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The following case study focuses on a 55-year-old male with multiple myeloma and prognosis of undetermined significance. Test your knowledge by reading the background information below and making the proper selection.

A 55-year-old male presents to your office with new symptoms of exertional fatigue. He is otherwise well with no significant past medical history. His hemoglobin is found to be low at 10.6g/dl, with an MCV of 92. He has normal serum ferritin, vitamin B12, and folic acid levels. Absolute neutrophil count is 1.3 x 10³/ul and platelets 117 x 10⁹/uL. He has a creatinine of 0.9 mg/dL, calcium of 9.2 mg/dL, and albumin of 3.8 g/dL. A serum protein electrophoresis is performed that demonstrates a monoclonal IgA protein of 1.5 g/dL. A skeletal survey shows occult lytic lesions in the skull and bilateral humeri, and a bone marrow biopsy shows 30 percent involvement by abnormal appearing plasma cells, confirmed by CD138+ immunohistochemical stain.

You make a diagnosis of symptomatic multiple myeloma and review the findings and need for treatment with the patient. The patient wishes to know more about his prognosis and chances of responding to therapy. You explain that you are awaiting a few additional test results that will help you answer his question. Which result would not be considered a poor prognostic feature in this patient with newly diagnosed multiple myeloma?

1. (4;14) by FISH
2. Beta-2 microglobulin of 7mg/L
3. t(11;14) by FISH
4. Deletion 13 abnormality by standard karyotype

Answer

3. t(11;14) by FISH

Explanation

Initial diagnostic work-up for patients with multiple myeloma (MM) should include both conventional karyotyping as well as fluorescence in situ hybridization (FISH) of plasma cells obtained from bone marrow aspiration. FISH should be assessed for poor-risk translocations, including t(4;14) (MMSET translocation; 75 percent of which express FGFR3), t(14;16) (MAF translocation), and deletion 17p (loss of p53). The presence of a chromosome 13 abnormality (monoallelic loss of chromosome 13 or deletion of its long arm 13q) by standard karyotype also confers a poor prognosis. However, when a chromosome 13 abnormality is detected only by FISH the significance is less clear and does not seem to confer the same poor prognosis. It has been suggested that detection of del 13 on karyotype analysis is a surrogate for the proliferative rate of the tumor clone. The t(11;14) translocation, which juxtaposes the cyclin D1 gene with the IgH promoter, is associated with a neutral to favorable prognosis in multiple myeloma. Additionally, a hyperdiploid karyotype also carries a more favorable prognosis in multiple myeloma and is a distinct biologic entity from non-hyperdiploid MM.^1-4

The International Staging System (ISS) for multiple myeloma uses β-2 microglobulin and serum albumin to divide patients into stage I, II, or III disease. A β-2 microglobulin level ≥ 5.5 mg/L would classify a patient as stage III disease, with a median survival of 29 months with conventional chemotherapy (about 80 percent of studied patients) or upfront high-dose chemotherapy and autologous stem cell transplantation (about 20 percent of studied patients). This is compared to a median survival of 62 months for those with stage I disease (β-2 microglobulin < 3.5 mg/L and serum albumin ≥ 3.5 g/dL).⁵ Therefore, the ISS remains a powerful and simple non-genetic model to stratify MM patients. However, it should be noted that the ISS prognostic model will need to be validated in the era of novel agents, since drugs such as bortezomib and lenalidomide may overcome the negative predictors in this model.

Currently, there is not a standard recommendation to treat poor-risk patients differently from standard-risk patients, however this is the subject of ongoing clinical studies. It is important to note though that bortezomib appears to ameliorate or eliminate the prognostic significance of these historically poor-risk features (particularly deletion 13, and translocation 4;14) and is generally recommended as part of the induction strategy in such patients. The ability of immunomodulatory drugs such as lenalidomide to overcome poor-risk features has not been as clearly shown to date.^6-8

Note: The true teaching point of this case study is that t(11;14) exists in mantle cell lymphoma and multiple myeloma, and it may identify a possibly good prognostic group.

References

1. Fonseca R, Barlogie B, Bataille R, et al. . Cancer Res. 2004;64:1546-1558.
2. Avet-Loiseau H, Attal M, Moreau P, et al. . Blood. 2007;109:3489-3495.
3. Chng WJ, Santana-Dávila R, Van Wier SA, et al. . Leukemia. 2006;20:807-813.
4. Fonseca R, Bergsagel PL, Drach J, et al. . Leukemia. 2009;23:2210-2221.
5. Greipp PR, San Miguel J, Durie BG, et al. . J Clin Oncol. 2005;23:3412-3420.
6. Jagannath S, Richardson PG, Sonneveld P, et al. . Leukemia. 2007;21:151-157.
7. San Miguel JF, Schlag R, Khuageva NK, et al. . N Engl J Med. 2008;359:906-917.
8. Kumar SK, Mikhael JR, Buadi FK, et al. . Mayo Clin Proc. 2009;84:1095-1110.

Case study submitted by Nicholas Burwick, MD, Hematology/Oncology Fellow, University of Washington, Fred Hutchinson Cancer Research Center.