Presentation of Case

A 64-year-old man had a routine physical exam and blood tests. He appeared well and had no abnormal physical findings. His serum globulin was elevated to a level of 4.5 g/dl and there were no other laboratory abnormalities seen on a CBC or chemical profile.

Q. What are the possibilities and what if any further evaluation is warranted?

A. The first distinction to be made is between "broad band" hyperglobulinemia and the presence of a monoclonal protein. Protein electrophoresis or the more sensitive immunofixation usually does this. Broad band hyperglobulinemia is typical of many infectious or inflammatory conditions and is very non-specific. The presence of a discrete "spike" of globulin implies that there is a clone of globulin-producing cells and raises questions of malignancy.

In this case, serum immunofixation revealed the presence of a monoclonal protein (M-protein) that was an IgG with kappa light chains, i.e., a monoclonal gammopathy.

Q. Does this finding indicate that the patient has multiple myeloma?

A. No. Monoclonal gammopathy is a very common finding, especially in older people. The prevalence may be about 20% in individuals over the age of 90. Most of these individuals have no evidence for malignant plasma cell dyscrasia. This was formerly called benign monoclonal gammopathy. However, the preferred term is now monoclonal gammopathy of unknown significance (MGUS), since some of these will develop into multiple myeloma or other plasma cell dyscrasias. Many different conditions have been reported in association with MGUS. However, these associations may result from chance since MGUS is so prevalent.

Q. How is the diagnosis of MGUS confirmed?

A. There are several features which help differentiate between MGUS and myeloma or some other plasma cell malignancy.

This individual met all of the features of MGUS when he first presented.

Q. What is the prognosis?

A. There is no way to tell, at the onset, which patient will progress to a plasma cell malignancy. Serial observation of the clinical and laboratory features is necessary. In a series at the Mayo Clinic, the actuarial rate of development of serious disease was 16% at 10 years and 40% at 25 years.(1)

This patient remained well for the next 12 years and then developed progressive anemia (Hgb 9.5 g/dL) and a rising level (3.5 g/dL) of his IgG kappa monoclonal protein. A repeat bone marrow examination now revealed 35% infiltration with plasma cells that stained for kappa light chains and not for lambda light chains.

Q. Does this mean he has now developed multiple myeloma?

A. Yes. This patient meets the criteria established by several different authors including the Durie/Salmon classification and the Kyle/Greipp system.

Unfortunately, there is no one standard set of diagnostic criteria. However, discrepancies are not usually a problem. Further work-up would usually include skeletal X-rays looking for lytic lesions or osteoporosis and determination of serum calcium, beta-2 microglobulin and urinary Bence-Jones protein. The information would be used in staging the disease.

Stage I multiple myeloma is characterized by all of the following:

1. Hemoglobin greater than 10 g/dL
2. Normal serum calcium
3. Normal bone structure
4. Low M-protein production as shown by:
   1. IgG less than 5.0 g/dL
   2. IgA less than 3.0 g/dL
   3. urinary kappa or lambda less than 4 g/24 hours.

Impaired renal function worsens prognosis regardless of stage.

Stage II multiple myeloma is multiple myeloma that fits in neither stage I nor stage III.

Stage III multiple myeloma is characterized by one or more of the following:

1. Hemoglobin less than 8.5 g/dL
2. Serum calcium greater than 12.0 mg/dL
3. More than 3 lytic bone lesions.
4. High M-protein production as shown by:
   1. IgG greater than 7.0 g/dL
   2. IgA greater than 5.0 g/dL
   3. urinary kappa or lambda greater than 12.0 g/24 hours.

This staging system reflects the tumor mass but the prognosis also depends on the inherent proliferative nature of the tumor, the patient's renal function, the level of beta-2 microglobulin and the patient's response to the tumor. Multiple myeloma is well known to have some unexpectedly long survivors. It is certainly inappropriate to believe that a patient is in an advanced stage with a short prognosis simply because of a pathologic fracture. Many such patients stabilize for long periods of time with treatment. This patient appears to be at Stage II.

