasone. However, significant long-term toxicity also can occur with steroids that generally are considered benign, as is the case with prednisone, when given three times a week. [View Reference]

In summary, steroids are a very effective group of drugs, but it is extremely important for the physician to closely balance and monitor the efficacy versus the short- and long-term toxicity.

What is the role of thalidomide in treating multiple myeloma?

View Topic Summary by Seema Singhal, MD

Dr. Seema Singhal: Although the role of thalidomide for the treatment of relapsed refractory myeloma has been well established, its role in the initial treatment of this particular disease is still being explored. Data are just emerging about the use of thalidomide for the initial treatment of multiple myeloma. Various doses are being tried. I have started patients on doses of approximately 200 mg and tried to increase doses to the maximal amount each patient can tolerate. I've observed 50% to 60% responses, although the follow-up is quite short. [View Reference]

The Mayo Clinic recently has run a trial that combined thalidomide with dexamethasone, with excellent response rates of about 70% to 77%.[View Reference] Data are just coming in from a trial in New York that combined thalidomide with clarithromycin as well as dexamethasone. The results are very promising for this combination. [View Reference]



How is stem cell transplantation used in the treatment of multiple myeloma?

View Topic Summary by William I. Bensinger, MD

Dr. William Bensinger: In the last 10 years, stem cell transplantation has emerged as an important treatment modality for some patients with multiple myeloma. Stem cell transplants rely on the use of very high-dose chemotherapy, with or without radiation treatments, to ablate the patient's bone marrow. Later, stem cells obtained from either the patient or donors are transplanted to restore hematopoietic cell function. Generally, stem cell transplants can be classified into autologous or allogeneic transplants, depending on the source of stem cells from either the patient or suitably matched donors.

Autologous stem cell transplants seem to offer improved response rates and survival in comparison with chemotherapy. This is always a "moving target" as newer treatment modalities are developed. We do not yet have outcomes comparing newer treatments, such as thalidomide, with transplantation or even conventional therapy.

Allogeneic stem cell transplants rely on an immunologic graft-versus-myeloma effect but can result in higher complication rates compared with autologous transplants.

In recent years, so-called minitransplants, or the more correct term, nonablative transplants (also called nonmyeloablative, because all the bone marrow is not destroyed), have been used to rely on the immunologic graft-versus-myeloma effect while lowering some of the complication rates from a standard allograft. [View Reference]

Procedure for an Autologous Transplant

Typically, when we perform an autologous transplant, patients receive four tosix cycles of induction therapy, and then stem cells are harvested from the patient.Stem cell harvesting usually is performed with the use of growth factors or withthe combined use of chemotherapy plus growth factors to achieve additional reductionin the tumor burden and improve the yield of stem cells. Following that, patientsreceive high-dose therapy, usually melphalan, but sometimes similar agents withradiation, followed several days later by the reinfusion of their autologous stemcells. [ViewReference]

Procedure for an Allogeneic Transplant

For an allogeneic transplant, patients generally receive very high-dose chemotherapy (with or without radiation) to ablate or destroy the existing bone marrow, followed by transplant of the donor stem cells. Immunosuppressive drugs, such as methotrexate and cyclosporine, are used to facilitate engraftment and to prevent the development of graft-versus-host disease (GVHD), which is one of the more serious complications of allogeneic transplants. [View Reference] The challenge in employing this therapy is to balance the degree of immunosuppression to prevent severe GVHD while allowing a graft-versus-myeloma effect.

The term graft-versus-myeloma refers to the ability of the transplanted donor cells to destroy myeloma cells in the patient. The most dramatic demonstration of this effect occurs for patients who have relapsed after an allogeneic stem cell transplant. When these patients receive a transfusion of lymphocytes from their original stem cell donor, up to 50% may experience another remission of their myeloma, without the need for other therapies.

Procedure for a Nonablative (Mini-Allograft) Transplant

(Nonmyeloablative Conditioning for Allogeneic Transplantation)

(Nonmyeloablative Hematopoietic Cell Transplantation)

(Submyeloablative Conditioning for Allogeneic Transplantation)

The nonablative, or so-called mini-allograft, transplants rely on very low-dose chemotherapy but heavy immunosuppression to achieve donor engraftment. The graft-versus-myeloma effect achieves the major effect of this type of transplant. [View Reference][View Reference]

What are the objectives of treatment? How does one know when to stop? What constitutes a successful treatment?

Dr. Brian Durie: The primary objectives in treating multiple myeloma are to reduce or eliminate the symptoms of the disease and to reduce or eliminate the organ dysfunctions that may have developed as a part of the disease.

These organ dysfunctions are development of bone destruction, the onset of renal insufficiency, and the onset of marrow dysfunction with the evolution of anemia or reduction in platelet count or white count.

The goals of treatment are to reverse the basic complications that have occurred as a result of active myeloma growth. Specific goals of treatment include eliminating symptoms, such as bone pain or fatigue; restoring kidney function to normal; improving blood counts; and recovering overall organ function throughout the body.

The duration of treatment is determined by the magnitude of the initial problems and the sensitivity of the disease to treatment. The exact length of treatment required is not defined clearly, although treatment typically is continued for a minimum of 6 months and most often for 1 year.

Since the introduction of high-dose therapy with stem cell transplant, the duration of treatment is linked primarily to the time required to complete initial induction therapy followed by the transplant procedure.

Success in treatment is measured by the recovery of normal organ function andthe reversal of the initial symptoms. The goal is to achieve normal day-to-dayfunctioning and recover normal blood counts, chemistries, and other test results.There continues to be controversy about the timing of stem cell transplantationin appropriate patients. Is it better to perform autologous transplantation aspart of initial therapy or at a later point in the disease?

When making treatment decisions, are there non clinical issues that should be considered?

Dr. Brian Durie: There are many factors that have impact on the decisions related to various treatment options for multiple myeloma. With current knowledge, there is no single answer as to what initial therapy should be used to achieve maximal benefit. In discussions between physicians and patients, the outcome of therapy needs to be considered in addition to the goals and objectives of patients in terms of their day-to-day lives, their families, their work situations, and their financial status. All these elements need to be taken into consideration in selecting the optimal therapy.

For example, if a patient needs to continue with work to retain insurance coverage, that factor could be critical in organizing the timing of induction and transplant therapy. Similarly, if a patient has concerns about the toxicity or side effects of high-dose therapy, those concerns may complicate an already difficult choice the patient is facing. When selecting treatment options, the patient must consider many factors including side effects, complications, time off from work, and impact on day-to-day life. Sometimes, it is very difficult for a patient to work through all of the different treatment options and select from among them.

Initially, one of the more difficult areas for patients to work through is accepting the diagnosis and consequent need for therapy. In this process, seeking a second opinion can often be helpful in evaluating different therapies. With these second, or in some cases even third or fourth opinions, the advantages and disadvantages of different treatment options can be evaluated. It is important to encourage patients to proceed with therapy despite their concerns to avoid unnecessary complications.

Dr. David Roodman: Seeking a second opinion is important for patients to make adequately informed decisions about their therapy. However, seeking multiple opinions may result in "doctor shopping" and can confuse patients about treatment options. An informed second opinion can help a patient make decisions with more confidence.

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Overview of Treatment Options | Transplants | Thalidomide | Radiotherapy, Bisphosphonates, and Other Supportive Therapies for Multiple Myeloma |

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