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Complications Associated With This Disease

Module 1: Screening, Diagnosis, and Staging of Multiple Myeloma

Section 6: Complications Associated With This Disease

Could you discuss hypercalcemia and bone loss in multiple myeloma?

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Dr. David Roodman: Hypercalcemia in patients with myeloma results from increased bone resorption by activated osteoclasts. These osteoclasts are activated by the myeloma cells themselves as well as by marrow stromal cells in the myelomatous lesion.

(Myeloma/Stroma Cell Interactions)

Most patients who have hypercalcemia have renal insufficiency. It is extremely rare to see a patient with hypercalcemia who does not have some degree of renal insufficiency.

Identifying all the factors responsible for increased bone resorption in patients with myeloma is still an area of intensive investigation. Factors that have been implicated include interleukin 6, interleukin 1, tumor necrosis factor alpha, macrophage inflammatory peptide 1 alpha, and RANK ligand. RANK ligand is a recently described factor that stimulates osteoclast formation and is made by marrow stromal cells in response to myeloma cells. It is also upregulated by other factors produced by myeloma cells or by cells in the marrow microenvironment of the myeloma cells that further stimulate osteoclast formation and bone resorption.

How does anemia develop in patients with multiple myeloma?

Dr. David Roodman: Anemia in patients with myelomais multifactorial. It is due to direct marrow suppression by the tumor cells aswell as by the anemia of chronic disease and the anemia of renal insufficiency.The anemia of chronic disease is still an area of investigation but is thoughtto be secondary to cytokines produced in response to the tumor that suppress erythropoiesis.The anemia of renal insufficiency occurs because erythropoietin production decreasesas renal function deteriorates. [ViewReference]

(Indications for Therapy With Erythropoietin)

Could you describe renal insufficiency in multiple myeloma?

Dr. Robert Kyle: Renal insufficiency is a common manifestation of multiple myeloma. The two major mechanisms of renal failure are hypercalcemia and the development of myeloma kidney. Myeloma kidney is characterized by the deposition of light chains and Tamm-Horsfall protein in the renal tubules producing large casts. These damage the renal tubular cells and ultimately the glomerulus.

Physicians must emphasize the need for increased fluid intake in their patients. Patients with multiple myeloma should drink enough fluid to produce 3 liters of urine daily. This definitely decreases the incidence of renal insufficiency.

Lambda light chains are more likely than kappa to be associated with renal insufficiency. However, there have been no specific amino acid sequences or any other features of the light chain that appear to be directly responsible for the development of casts and renal failure.

Immunosuppression is said to be one of the effects of multiple myeloma. Could you explain this further?

Dr. Brian Durie: Immunosuppression is a characteristic feature of multiple myeloma in which impaired production of the normal immunoglobulins is reflected by low levels of IgG, IgA, or IgM, depending upon the type of the monoclonal protein. There is usually also some impairment of the innate or cell-mediated immune responses in patients with multiple myeloma.
The mechanisms for these types of impairment the hypogammaglobulinemia and the reduced innate immune responses are still unclear. A number of investigators have attempted to assess the mechanisms involved. Dr. Susan Zolla-Pasner is perhaps the one investigator who has come the closest to showing what may be the mechanism. In elegant studies in mice, she showed that there is a soluble factor that can pass through semipermeable membranes that can mediate the immunosuppression. [View Reference]

The source of this soluble factor is still under investigation, although most research studies by a variety of investigators suggest that the source of the soluble factor that mediates immunosuppression is in the cell category of monocyte or macrophage. Clearly, further studies are necessary to further delineate the nature of the substance or substances involved.

Dr. Robert Kyle: Brian, I know you already mentioned intravenous gammaglobulin, but I wonder if you ought to note again that even if the IgG level is low, the patient may not need treatment with intravenous gammaglobulin. Many physicians call me and say,  Oh, this patient needs to have intravenous gammaglobulin because the IgG value is low.

Dr. Brian Durie: Right. An important aspect of immunosuppression in these patients is hypogammaglobulinemia, but just because there is hypogammaglobulinemia does not mean that high-dose intravenous gammaglobulin must be administered. Only a small minority of patients who have truly serious recurrent infections require intravenous gammaglobulin, so there is no need for the widespread use of intravenous gammaglobulin to replace the hypogammaglobulinemia, even though it is such a common manifestation of myeloma.

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