Case Report

The patient was a 46-year-old man who was in apparent good health until he developed a sudden onset of vertigo and syncope while at a dinner party. His initial evaluation at an Emergency Room revealed an essentially normal physical exam but laboratory testing disclosed a mild anemia and an elevated globulin level at 8.0 mg/dl. After transfer to a referral center, he was treated with total plasma exchange, using a plasmapheresis machine. His vertigo then resolved.

Further evaluation then revealed that he had a normal serum calcium, creatinine and uric acid. Roentgeno-graphic survey of his bones revealed no lytic lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal protein characteristic of myeloma which was of the IgA lambda type. The concentration of the abnormal protein was 5.3 gm/dl. A routine urinalysis was normal and immunoelectrophoresis of the urine failed to reveal Bence-Jones protein (light chain). A bone marrow aspirate and biopsy demonstrated subtotal replacement of the marrow with a uniform population of plasma cells.

The Patient's Treatment and Progress

With the diagnosis of multiple myeloma clearly established in a man younger than 65, clearly symptomatic, the decision was made to go ahead with high-dose chemotherapy and autologous peripheral blood stem cell transplantation for hematopoietic reconstitution.

Chemotherapy is the standard of care for the initial treatment of symptomatic multiple myeloma but autologous peripheral blood stem cell transplantation, though less commonly used, is widely recommended, often as part of a clinical trial. See also http://myeloma.org/MyelomaToday/Volume2/Number7/imf_BMT17h.html

He was then treated with vincristine, doxorubicin (AdriamycinR), and dexamethasone (VAD). His initial stay in the hospital, following treatment, required transfusion support and treatment for an episode of pneumonia but the patient, however, did achieve a complete recovery of his platelet and white counts. An examination of the bone marrow showed normal marrow elements with 3% plasma cells and could not be distinguished from a normal bone marrow.

Serum protein electrophoresis, however, continued to demonstrate a small monoclonal spike but now only at a level of 0.6 g/dl. Interferon therapy was then instituted as maintenance.(2) The patient remained well and went about his usual activities, though the small protein spike remained.

This stable situation persisted for two years until the patient developed a visible swelling of his left lower rib cage. Plain x-ray films revealed destruction of the rib and the presence of a soft tissue mass that was extrapleural in location. He received radiation therapy to the mass and was started on combination chemotherapy, including vincristine, carmustine (BCNU), melphalan, cyclophosphamide and prednisone.

He remained clinically stable on that regimen for about six months, at which time he experienced a sudden onset of pain in the arm when trying to remove a tight cap from a container. X-rays revealed a fracture of the humerus occurring at the site of a lytic lesion. He was treated with a cast and radiation therapy to the arm.

At the time of this man's treatment, biphosphonates were in their early trial phase and had not yet been shown to be effective. They were not used. The patient entered into an experimental trial designed to explore the possibility that a graft-versus-myeloma effect could be generated by the infusion of leukocytes collected from his brother, who was a complete HLA match. He had three such infusions with no evidence of response.

The chest wall mass recurred. He developed back pain and swelling around the T-11 vertebra. An MRI showed a very large mass which was extending from T-7 to T-12 with 50% cord compression and encasement of the abdominal aorta.

The patient chose to embark on another course of experimental therapy at a different institution where he was started on high-dose steroids, radiation therapy and an experimental drug. He declined over the ensuing few days with marked edema, development of acscites and progressive fatigue, followed by shakes, chills and fever, and purulent drainage from his previous chest tube site. The patient died from multimicrobial sepsis and progressive tumor enlargement.

Discussion

Multiple myeloma is a common hematologic malignancy with an incidence of approximately 5/100,000 a year and an estimated 13,800 new cases expected in 1998.(3) Most cases of multiple myeloma are of unknown cause. However, the increased incidence in atomic bomb survivors suggests that radiation may be a factor. In mice, some cases of myeloma appear to be generated by chronic inflammatory stimulation but this does not appear to be the case in people. There have been many reported family clusters and there have been cases in identical twins, suggesting that there is a possible inherited genetic element.