Q. When should treatment be initiated?

A. Although this patient was not treated during the phase of MGUS, or even when asymptomatic and in Stage I, it is appropriate to start treatment now that there are progressive clinical and laboratory changes. Systemic chemotherapy is the treatment of choice and should be directed at reducing the tumor cell mass. Medical management should also be undertaken to reverse any complications of disease, such as renal failure, infection, hyperviscosity or hypercalcemia.

This patient received melphalan and prednisone for 4 days a month, a combination that is the standard chemotherapy for newly diagnosed symptomatic myeloma. He responded, as about half the patients do, with a decrease in his IgG protein level, a rise in hemoglobin and improvement in well being. Steroid sensitive myeloma cell lines have high levels of glucocorticoid receptors and steroids are used in many of the first line chemotherapy regimens. Steroids are not myelotoxic and can also be used in late stage disease with pancytopenia.

This patient entered a stable phase of disease and was maintained on the melphalan and prednisone in an attempt to prolong the response. Interferon has also been used to prolong this stable phase but side effects may limit its usefulness.

About two years later, the patient developed left thigh pain. Bone X-rays were normal. There was no evidence of spinal cord or nerve root disease.

Q. How should this be treated?

A. Without a diagnosis, there is no clear answer. However, osteopenia and osteolytic lesions are very common in multiple myeloma and may cause pain even before they are visible. Since biphosphonates have been shown to be effective in reducing and delaying the onset of osteolytic lesions, this patient was given pamidronate 90 mg by intravenous infusion monthly and had resolution of the pain. Other biphosphonates such as zoledronate may also be used. These agents are also useful in managing multiple myeloma-related hypercalcemia.

Eventually, despite the initial therapy, this patient's disease progressed.

Q. What treatment would you now recommend?

A. There are many combinations that can be used. If patients were initially treated with melphalan/prednisone, a combination of vincristine, doxorubicin and dexamethasone (VAD) or even intermittent dexamethasone alone are often effective. Thalidomide has also been shown to have some efficacy in this setting and is believed to work by virtue of inhibiting angiogenesis.

Intensive chemotherapy followed by autologous stem cell transplantation is effective but not curative, as is allogeneic bone marrow transplantation. This has been well summarized in a review from Dr. Barlogie's group at the University of Arkansas.

The authors make the point that advanced age (>50 years), duration of prior standard therapy (>12 months) and a low CD34 mobilization potential (<20 x 10⁶/kg) are associated with a higher incidence of cytogenetic myelodysplasia. Myelodysplasia and acute leukemia are both well-known treatment associated malignancies.

In multiple myeloma and acute lymphoblastic leukemia, the dose of melphalan is a determinant of the likelihood of developing acute leukemia.

This patient was treated eventually with steroids and thalidomide. He initially responded but then developed progressive pancytopenia despite the fact that his monoclonal protein level stayed low.

Q. What are the likely causes?

A. The pancytopenia could result from progressive multiple myeloma in the bone marrow causing pancytopenia. However, the low monoclonal protein level speaks against this. An alternative explanation is that the pancytopenia occurs because of the development of myelodysplasia or possibly long-term bone marrow toxicity from the prior chemotherapy.

Q. How do you make the differential diagnosis?

A. Perform a bone marrow examination.

This was done and revealed no evidence of myeloma but, instead, demonstrated a cellular marrow with 10% myeloblasts.

Q. What does this indicate?

A. The presence of the myeloblasts indicates the development of myelodysplastic syndrome. In this case, it would be called refractory anemia with excess blasts according to the FAB classification.

At this point in the patient's course, there is no therapy other than bone marrow transplantation that definitively alters the natural history of myelodysplastic syndrome.(2) Indeed, this patient was treated with supportive care and eventually an experimental agent in early trials. Despite this, his myelodysplastic syndrome went on to evolve into acute myeloid leukemia from which he succumbed.

In summary:

1. MGUS is common.
2. MGUS may remain benign or progress to multiple myeloma.
3. Typical manifestations of multiple myeloma are related to bone marrow failure, bone lesions and the protein abnormality.
4. Multiple myeloma responds to treatment but is not curable with chemotherapy.
5. Alkylating agent therapy of multiple myeloma may result in the development of myelodysplastic syndrome and acute leukemia.