Multiple Myeloma
Isolated Plasmacytoma of Bone
Extramedullary Plasmacytoma
Macroglobulinemia
Monoclonal Gammopathy of Undetermined Significance

Multiple Myeloma

The International Myeloma Working Group studied 11,171 patients, of whom 2,901 received high-dose therapy and 8,270 received only standard-dose therapy.[1] An International Staging System was derived as follows:

Stage I multiple myeloma: Beta-2-microglobulin less than 3.5 and albumin greater than or equal to 3.5 (median survival of 62 months).

Stage II multiple myeloma: Beta-2-microglobulin less than 3.5 and albumin less than 3.5 or beta-2-microglobulin 3.5 to less than 5.5 (median survival of 44 months).

Stage III multiple myeloma: Beta-2-microglobulin greater than or equal to 5.5 (median survival of 29 months).

Impaired renal function worsens prognosis regardless of stage. Genetic aberrations detected by interphase fluorescence in situ hybridization (FISH) may define prognostic groups in retrospective and prospective analyses.[2,3] Short survival and shorter duration of response to therapy have been reported with t(4;14)(p16;q32), t(14;16)(q32;q23), cytogenetic deletion of 13q-14, and deletion of 17p13 (p53 locus).[2-6] Whether choice of therapy based on FISH analysis can influence outcome must await further prospective trials.

Newer clinical investigations are stratifying patients with multiple myeloma into a so-called standard-risk group, which accounts for 75% of patients, with a median survival of 3 to 6 years, and a high-risk group, which has a median survival of less than 3 years.[2-7] This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation.[7] Bone marrow samples are sent for cytogenetic and FISH analysis.

Standard risk is defined as any one of the following cytogenetic findings:

• No adverse FISH or cytogenetics.
• Hyperdiploidy.
• t (11;14) by FISH.
• t (6;14) by FISH.

These patients most often have disease that expresses IgG kappa monoclonal gammopathies, and they present with lytic bone lesions.

High risk is defined as any one of the following cytogenetic findings:

• del 17p by FISH.
• t (4;14) by FISH.
• t (14;16) by FISH.
• Cytogenetic del 13.
• Hypodiploidy.

These patients often have disease that expresses IgA lambda monoclonal gammopathies and less often have skeletal-related complications.

If a solitary lytic lesion of plasma cells is found on skeletal survey in an otherwise asymptomatic patient, and a bone marrow examination from an uninvolved site contains less than 5% to 10% plasma cells, the patient has an isolated plasmacytoma of bone.[8-10] About 25% of patients have a serum and/or urine M protein; this should disappear following adequate radiation of the lytic lesion. When clinically indicated, magnetic resonance imaging may reveal unsuspected bony lesions that were undetected on standard radiographs.

Patients with isolated plasma cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses, should have skeletal x-rays and bone marrow biopsy.[11-13] If these tests are negative, the patient has extramedullary plasmacytoma. About 25% of patients have serum and/or urine M protein; this should disappear following adequate radiation.

Macroglobulinemia is a proliferation of plasmacytoid lymphocytes secreting an IgM M protein. Patients often have lymphadenopathy and hepatosplenomegaly, but bony lesions are uncommon. No generally accepted staging system exists.

The term macroglobulinemia describes an increase in the serum concentration of a monoclonal IgM.[14] Most patients are asymptomatic and do not require treatment. The most common symptoms and signs are fatigue, manifestations of hyperviscosity (e.g., headache, epistaxis, and visual disturbances), and neurologic abnormalities. Serum or plasma viscosity (relative to water) measures the risk of symptoms. The normal viscosity level is 1.7 to 2.1; symptoms may rarely appear between 3.0 and 4.0 but more commonly appear above 4.0. Emergent therapy (i.e., plasmapheresis and chemotherapy) is usually required above a viscosity level of 4.0. Lymphadenopathy and splenomegaly are found in about 33% of patients. The increased intravascular concentration of high molecular weight IgM leads to an expansion of the plasma volume, a dilutional anemia, and in extreme cases, congestive heart failure. Sludging of the blood can be seen in conjunctival and retinal veins with dilatation and segmentation of vessels (i.e., a link of sausage appearance), retinal hemorrhages, and papilledema. Similar problems with the circulation of blood in the central nervous system can cause ataxia, nystagmus, vertigo, confusion, and disturbances of consciousness.