Recently, Hallek et al have proposed that there are progressive genetic events in multiple myeloma,(4) with the first transformation from a normal plasma cell to a monoclonal gamopathy of unknown significance (MGUS) where the cells are immortalized but not transformed and do not progressively accumulate or cause bone destruction. The next mutation event would then lead to an intra-medullary myeloma where the cells are confined to the bone marrow microenvironment and a subsequent mutation resulting in an extra-medullary myeloma where the cells proliferate more rapidly.

The article referred to above by Hallek et al discusses this hypothesis and the various genetic mutations that are found and appear to accompany these sequences of change.
See http://www.bloodjournal.org/cgi/content/full/91/1/3.

Differential Diagnosis

Diagnosis is often easy to make, as it was in this patient who had a replaced bone marrow with characteristic cells and a markedly elevated abnormal protein peak. The minimal criteria consist of more than 10% plasma cells in the bone marrow or a plasmacytoma accompanied by a protein spike of more than 3 g/dl, a protein spike in the urine or lytic bone lesions. These criteria are not specific and could be related to metastatic carcinoma, cirrhosis, sarcoidosis or other diseases. They are diagnostic only when they are known not to be caused by other disorders and the patient has the features of myeloma. A standard work-up for a patient suspected of having multiple myeloma would consist of the tests that were done in this case.

Prognosis

Once the individual has frank multiple myeloma and not MGUS or smoldering multiple myeloma, the prognosis is quite grim. If no treatment is given, a median survival of six months can be expected.

Treatment

Standard chemotherapy consists of a combination of melphalan and prednisone which produces an objective response in 50-60% of patients and results in median survival of about three years.(5) High-dose therapy and stem cell transplantation have not yet been proved to prolong survival.(6) The patient discussed survived four years but approximately 25% of patients may survive that long with standard therapy.

Whether one chooses melphalan and prednisone or VAD, as we did in this patient, or one of the other combinations, such as vincristine, carmustine, melphalan, cyclophosphamide and prednisone, chemotherapy is often continued for a prolonged period of time to be sure the patient is in a plateau state. Unfortunately, this sometimes results in the development of a secondary malignancy, such as a myelodysplastic syndrome or acute leukemia.

Interferon is an active agent which is capable of giving an objective response or stabilization of disease and has been reported to produce a longer response duration when used as maintenance therapy.(2)

Since virtually all patients will relapse, a variety of high-dose regimens for refractory myeloma have been in use but, clearly, they are less than satisfactory and new agents are needed.

As patients relapse and fail, any bone destruction, such as in this patient, can lead to fractures, spinal cord compression, pain, hypercalcemia and often death. Many agents have been used but found wanting in the past, including glucocorticoids, androgenic steroids, fluorides, calcium and even some biphosphonates.

Newer Therapies

The development of potent biphosphonates, such as pamidronate, clearly reduce the number of skeletal events, reduce bone pain and improve the quality of life. Pamidronate is a specific inhibitor of osteoclastic activity, inhibits the production of IL-6 by bone marrow stromal cells and is, clearly, a useful palliative agent.(7)

High-dose chemotherapy with stem cell transplantation has a clear rationale and can result in dramatic reduction in tumor mass with complete response but durable complete response is rare. The European Bone Marrow Transplant Group (EBMT) has been using allografting and this is associated with a 40-50% transplant-related mortality, and overall survival may not be improved.(8)

Barlogie and other investigators are trying multiple high-dose therapies(9) and a French trial is comparing single versus double high-dose therapy. Others are adding cyclosporine(10) or attempting to immunize patients(11) to eliminate minimal residual disease. Hope for the myeloma patients clearly rests on future studies, such as the use of thalidomide to inhibit angiogenesis which now clearly has been shown to be active against myeloma.(12)

This brief summary of multiple myeloma should leave you with an appreciation of how lethal and incurable this disease is, while at the same time, demonstrating that it is a tumor that is highly responsive to chemotherapy. Future advances in therapy may come from the rapidly advancing knowledge of the molecular events of neoplasia, as they relate to this and other tumors of B-cell origin.