Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis

Abstract

Between December 1990 and January 1994, bone marrow (BM) samples from 151 patients with multiple myeloma (MM), including 117 patients evaluated at diagnosis, were collected for cytogenetic analysis. A total of 129 patients had assessable metaphases (100 patients at diagnosis). Cytogenetic studies were performed on BM cells after longterm cultures (6 days) with stimulation of cultures by granulocyte-macrophage colony-stimulating factor (GM-CSF), GM-CSF plus interleukin (IL)-6, IL-3 plus IL-6, or GM-CSF plus IL-3 plus IL-6 to improve myeloma cell growth, and 91 patients had an additional unstimulated culture. Sixty-six patients (51%) had cytogenetic abnormalities, including 47 of 100 patients at diagnosis (47%) and 17 of 24 patients at relapse (71%; P = .04). The aberration rate increased with stage (P = .007), BM plasmacytosis (P = .003), beta 2 microglobulin level (P = .001), C-reactive protein (CRP) level (P = .001), and Ki-67 (P = .007). The abnormality detection rate was higher in stimulated than unstimulated cultures, and the difference was statistically significant (P < .01). Hyperdiploidy was observed in 39 patients (30% of patients with an assessable karyotype) and hypodiploidy in 19 patients (15%). Among numeric changes, gains predominantly involved chromosomes 3, 5, 7, 9, 11, 15, 19 and losses, chromosomes 8, 13, 14, and X. The most frequent loss was loss of chromosome 13, observed in 22 patients (15%), including 18 patients at diagnosis (12%). We observed frequent structural changes of chromosomes 1 (15%) and 14 (10%) but also a 5% incidence of 19q13 abnormality and two patients with translocation t(1;16)(p11;p11). By using the proportional hazard univariate model, patients with abnormal karyotypes were demonstrated to have 2.5-fold greater chance of death than patients with normal karyotypes (P < .014). Despite a multivariate approach with the same model, the respective roles of karyotype abnormality, age, stage, and beta 2 microglobulin level could not be clearly ascertained. From these results we conclude that cytogenetic analysis using stimulation of cultures by cytokine(s) may be a promising method to identify about 50% of cytogenetic abnormalities in patients with newly diagnosed MM. Cytogenetic analysis may help to define a high-risk population that would benefit from intensive therapeutic approaches.

Cytogenetic study of 30 patients with multiple myeloma: comparison of 3 and 6 day bone marrow cultures stimulated or not with cytokines by using a miniaturized karyotypic method

“…We confirmed that the abnormality rate increased with the Durie and Salmon stage of the disease from 50% in stage I, to 62 . 5% in stage II and 94% in stage III, as well as with the evolution profile, but not with BM plasmacytosis (Weh et al, 1993;Lai et al, 1995;Smadja et al, 1995).…”

“…The detection of aneuploid malignant PC by flow cytometry and fluorescence in situ hybridization in about 80% of patients (Zandecki et al, 1994;Drach et al, 1995), demonstrated that the 20-60% incidence of karyotypic abnormalities (Dewald et al, 1985;Gould et al, 1988;Gutensohn et al, 1992;Cigudosa et al, 1994;Lai et al, 1995;Sawyer et al, 1995) largely underestimated the frequency of genetic damage in MM (Zandecki et al, 1996).…”

“…In most cases this is probably due to the low proliferative index of malignant PC, as evidenced by studies of the percentage of PC in S phase (Greipp et al, 1993). The percentage of patients with detectable karyotypic abnormalities in most series varied from 20% to 60% with a median of 30-40% (Dewald et al, 1985;Gould et al, 1988;Gutensohn et al, 1992;Cigudosa et al, 1994;Lai et al, 1995;Sawyer et al, 1995). As IL-6 and GM-CSF stimulate the proliferation of malignant PC in vitro (Zhang et al, 1990;Klein et al, 1995), some groups tested and showed that addition of IL-6 (Weh et al, 1993) or IL-6 + GM-CSF (Facon et al, 1993) to 3 or 6 d BM liquid cultures improved the detection of clonal karyotypic abnormalities in MM.…”

The Use of Biological Variables to Predict Outcome in Multiple Myeloma

“…Numerical chromosomal abnormalities are common, 61-68% of patients show hyperdiploidy, 9-20% pseudodiploidy and 10-30% hypodiploidy . The most common abnormalities are trisomy 3, 7, 9 and 11 monosomy 13 and, in females monosomy X (Drach et al, 1995;Flactif et al, 1995;Lai et al, 1995;Tabernero et al, 1996). Recent data (Smadja et al, 1996) suggests that if patients are classified according to karyotype, those with hyperdiploidy may have a survival advantage.…”

“…Chromosome 14 abnormalities are common, with a reported frequency of 10-40% (Weh et al, 1993;Lai et al, 1995;Sawyer et al, 1995) and are associated with a poor prognosis, being seen mainly in stage III and the terminal phase of the disease (Liang et al, 1979;Philip et al, 1980). Translocations involving the switch region of the IgH gene on chromosome 14q have been characterized in cell lines.…”