The Role of Personalized Therapy in the Management of Multiple Myeloma: Case Study of a Patient With a Cytogenetic Abnormality

Sagar Lonial, MD

Multiple Myeloma

At the 2012 conference of the Global Biomarkers Consortium, which took place March 9-11, 2012, in Orlando, Florida, Sagar Lonial, MD, from the Winship Cancer Institute and Emory University in Atlanta, Georgia, discussed the use of personalized therapy in the management of multiple myeloma.

Case

• A 55-year-old woman presents with new-onset anemia (Hb 9.6 g/dL)
• Skeletal survey is normal
• Chemistries are normal except for an elevated total protein (10.2 g/dL)
• Albumin is 3.9 g/dL; ?2-microglobulin is 4.4 mg/L
• Marrow shows 55% clonal plasma cells
• Serum protein electrophoresis shows IgA kappa protein of 3.6 g/dL
• Free light chain ratio is abnormal (20:1)
• 24-hour urine protein electrophoresis shows 350 mg of kappa light chains
• Conventional cytogenetic results are normal
• FISH performed at outside laboratory was negative for cytogenetic abnormalities; however, FISH performed at Emory is positive for t(4;14)

FISH indicates fluorescence in situ hybridization; Hb, hemoglobin.

Certain chromosomal abnormalities are associated with prognosis in multiple myeloma (MM). The translocations t(4;14) and t(14;16), or deletion del(13), are poor prognostic factors in MM. Patients with these abnormalities are considered high risk.

Genetic abnormalities are assessed both by routine cytogenetic karyotyping and by fluorescence in situ hybridization (FISH). FISH detects genetic abnormalities on both dividing and nondividing cells, while conventional cytogenetics only detects abnormalities in dividing cells.

While FISH is more sensitive than conventional karyotyping in detecting genetic aberrations, it is important to note that not all laboratories perform FISH the same way. Detection of genetic abnormalities by FISH can be limited by the percentage of plasma cells in the specimen. If all the lab is doing is looking at 200 random cells under a microscope and doing FISH, you may receive false-negative FISH results in the case of low mono­­clonal plasma cell tumor burden. A more reliable FISH test is one in which the lab uses a plasma cell enrichment technique, such as cytoplasmic immunoglobulin FISH (cIg-FISH), which uses light chain–specific immunofluorescence, or by using CD138 magnetic microbeads to sort the plasma cells.

One way to do a quality control check on the lab that’s doing your FISH tests is to request an analysis for del(13). This marker is present in about 50% of all newly diagnosed MM patients. If your lab does not return a result showing 50% expression of del(13) in all your newly diagnosed MM patients, then the lab is not using a plasma cell enrichment technique, and it is not giving you reliable data.

Prognosis for Patients With t(4;14)

The patient in our case was found by cIg-FISH to have t(4;14), which indicates a poor prognosis. This genetic aberration occurs in about 15% of MM patients.¹ Results from a 2005 study by Jaksic and colleagues² showed that patients identified with t(4;14) by cIg-FISH who received induction followed by autologous stem cell transplantation (ASCT) had a median progression-free survival (PFS) from the time of ASCT of only 14.1 months (Figure 1).² This was significantly shorter than for t(4;14)-negative patients, who had a median PFS of 25.8 months (P=.0003). The median overall survival (OS) for t(4;14)-positive patients from the time of ASCT was only 24.2 months.²

Results from a study by Moreau and colleagues in 2007 shows, however, that genetics alone does not tell the whole story. In this study, researchers identified a subgroup of t(4;14) patients with both low ?2-microglobulin (<4 mg/L) and high hemoglobin (Hb; ?10 g/dL) who experienced prolonged survival (median OS of 54.6 months and median PFS of 26 months) after tandem transplant and benefited from high-dose therapy (Figure 2).³

Novel Therapies in the Treatment of Patients With t(4;14)

In the Intergroupe Francophone du Myélome 2005-01 trial, newly diagnosed MM patients with t(4;14) who received short-term induction with 4 cycles of bortez­omib-dexamethasone before high-dose melphalan experienced significantly improved survival compared with those treated with vincristine, doxorubicin, and dexamethasone induction therapy (Figure 3).⁴

Cavo and colleagues from the GIMEMA Italian Myeloma Network compared thalidomide plus dexa­methasone (TD) versus bortezomib plus TD (VTD) as induction therapy before, and consolidation therapy after, double ASCT in 480 patients with newly diagnosed MM.5 Results showed that while TD failed to overcome the poor prognosis related to the presence of t(4;14), VTD completely overcame the poor prognosis related to the presence of t(4;14).

In the area of personalized medicine for myeloma, it may be different from other solid tumors. In myeloma, with good induction therapy, most patients will respond, and thus the challenge remains how to keep them in a major response. Because combinations of agents are so successful for newly diagnosed patients, the real personalization occurs in the maintenance setting, where we can use novel methods of keeping disease in control, such as stratified maintenance. This appears to be the future, as specific targeted maintenance holds the promise for better long-term disease control while still taking advantage of the combination effect when patients are initially diagnosed.

References

1. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Franco­-p­hone du Myélome. Blood. 2007;109:3489-3495.
2. Jaksic W, Trudel S, Chang H, et al. Clinical outcomes in t(4;14) multiple myeloma: a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance. J Clin Oncol. 2005;23:7069-7073.
3. Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia. 2007;21:2020-2024.
4. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634.
5. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.

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