The various disorders associated with the appearance of a monoclonal IgM include:

1. Monoclonal Gammopathy of Undetermined Significance (MGUS). Patients are asymptomatic, the M protein is stable, and no lymphadenopathy, splenomegaly, or bony lesions are present.
2. Waldenström Macroglobulinemia (WM). This entity is called lymphoplasmacytic lymphoma in the World Health Organization/Revised European-American Lymphoma classification system. Patients are symptomatic, have lymphoplasmacytic marrow infiltration, and a rising serum IgM concentration, and may have lymphadenopathy or splenomegaly. Rarely, patients with WM have lytic bone lesions. (Refer to the PDQ summary on Adult Non Hodgkin Lymphoma Treatment for more information.)
3. Absolute lymphocyte count exceeding 5,000 cells/mm³. The patient may be classified as having chronic lymphocytic leukemia (CLL) if the lymphocytes are of the small, well-differentiated variety. CLL must be differentiated from the lymphoplasmacytosis that may occur as a peripheral blood manifestation of WM. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
4. Chronic cold agglutinin disease. Patients have a high cold agglutinin titer and no morphologic evidence of neoplasia. These patients often have a hemolytic anemia that is aggravated by cold exposure. The IgM has kappa light chains in more than 90% of these types of patients.

Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma, and with less than 10% of plasma cells in the bone marrow.[14-16] These types of patients are asymptomatic and should not be treated. They must, however, be followed carefully since about 1% to 2% per year will progress to develop one of the symptomatic B-cell neoplasms and may then require therapy.[17,18] Risk factors predicting progression include an abnormal serum-free light chain ratio, non-IgG class MGUS, and a high serum M protein level (≥15 g/L).[19]

References

1. Greipp PR, San Miguel J, Durie BG, et al.: International staging system for multiple myeloma. J Clin Oncol 23 (15): 3412-20, 2005.  [PUBMED Abstract]
   
   
2. Fonseca R, Blood E, Rue M, et al.: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101 (11): 4569-75, 2003.  [PUBMED Abstract]
   
   
3. Avet-Loiseau H, Attal M, Moreau P, et al.: Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 109 (8): 3489-95, 2007.  [PUBMED Abstract]
   
   
4. Gertz MA, Lacy MQ, Dispenzieri A, et al.: Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 106 (8): 2837-40, 2005.  [PUBMED Abstract]
   
   
5. Gutiérrez NC, Castellanos MV, Martín ML, et al.: Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 21 (1): 143-50, 2007.  [PUBMED Abstract]
   
   
6. Sagaster V, Ludwig H, Kaufmann H, et al.: Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia 21 (1): 164-8, 2007.  [PUBMED Abstract]
   
   
7. Dispenzieri A, Rajkumar SV, Gertz MA, et al.: Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc 82 (3): 323-41, 2007.  [PUBMED Abstract]
   
   
8. Ozsahin M, Tsang RW, Poortmans P, et al.: Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys 64 (1): 210-7, 2006.  [PUBMED Abstract]
   
   
9. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.  [PUBMED Abstract]
   
   
10. Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002.  [PUBMED Abstract]
    
    
11. Tournier-Rangeard L, Lapeyre M, Graff-Caillaud P, et al.: Radiotherapy for solitary extramedullary plasmacytoma in the head-and-neck region: A dose greater than 45 Gy to the target volume improves the local control. Int J Radiat Oncol Biol Phys 64 (4): 1013-7, 2006.  [PUBMED Abstract]
    
    
12. Michalaki VJ, Hall J, Henk JM, et al.: Definitive radiotherapy for extramedullary plasmacytomas of the head and neck. Br J Radiol 76 (910): 738-41, 2003.  [PUBMED Abstract]
    
    
13. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.  [PUBMED Abstract]
    
    
14. Kyle RA, Bladé J, Rajkumar SV: Monoclonal gammopathies of undetermined significance. In: Malpas JS, Bergsagel DE, Kyle RA, et al.: Myeloma: Biology and Management. 3rd ed. Philadelphia, Pa: WB Saunders Co, 2004, pp 315-52. 
    
    
15. Kyle RA, Therneau TM, Rajkumar SV, et al.: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354 (13): 1362-9, 2006.  [PUBMED Abstract]
    
    
16. International Myeloma Working Group.: Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121 (5): 749-57, 2003.  [PUBMED Abstract]
    
    
17. Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 335 (2): 91-7, 1996.  [PUBMED Abstract]
    
    
18. Kyle RA, Therneau TM, Rajkumar SV, et al.: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346 (8): 564-9, 2002.  [PUBMED Abstract]
    
    
19. Rajkumar SV, Kyle RA, Therneau TM, et al.: Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 106 (3): 812-7, 2005.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >