Multiple myeloma is a common malignancy with about 12,000 cases each year in the United States and 9000 deaths. The incidence of the disease increases dramatically with advancing age. The incidence is approximately 2 per 100,000 under the age of 50, but 20 to 25 per 1000,000 of those in the seventies. The mean age of diagnosis is in the upper sixties. Given the increase in the geriatric population in the United States, we should continue to see an increasing incidence of multiple myeloma.

The etiology of myeloma is unknown, but there are genetic as well as environmental factors. Controversy exists regarding the role of viral factors in the development of myeloma. Specifically, human herpesvirus 8 (HHV-8) has been associated with some patients with myeloma. The disease occurs more frequently in blacks than whites and more frequently in males than in females. Radiation exposure, as well as occupational exposure to asbestos and petroleum products, is associated with increased risk for the development of myeloma. Multiple myeloma can evolve from a monoclonal gammopathy of uncertain significance (MGUS).

The cell of origin in multiple myeloma remains unknown. Plasma cells themselves have little proliferative potential. It is likely that clonogenic pre-B cells account for the majority of proliferation in multiple myeloma. Thus, it is at the level of the pre-B cell or earlier that the transformation to malignancy occurs.

Karyotypic alteration is frequently seen in myeloma, with 30% to 50% of patients having abnormalities of their chromosomes. Oncogenes and tumor suppressor gene abnormalities, such as ras, myc, bcl-1/PRAD-1/cyclin D-1, bcl-2, Rb, and P53, have recently been implicated in the development of myeloma. The low proliferative potential of plasma cells has hampered the elucidation of genetic events in this disease.

Clinically, the manifestations of the disease are usually caused by one or a combination of the following factors: (1) proliferation of the malignant clone causing replacement of normal structures; (2) elaboration of cytokines by the malignant plasma cells; and (3) accumulation of the M component in plasma and in tissue.

The most common findings include fatigue, anemia, renal failure, hypercalcemia, hypogammaglobulinemia, and infections. Rarely, hyperviscosity or complications of amyloid infiltration of tissues can occur. The diagnosis of multiple myeloma requires a significant M spike (3.5 g/dL of IgG or 2.0 g/dL of IgA), plasmacytosis greater than 30% in the marrow, or plasmacytoma on tissue biopsy. Additionally, the presence of lytic bone lesions or low residual immunoglobulins can provide supportive evidence in the diagnosis of myeloma.

Pathophysiology
We now understand the pathophysiology of many of the characteristic clinical manifestations of multiple myeloma. Skeletal complications occur quite commonly. Because the lesions are typically osteoclastic with minimal osteoclastic activity, bone scans are typically negative. Plain x-ray and magnetic resonance imaging (MRI) of the bone are more sensitive than a bone scan.

The excessive bone resorption that occurs has been the subject of much research. The plasma cells in the marrow secrete tumor necrosis factor (TNF) and interleukin 1 (IL-1), among other cytokines. These cytokines contain most of the activity previously referred to as osteoclast-activating factor (OAF). Further, the TNF and IL-1 secreted by the plasma cells stimulate secretion of IL-6 by marrow stromal cells. IL-6 not only adds to the osteoclastic activity but also is one of the major growth factors for the myeloma cell clone. A cascade of bone resorption and myeloma cell growth with continued secretion of cytokines can quickly result in clinical hypercalcemia.

The hypercalcemia associated with multiple myeloma usually is multifactorial, with increased bone turnover, dehydration commonly found in the elderly, and renal insufficiency all playing a role. Inactivity secondary to debilitation or bone pain also adds to the progression of hypercalcemia.

The anemia of multiple myeloma is also a multifactorial process. The major influence, however, remains the proliferation of the myeloma cell clone within the bone marrow. Renal insufficiency, chemotherapy, and shortened red cell survival also play a role. Renal insufficiency in the setting of myeloma is a bad prognostic indicator. Monoclonal light chains (known as Bence-Jones proteinuria) accounts for more than 90% of the renal dysfunction. However, amyloid, infection, Fanconi’s syndrome, and hyperuricemia can be other mechanisms for renal insufficiency.

Hypogammaglobulinemia is common and frequently results in recurrent infection by encapsulated organisms. Amyloid may develop in the setting of myeloma, with light chain deposition in susceptible organs. Hyperviscosity typically occurs in the setting of IgM production but can occur with very high levels of IgG or IgA. Transfusion in the setting of subclinical hyperviscosity can precipitate symptomatic hyperviscosity because the increased hematocrit after transfusion can adversely affect the whole blood viscosity.

Staging
The Durie and Salmon staging system combines easily obtainable clinical parameters and divides patients into three groups with significantly different expected survival (

Table 38.3). More recently, additional prognostic factors have been evaluated. Of these, beta-2-microglobulin and plasma cell labeling index appear to be useful individual parameters. Overall, the median survival is 2 to 3 years with treatment.

Treatment
Treatment for myeloma has shown marked improvements over the last several years, but cure remains elusive. In the 1960s, melphalan and prednisone were first used and improved survival from about 7 months to the current level of about 3 years.

