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Fall 1999 Volume 3, Issue 6:
Melphalan and Prednisone
By Morie A. Gertz, M.D.and Angela Dispenzieri, M.D.
Still the right therapy for many patients with myeloma
Much progress has been made in the treatment of multiple myeloma over the past 30 years. Improved supportive care, methods to reduce the impact of impaired kidney function, modern antibiotics, and bisphosphonates for reduction of skeletal events have all been important steps forward in enhancing the quality and quantity of life in patients with myeloma. Recently, the use of erythropoietin has been shown to be effective in selected patients with multiple myeloma in reducing their dependency on transfusion. These supportive regimens are critical to ensuring the best possible quality of life for patients with multiple myeloma.

It is important to recognize that no two patients with myeloma are alike. Therefore, it would be naive to think that there is only one treatment regimen that is correct for all patients with multiple myeloma. The purpose of this article is to assist the patient in making decisions about appropriate treatment.

Over the past ten years, definite benefits have been demonstrated in the use of stem cell transplantation in the management of patients with myeloma. One study in which patients had their treatment decided by the “toss of a coin”, with one half having a transplant and the other half having traditional chemotherapy, demonstrated some survival benefit for patients receiving a transplant. This study, however, demonstrated that transplant is not a cure for the disease and that for some patients the survival prolongation is less than hoped. Moreover, this study excluded patients over the age of 65 and patients with any degree of impaired kidney function. Finally, patients had to be physically fit to participate in this study. Patients who were confined to bed or chair as a consequence of myeloma-related complications were not considered candidates for transplants because the risks to them were deemed excessive.

There have been studies looking at transplantation in patients over the age of 65 and in those with impaired kidney function which have suggested benefit. These types of studies compare modern-day patients with patients who were treated years earlier, during a time when the benefits of erythropoetin and new antibiotics were not available. This type of "historical" comparison is fraught with difficulty and conclusions drawn from these types of studies are not as powerful as studies where treatment is determined by the "toss of a coin."

Stem cell transplantation usually requires an initial phase where chemotherapy is given through a catheter in order to prepare patients for an adequate stem cell (seed) collection. At some centers, this type of treatment requires four days in the hospital every month, and the presence of an indwelling, intravenous catheter can result in complications such as infection or clotting. Also, since stem cell transplants are generally not done at community hospitals, many patients need to travel to specialized centers in order to receive this treatment from experienced teams.

Transplants also carry some risk. During a transplant, the patient’s immune system is destroyed, albeit for a short period of time. During this time infections commonly occur, though the majority are successfully treated with antibiotics. Occasionally, however, overwhelming infection develops in the form of either blood poisoning or double pneumonia, and the patient succumbs as a consequence of the transplant. In our experience, the ability to procure adequate numbers of seed cells from older patients is a bit more difficult than in younger patients. Furthermore, the rehabilitation period following the transplant can often take as long as six months in older patients, and during this time these patients typically have significant fatigue and loss of stamina which impacts on the quality of their lives.

It would be wrong to specify a specific age cutoff for transplantation. We all know patients who are 50 years old and look like they are 75. Conversely, we all know patients who are in their late 60's and look like they are in their early 50's. It is this biologic age which we believe is far more important than chronologic age, and this must be taken into account when counseling the pros and cons of the various treatments available for multiple myeloma.

What is melphalan (alkeran) and prednisone? Melphalan is a class of drugs called alkylating agents. This medication has the ability to poison the DNA (the "blue-print") of cancer cells making it impossible for them to divide and ultimately resulting in their death. Prednisone is a cortisone drug. Cortisone is frequently used to treat certain forms of arthritis, and its anti-inflammatory properties are frequently used in the treatment of certain neurological disorders and disorders of immunity. The cells of multiple myeloma appear to have on their surface binding sites for cortisone and cortisone derivatives, and cortisone medications such as prednisone are actually capable of killing myeloma cells.

The use of melphalan and prednisone was popularized in this country by Dr. Raymond Alexanian, a contributor to this newsletter and a well-regarded authority in this field. Melphalan and prednisone are both oral agents that are usually given for four days every month or for seven days every six weeks. Both regimens are effective, and one is not preferred over the other but rather is chosen for patient convenience. Because they are oral, hospitalization is not required. Most patients initially treated have no impairment related to chemotherapy. Multiple myeloma is effectively treated with melphalan and prednisone although the effect on the protein levels is not as dramatic as is seen with bone marrow transplantation. Nonetheless, because of its ease of use, the lack of side effects, and the ability to maintain a normal lifestyle, it is an option for some patients who are weighing the pros and cons of the various therapies.

It would be fair to say that today at most university medical centers younger patients with multiple myeloma are selecting transplantation as the primary modality of management because it has had some demonstrated benefit in terms of survival. For patients who are older or are not interested in a rigorous approach with stem cell transplants or are heavily focused on maintaining continuity of lifestyle, melphalan and prednisone remains a reasonable choice.

With the proper use of melphalan and prednisone, infections as a complication of chemotherapy are uncommon. Melphalan and prednisone do lower the white blood cell and platelet count, but when properly administered, these changes are generally very modest and usually do not impair the immune system to the same degree more intensive regimens do. Patients can take melphalan and prednisone for years in some instances without developing serious side effects. Moreover, when a patient stops melphalan and prednisone and should the myeloma subsequently recur later on, reuse of melphalan and prednisone is capable of producing a second response.

Common mistakes using melphalan and prednisone include initially using too high a dose, basing it solely on body weight. Commonly published schemes for the treatment of multiple myeloma commonly recommend one pill of alkeran for every four pounds of body weight each course, and for many patients this is excessive. In my practice, I would rarely give a patient a dose higher than what I would give for a patient weighing 140 pounds (maximum five pills daily for seven days). Failing to recognize that the effect of alkeran is cumulative can result in excessive administration of medication. Virtually all patients develop a progressive reduction in the white blood cell count over time, and it is typical for patients who have been on melphalan for more than six months to have a white count ranging between 2,000 and 3,000. Such white blood cell reductions do not necessarily require alkeran dose modifications since further treatment generally does not further suppress the white blood cell count. Occasionally, the interval between treatments needs to be increased in order to avoid excessive suppression of normal healthy blood cells.

Although melphalan and prednisone is a well-established easy-to-administer regimen, it carries one very serious side effect. Melphalan, as do all alkylating agents, has the ability to damage the normal healthy seed cells in the bone marrow. Sometimes this damage can be permanent and can cause the healthy elements of the bone marrow to malfunction. The most common outcome seen in approximately

7% of all myeloma patients who take melphalan and prednisone is called myelodysplasia. Occasionally, this myelodysplasia can actually turn into acute leukemia. Unfortunately, these problems when caused by melphalan are relatively unresponsive to treatment and are a serious late complication of treatment with these agents. All patients who make this decision must be aware of this risk.

It remains important to remember that there is no one right treatment for all patients with multiple myeloma. We do not treat multiple myeloma, we treat patients as people who have multiple myeloma. Their wishes and the experience of the treating physician must all come into play at arriving at a mutually beneficial decision optimizing both the quantity and quality of life for patients with multiple myeloma.

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