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Spring 2004 Volume 5, Issue 10:
The Genetics of Multiple Myeloma
By Prof. Hervé Avet-Loiseau
Extensive genetic lesions, both at the chromosome and gene levels, characterize malignant plasma cells. Although most patients present with a large number of malignant plasma cells at diagnosis (up to 1,000 billion malignant cells), chromosomal analy
04.26.04
Multiple myeloma is characterized by the accumulation within the bone marrow of large amounts of malignant plasma cells. This accumulation is responsible for the most common features of the disease, like painful lytic bone lesions, or inhibition of the normal hematopoiesis(1). However, despite these common characteristics, patients differ from each other in many aspects, including number of bone lesions, response to treatment, or duration of response. These differences probably reflect heterogeneity(2) in the disease, heterogeneity that can also be recognized at the cellular or molecular levels.

Professor Hervé Avet-Loiseau
Laboratory of Hematology
University Hospital
Nantes, France

Extensive genetic lesions, both at the chromosome and gene levels, characterize malignant plasma cells. Although most patients present with a large number of malignant plasma cells at diagnosis (up to 1,000 billion malignant cells), chromosomal analyses are still a difficult art in multiple myeloma. Because plasma cells are quiescent(3) rather than proliferant, and because cytogenetics(4) requires the passage through mitosis(5), chromosomes are difficult to obtain in myeloma cells. Despite these difficulties, several studies have shown that several chromosomal patterns can be identified, mostly based upon the ploidy(6) mode (i.e., the modal number of chromosomes), and on a few specific chromosomal abnormalities. The first classification distinguishes myelomas on the basis of the number of chromosomes, i.e., 46 chromosomes or less (hypopseudodiploidy), and more than 47 chromosomes (hyperdiploidy). These two categories represent about half of the patients each, and seem to differ by several parameters, including other chromosomal changes and prognosis; those patients with hyperdiploidy presenting a better outcome. Other important chromosomal rearrangements involve the 14q32 region. Such rearrangements are observed in 50% to 70% of the patients with myeloma, depending on the studies and the techniques used. Although a wide variety of chromosomal partners have been described, two specific translocations involving the 14q32 region are observed with a higher frequency: the translocation t(11;14) and the t(4;14). This latter translocation is invisible using classical cytogenetics and requires other techniques like FISH (fluorescence in situ hybridization) or molecular techniques. The identification of these chromosomal changes is important in order to define the prognosis of the patients, t(4;14) being associated with a poor prognosis, whereas t(11;14) is associated with a longer survival.
TERMS & DEFINITIONS

(1) The normal production of peripheral blood cells.

(2) Diversity, nonuniformity.

(3) A resting cell, not dividing, but not dying.

(4) Study that relates the appearance and behavior of chromosomes to genetic phenomena.

(5) Cell division in which the nucleus divides into nuclei containing the same number of chromosomes, all of which are genetically identical to each other.

(6) The number of sets of chromosomes within a cell or organism.

(7) Sets of miniaturized chemical reaction areas

Finally, and probably most importantly, about half of the patients present a loss of part or all of chromosome 13. This abnormality has also been related to a poorer prognosis, even though the technique to use to identify it (classical cytogenetics or FISH) is still a matter of debate.

What is the role of these specific chromosomal abnormalities in the occurrence and/or the evolution of multiple myeloma? This important question is so far unresolved, albeit some recent studies have started to address this issue. The major related question is whether multiple myeloma is a unique disease, or several diseases. In other hematological malignancies, genetics have identified novel entities, leading to adapted therapeutic strategies. Similar implications can be envisaged for multiple myeloma. For instance, the two major 14q32 translocations, t(4;14) and t(11;14), might identify two different forms of myeloma, possibly requiring different therapeutic approaches. The development of more global genomic analyses should enable investigators to further decrypt the disease. The recent use of microarray(7) technology has opened the door to a new understanding of diseases, based on the definition of pathological entities on molecular signatures. The analysis of large numbers of patients presenting different forms of multiple myeloma should modify our knowledge of myeloma, and possibly should modify the way to manage patients.

In conclusion, multiple myeloma is probably entering a novel era, the genetic era. The systematic evaluation of the chromosomal and gene aberrations should modify our view of the disease, leading to individual disease-adapted therapeutic management. MT

Note: Prof. Avet-Loiseau is the recipient of 2001 and 2002 IMF Senior Grant awards.


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