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Diseases Related to Multiple Myeloma
08.09.02

Module 3: Post-Treatment Maintenance, Relapsed or Refractory Disease, and Other Issues Related to Multiple Myeloma

Section 5: Diseases Related to Multiple Myeloma

Dr. Robert Kyle: Primary amyloidosis of the amyloid light chain (AL) type is closely related to multiple myeloma. The diagnosis of AL amyloidosis depends upon the demonstration of amyloid in tissue. The easiest source of tissue is a subcutaneous fat aspirate. It is positive in about 70% of patients with AL amyloidosis. Bone marrow samples should be stained with Congo red and viewed under a polarizing light source looking for the presence of amyloid. The results of bone marrow tests are positive in about 55% of patients. [View Reference]

About 90% of patients with AL amyloidosis will test positive if evaluated with both a subcutaneous fat aspirate and a bone marrow examination. [View Reference] If the clinician still suspects amyloidosis, a biopsy of a specific organ should be performed. For example, if the patient has nephrotic syndrome, a kidney biopsy is a very good tissue source. If the patient has cardiac abnormalities on an echocardiogram, endomyocardial biopsy is a good tissue source to determine whether amyloid is present.

If the patient has a large liver, the physician can very carefully do a liver biopsy. There have been incidents of bleeding in these patients, and there are reports in the literature of the liver splitting open following a liver biopsy.

If the patient has a severe peripheral neuropathy, biopsy of the sural nerve is an important diagnostic procedure to exclude the possibility of amyloidosis. It is imperative that physicians obtain appropriate biopsy tissues to exclude or to include the diagnosis of primary amyloidosis in patients with unexplained nephrotic syndrome, renal insufficiency, unexplained congestive heart failure, sensory motor peripheral neuropathy, or orthostatic hypotension who also have monoclonal protein in their serum or urine.

The prognosis for patients with primary amyloidosis is poor. In our experience with 474 patients who were diagnosed within 30 days of being seen at the Mayo Clinic, the overall median survival was 13 months. [View Reference] All patients who were seen with primary amyloidosis at the Mayo Clinic during the same period of time had a median survival of 25 months. Patients who present with overt congestive heart failure from primary amyloidosis have a median survival of 6 months. [View Reference] We are talking about an extremely serious disease.

Available treatment for this disease is not satisfactory. For years, we have been using conventional melphalan and prednisone, and although we have demonstrated that this is superior to no treatment whatsoever, most of these patients will relapse and die.
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In the last 4 or 5 years, autologous stem cell transplant has become available for primary systemic amyloidosis. This does result in a higher percentage of hematologic and organ responses when compared historically with melphalan and prednisone. However, the physician must be careful to select the patients appropriately.

Patients with cardiac involvement as manifested by an interventricular septal thickness of 15 mm or more should not have an autologous stem cell transplant. When we looked at our patients who had died within 3 months after an autologous transplant, the vast majority of them had an interventricular septal thickness greater than 15 mm. [View Reference]

Patient selection is also a very important factor in evaluating patients for possible autologous stem cell transplants. Of 1288 patients with primary amyloidosis who came to the Mayo Clinic, approximately 229 patients fulfilled the criteria that we use for autologous stem cell transplant. These patients were all treated with melphalan and prednisone or a combination of alkylating agents. The median survival of these 229 patients was 42 months, which is very good. Careful selection of patients for transplant is a very important prognostic feature as far as survival is concerned. [View Reference]

A few years ago, Dr. Merlini reported on the use of IDOX, an iodinated anthracycline that is administered intravenously. The Italian investigators demonstrated that there was an affinity between IDOX and the amyloid fibril that contributed to the dissolution of amyloid deposits. In a prospective study, we have now treated about 40 patients, and of those patients, only six had a very modest evidence of benefit. In short, IDOX, at least in the dosage that we used, is disappointing.[View Reference]

Dr. Berenson has reported that thalidomide has shown some benefit in a small number of patients with amyloidosis.[View Reference] We have treated about a dozen patients at our institution, but it is too early to know yet whether this will be an effective agent for primary amyloidosis.

In what ways are these illnesses different from multiple myeloma? What additional tests are necessary for diagnosis? What additional therapies are available?

Dr. Robert Kyle: Waldenström s macroglobulinemia is a malignant proliferative process involving lymphocytes that produce a monoclonal IgM protein. The diagnosis of Waldenström s macroglobulinemia must be differentiated from the patient with monoclonal gammopathy of undetermined significance (MGUS) of the IgM type and from patients with smoldering Waldenström s macroglobulinemia. The decision to treat the patient depends upon the presence or the development of constitutional symptoms or, rarely, symptomatic hepatomegaly or lymphadenopathy.

There are a variety of treatments available for Waldenström s macroglobulinemia, but none is curative. [View Reference] In addition, there have been no prospective studies comparing these therapies. At present, rituximab is a reasonable agent to use for the initial treatment of this disease. It is well tolerated and does not produce significant cytopenias. [View Reference]

Other possibilities include 2-chlorodeoxyadenosine (2CDA), but this is associated with considerable cytopenias after treatment, and some patients can experience marked immune suppression, resulting in chronic fungal infections. [View Reference] Fludarabine has generally been considered to be equivalent in activity to CDA, producing an objective response in approximately 80% of patients in the initial studies. However, in a recently published study from SWOG, the response rate with fludarabine was 36%. There is no apparent explanation for this markedly lower response rate compared with the initial studies. [View Reference]

Chlorambucil, which has been used for more than 40 years to treat patients with Waldenström s macroglobulinemia, is still an effective agent, particularly for elderly patients. It results in an objective response in about 70% of patients. However, it takes several months to obtain an objective response to chlorambucil, and there is some risk of myelodysplasia from this alkylating agent. [View Reference]

Not infrequently, a patient with Waldenström s macroglobulinemia will present with hyperviscosity. The clinician should be alert for hyperviscosity if the patient complains of blurred vision or oronasal bleeding. The measurement of viscosity is not an indication for or against performing plasmapheresis. The decision to perform plasmapheresis should be clinically based. The best single evaluation of this kind of patient is examination of his or her eye grounds. A patient with hyperviscosity will have dilated veins and often hemorrhages in the retina. If this occurs, the patient needs to have emergency plasmapheresis, which is effective in reducing the viscosity. [View Reference]

For the newly diagnosed patient, periodic plasmaphereses can be performed, but, generally speaking, the disease is not controlled in this fashion. Systemic therapy and repeated plasmapheresis are needed to control symptomatic hyperviscosity.

There are a few patients who become refractory to all therapeutic modalities and who have hyperviscosity. These patients can be maintained with periodic plasmaphereses over a long period of time.

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Maintenance Therapy | Relapse | Therapies for Relapsed or Refractory Disease | Complications of Treatment for Disease | Diseases Related to Multiple Myeloma


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