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Multiple myeloma

Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler) is a presently incurable hematological malignancy of plasma cells, the cells of the immune system that produce antibodies. Its prognosis despite therapy is generally poor, and treatment may involve chemotherapy and stem cell transplant. more...

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Signs and symptoms

Symptoms can include: malaise, bone pain, anemia, infections (due to decreased immunity) and fractures (due to breakdown of bone by malignant cells, as well as a tendency to brittle bones). Often, the diagnosis of multiple myeloma is made incidentally during routine blood tests for other conditions. The antibody that is produced in excess may cause specific medical problems, such as amyloid, acute renal failure and chronic renal failure, polyneuropathy and other disorders.

A mnemonic doctors use to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions.

Diagnosis

Investigations

The existence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised globulin) may suggest further testing. A doctor will then order protein electrophoresis of the blood and urine, on which a paraprotein (monoclonal protein, or M protein) band can be noticed. A type of paraprotein is the Bence Jones protein which is paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to determine the severity of the disease. The paraprotein is a deviant immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).

In theory, myeloma can produce all classes of immunoglobulin, but IgD, IgM and IgE myeloma are very rare compared to IgG and IgA. In addition, light and heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).

Additional findings are: a raised calcium (when myeloma cells are breaking down bone, releasing calcium into the bloodstream) and decreased renal function, which may be due to paraprotein deposition in the kidney).

Workup

The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma deposits appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions". A CT scan may be performed to measure the size of soft tissue plasmacytomas.

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD138 positive and CD19 negative. Cytogenetics may also performed in myeloma for prognostic purposes.

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Thalidomide Can Put the Brakes on Multiple Myeloma
From Family Pratice News, 2/1/00 by Guang-Shing Cheng

Of 180 patients, 30% responded. Half of them were still in remission at 13 months.

"Thalidomide is the first agent of note for multiple myeloma in the last 30 years," Dr. Raman Desikan said at the annual meeting of the American Society of Hematology

NEW ORLEANS -- The dusty armamentarium of drugs for multiple myeloma has a new member: thalidomide.

Results of several preliminary studies Presented at the meeting provide evidence that thalidomide (Thalomid) has dramatic activity in some patients with refractory multiple myeloma.

Although no more than one-third of the patients in any of the studies responded to the drug, the effect of thalidomide is remarkable in the treatment of a disease that strikes nearly 14,000 patients a year and has no cure, experts said. The overwhelming majority of patients fail high-dose chemotherapy and other salvage therapies.

"The bottom line is that in myeloma, with a single agent, you don't get this kind of response rate," said Dr.. Desikan of the University of Arkansas, Little Rock.

He presented an update of a study that was sponsored by Celgene Corp., the maker of Thalomid. The trial involved 180 patients who were treated with thalidomide starting at a dosage of 200 mg/day and escalating to a maximum dosage of 800 mg/day every 2 weeks as tolerated. More than 60% of patients had stage III disease at presentation; 77% of the patients had undergone prior highdose chemotherapy The mean age of the patients was 55 (N. Engi. J. Med. 341[21]:1565-71, 1999).

Of the 180 patients treated with thalidomide, 30% achieved at least a 50% reduction in levels of paraproteins (serum myeloma protein or urine Bence Jones protein). An additional 6% of the patients had at least a 25% reduction in paraprotein levels, Dr. Desikan reported.

A significant decrease in bone marrow plasmacytosis was seen in most of the patients who had an excellent response to thalidomide (a reduction of at least 90% in paraprotein levels).

Of all the responders, 50% are still in remission at 13 months, demonstrating the sustained activity thalidomide.

Almost 90% of the patients were able to reach the second dosage level of 400 mg/day, and 56% achieved the full dosage of 800 mg/day Toxicity was dose dependent. The most common adverse effects were constipation, weakness, fatigue, and somnolence.

In a smaller series of 16 patients with relapsed myeloma, 4(25%) achieved a partial response to thalidomide, defined as a 50% reduction in paraproteins, Dr. S. Vincent Rajkumar and his colleagues at the Mayo Clinic, Rochester, Minn., reported in a poster presentation. Six other patients had stable disease for 5 months.

All of the responders had significant improvement in symptoms, and responses could be sustained with 200-400 mg/day thalidomide. Major side effects were similar to those previously reported, and included constipation, sedation, and fatigue in 25% of patients. One patient discontinued the medication because of peripheral neuropathy and cardiac arrhythmia.

Low-dose thalidomide also can work for certain patients, Dr. Brian Dune and Dr. Daniel Stepan of the Cedars-Sinai Comprehensive Cancer Center, Los Angeles, reported in a poster presentation.

Straying from conventional thalidomide protocols--primarily because of the documented toxicity of the drug--the investigators started with a low dosage of 50 mg/day and increased it only if patients failed to respond within a month.

Of 40 patients who had previously failed stem cell transplant and chemotherapy 10 (25%) have responded to thalidomide. Of the responders-still alive at this writing--3 took 50 mg/day, 2 took 200 mg/day 3 took 300 mg/day, nd 2 took 400 mg/day The drug was minimally toxic at these dosages, Dr. Dune said in an interview

Dr. Desikan said in an interview that myeloma subtypes probably are irrelevant in predicting who will respond to thalidomide.

In the University of Arkansas study of 180 patients, he explained, the only factor that correlated with response was a low leveling index, a marker for tumors cells that proliferate slowly but are long lived. Among responders, those with less than 30% bone marrow plasma cells and no abnormalities of chromosome 13 experienced longer survival.

Multiple myeloma is characterized by increased bone marrow vascularization, but it's far from clear if thalidomide's effect is due to its antiangiogenic properties. In responders, bone marrow microvessel densky decreases after use of thalidomide, but no one knows if the blood vessels disappear first, leading to cell death, or vice versa, Dr. Desikan said.

Dr. Durie suspects that thalidomide kills tumor cells by inhibiting tumor necrosis factor-[alpha] rather than by inhibiting angiogenesis.

Other studies presented at the meeting, including one showing that thalidomide could be used in conjunction with dexamethasone and another in which thalidomide was used in patients who had failed stem cell transplants, were a testament to the revived interest in this drug.

Thalidomide, originally used as an over-the-counter preparation for morning sickness, was taken off the world market in the 1960s after the appearance of phocomelia and other birth defects in the offspring of women who used the drug. Interest in thalidomide has resurfaced in recent years because of its antiangiogenic properties, and in 1998 it was approved by the Food and Drug Administration for the treatment of erythema nodosum leprosum, a debilitating skin complication of leprosy.

The most tightly regulated drug in clinical use, thalidomide is being investigated for use in a number of diseases, including lupus, Crohn's disease, aphthous ulcers, and AIDS wasting. Although probably not a cure for multiple myeloma, thalidomide is good news for clinicians so far, and it has brought a few patients back from the brink of death when all else had failed, Dr. Desikan said.

"You can still fail chemotherapy but respond to thalidomide," he said. "It opens the door for a new class of agents to treat cancer that are powerful and less toxic."

COPYRIGHT 2000 International Medical News Group
COPYRIGHT 2001 Gale Group

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