Multiple regimens combining alkylating agents, nitrosourea, doxorubicin, vincristine, and prednisone, as well as interferon, have been studied over the last 15 years. An overview analysis comparing melphalan/prednisone versus several other combination chemotherapy (CCT) regimens demonstrated there was no improvement in overall survival for those patients who received the CCT regimen.

Although melphalan/prednisone remains an option, particularly for the majority of patients who are over the age of 65, high-dose therapy with bone marrow transplantation has been explored for younger patients as well as older patients with good performance status. A randomized study confirmed a survival advantage for those patients who underwent bone marrow transplant compared to those patients who received multiagent chemotherapy. Many of the patients who were over the age of 60 were unable to proceed on to their planned high-dose chemotherapy program. Nonetheless, a significant improvement in survival was noted with a dose-intense strategy.

The group in Arkansas has further explored the value of a high-dose strategy in older patients. In a separate report, among 49 patients over the age of 65 who underwent autotransplant for multiple myeloma, outcomes were identical to a matched-pair group of younger patients receiving the same therapy. This finding suggests that age alone is not sufficient to deny a high-dose strategy to the patient with multiple myeloma. The group further explored the value of an intermediate dose of melphalan (100 mg) in patients over the age of 60 compared to an historic control group of matched patients who received melphalan and prednisone. Overall survival was 56 months for the Mel 100 versus 48 months for MP. These studies suggest that every patient needs to be evaluated for a high-dose strategy regardless of the age of the patient.

Although high-dose strategies can improve duration of survival, they do not appear to induce a high rate of long-term control. Thus, relapses continue to be a problem both for the patients treated with standard dose chemotherapy as well as for those who have been through a high-dose program. For patients who either develop resistance or are refractory to melphalan/ prednisone, there are a variety of therapeutic choices. However, response rates are on the order of 25% to 30%. Pulse high-dose steroids appear to be as effective as more toxic combination regimens.

Recently, enthusiasm has been generated for the use of thalidomide in patients with myeloma. The initial reports suggested that as many as 30% of patients who had failed high-dose chemotherapy programs would have a significant response to the use of oral thalidomide. Multiple reports have confirmed significant activity of this compound. Continued clinical trials are evaluating the optimal role of thalidomide with consideration for both upfront therapy as well as therapy of relapsed disease. Combinations of thalidomide with dexamethasone appear to be particularly active even in patients who had failed dexamethasone regimens previously.

Resistance to chemotherapy that frequently develops in the setting of myeloma is caused by multiple mechanisms. One important mechanism is expression of the multidrug resistance (MDR) gene product. The MDR acts as an energy-dependent pump that can remove cytotoxic agents from the cytoplasm. This pump also transports other substances, such as cyclosporin. Trials have aimed at providing a molecule that will be transported by the pump and allow increased concentrations of cytotoxic agents to accumulate in the cell. Attempts at reversing the MDR phenotype have been promising in patients previously resistant to therapy. Overcoming resistance to treatment may be a valuable therapeutic tool in the future.

The typical response to therapy is the achievement of a plateau phase where the level of tumor, as reflected by the M spike, remains stable. Further therapy during this period has been termed maintenance, and many studies have attempted to evaluate the role of maintenance therapy. The most promising agent for maintenance therapy has been interferon. Studies have produced mixed results, but, for some patients who have a significant reduction in the M spike level, interferon given three times per week may prolong a stable plateau phase. The side effects of interferon include a flu-like syndrome, and this can be very bothersome for elderly patients. Newly available pegylated interferon may generate more enthusiasm for maintenance because this formulation is more convenient and has fewer side effects.

Future Direction
Thalidomide has been the most encouraging new drug to become available for the treatment of patients with myeloma. Optimal use of this drug continues to be explored. Unfortunately, it does not seem to induce a high rate of complete remission or to induce cures. Likewise, high-dose therapy with bone marrow transplant support has not been able to induce elimination of the malignant clone in most patients and has only been applied to older patients with excellent performance status.

Increased understanding of the biology of the disease, highlighted by the important role played by IL-6, has prompted studies aimed at interrupting the IL-6 cytokine loop with a variety of strategies. Although the initial reports were promising, this therapy has not produced a significant impact. Immunotherapy continues to be attractive. Several reports have demonstrated the feasibility of idiotype vaccine development in patients with myeloma. While the studies are early in development, they may prove particularly useful for older patients.

Supportive care measures have improved for patients with multiple myeloma. The anemia associated with multiple myeloma, although multifactorial, frequently responds to erythropoietin. The skeletal complications, including hypercalcemia, can be impacted on with bisphosphonates. These agents act as analogues of pyrophosphatases and are incorporated into the hydroxyapatite, subsequently inhibiting osteoclastic bone resorption. These compounds may exert some outright antimyeloma activity. Newer, more potent, and more convienient formulations of bisphosponates will be available soon. Last, bacterial infection is a major cause of morbidity and mortality. Prompt recognition and initiation of appropriate antibiotics are required. Intravenous gamma globulin may be helpful, although expensive.