Multiple Myeloma: Will Molecular and Genetic Studies Assist in Selection Treatment?

Treatment of multiple myeloma has improved considerably in the past decade, with integration of high dose therapy (with autologous bone marrow transplant) and/or new drug therapies such as thalidomide (Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade).  Of course, because the disease and the patients are very heterogeneous, no single treatment strategy is appropriate for all patients.   Researchers have been studying patient and disease characteristics that predict survival (prognostic factors) or predict outcome of specific therapy (predictive factors).  The hope is that patient’s disease can be better understood prior to therapy, and the patients can be offered the most effective treatment option available. 

Traditional factors based on the patient’s boney destruction, anemia, and thrombocytopenia (reflections of the myeloma marrow disease burden) and kidney function are encompassed in the Durie-Salmon staging system.  The International Staging System uses a combination of serum beta-2-microglobulin level and serum albumin to predict prognosis.  Neither of these systems incorporates new information about molecular or genetic subtypes or features of myeloma.  The prognosis (and perhaps treatment response) of such subtypes may be considerably different.

Genetic studies have identified that certain myeloma patients have disease with increased risk of shortened survival (high risk).  The Mayo stratification of myeloma and risk-adapted therapy (sMART) classification identifies the following features as high risk (25% of all myeloma patients): FISH (fluorescent in situ hybridization) detection of deletion of the short arm of chromosome 17 (17p-), translocations: t(4,14) and t(14,16), cytogenetic detection of deletion of chromosome 13, cytogenetic hypodiploidy (numerically reduced chromosomal number), and increased plasma cell labeling index (PCLI >=3%).  Chromosome 13 deletion is associated with diminished regulatory function of the Rb protein.  This may be a key factor in promoting clonal expansion. The sMART classification identifies patients (75% of all myeloma patients) as having standard risk, with hyperdiploidy, t(11,14), and t(6,14).   Certain additional genetic events may confer a negative effect on survival.  Deletion of the short arm of chromosome 17 (del 17p13) results in loss of the tumor suppressor gene p53. This deletion has been associated with short duration of response to high dose therapy, increased risk for CNS involvement, extramedullary disease, and occurrence of plasma cell leukemia.  K-ras mutations, chromosome 1 abnormalities, and NF-kB (nuclear factor-kB) activation may also have adverse effects on prognosis.  

As yet, a specific factor (or combination of factors) that might predict the best initial therapy for newly diagnosed patients have not been fully defined.   However, the t(4,14)(q16;q32) has an unequivocal negative influence on the prognosis of patients treated with melphalan-based chemotherapy.  Investigators have interpreted these findings and suggested that bortezomib (Velcade) therapy be introduced early in such high risk patients.  Guidelines in the form of algorithms for treatment selection have been developed, and these may be found at www.mSMART.org. 

CORT is conducting a clinical trial for patients who are not eligible for high dose therapy and transplant.  This study is the Millenium Oncology UPFRONT study, which randomly compares three treatments that contain borezomib (Velcade):

• Velcade-Melphalan-Prednisone (VMP)
• Velcade-Thalidomide-Dexamethasone (VTD)
• Velcade-Dexamethasone (VD)

For more information about the UPFRONT study, or other treatments for multiple myeloma, contact a CORT research coordinator at 972-566-5588, or visit the CORT website: www.CORTPA.com.