ALBERT

Description: Multiple myeloma (MM) may be preceded by a monoclonal gammopathy of undetermined significance (MGUS), but it is at present unclear whether or not MM post-MGUS is biologically and clinically different from MM de-novo. To address this issue, we have performed a molecular cytogenetic analysis of 32 cases of MM post-MGUS (median time between recognition of MGUS and transition to MM, 7.6 years; range, 2.6 years to 19.5 years) and compared the findings with those of 256 patients with MM de-novo, in whom no previous history of MGUS had been documented. FISH studies of clonal plasma cells (cytoplasmic Ig positive) with probes for IgH translocations [t(14q32)], t(11;14)(q13;q32), t(4;14)(p16;q32), and deletion of 13q14 [del(13q14)] revealed results summarized in Table 1: Serial studies of MGUS plasma cells and MM post-MGUS plasma cells from 12 of these patients have thus far indicated that all chromosomal abnormalities observed at MM post-MGUS were already present in the MGUS plasma cells; most notably, there was one patient with t(4;14) plus del(13q) who had both abnormalities at the time of MGUS 94 months prior to transition to MM. Collectively, our data suggest that MM post-MGUS is characterized by a distinct chromosomal pattern, in particular a high frequency of t(14q32) plus del(13q14), frequent occurrence of a t(11;14), but low frequency of a t(4;14). We are currently studying the t(14q32) plus del(13q) chromosomal pattern in MGUS to investigate its potential value as a risk factor for transition from MGUS to MM. Table 1: FISH of MM post-MGUS versus MM de novo Abnormality MM post-MGUS MM de-novo P-value Any t(14q32) 24/32 (75%) 114/256 (44.5%) .05 t(11;14)(q13;q32) 9/32 (28.1%) 32/256 (12.5%) .05 t(4;14)(p16;q32) 2/32 (6.3%) 27/256 (10.6%) .37 del(13q14) 19/32 (59.4%) 102/256 (39.8%) .13 del(13q14) plus t(14q32) 18/19 (94.7%) 57/102 (55.8%) .11 del(13q14) plus t(11;14) 6/19 (31.6%) 9/102 (8.8%) .03

Description: Previous studies have shown that specific chromosomal abnormalities are of major prognostic significance in patients with multiple myeloma (MM). It has been recently suggested that a t(11;14)(q13;q32) may be an indicator of favorable outcome in MM. In this investigation, we analyzed 163 patients with newly diagnosed MM (53% treated by high-dose therapy) to address the question whether or not the simultaneous occurrence of a t(11;14) and a deletion 13q [del(13q)], an established negative prognostic factor in MM, has any impact on prognosis. DNA-specific probes for IgH (14q32) and cyclin-D1 (11q13) were used for interphase FISH analysis of clonal plasma cells (cytoplasmic Ig positive). A t(11;14) by FISH was shown in 27 of the 163 MM patients (16.6%); the abnormality was present in the majority (median, 89%) of clonal plasma cells. Immunohistochemical analysis of CYCLIN-D1 expression was carried out in 72 patients, of whom 11 had a t(11;14) by FISH; all 11 patients had evidence for CYCLIN-D1 protein expression. Presence of a t(11;14) did not show significant correlations with standard laboratory and clinical MM features including type of the paraprotein, hemoglobin, creatinine, LDH, albumine, calcium, CRP, and beta-2-microglobulin (b2M). In contrast to a recent report, there was also no association with CD20 expression by MM cells. With respect to survival, presence of any 14q-translocation (52% of patients) was associated with similar overall survival times (OS) compared to patients lacking a t(14q), whereas patients with a t(11;14) experienced prolonged OS (median, 70+ months vs. 59.8 months among patients without t(11;14); P = .071). This survival advantage was even greater among the 16 patients with t(11;14) who were also normal for 13q (P = .02); however, occurrence of a del(13q) concomitantly with a t(11;14) was indicative for shortened progression-free survial (17.7 months vs. 31.6 months; P = .17) and OS (P = .07). A survival benefit of MM patients with a t(11;14) was particularly evident for the population receiving standard-dose chemotherapy (median OS not yet reached; P = .02). By multivariate Cox regression analysis, low serum b2M at diagnosis (P = .001), absence of a del(13q) (P = .004), high-dose therapy (P = .034), and presence of t(11;14)/no del(13q) (P = .069) emerged as independent favorable parameters for OS. Thus, according to the cytogenetic pattern, three prognostic groups of patients could be discriminated (P 〈 .001): patients with good [t(11;14), no del(13q)], intermediate [no t(11;14), no del(13q)], and poor prognosis [no t(11;14), del(13q)]. We conclude that MM with t(11;14) represents a heterogenous entity, and only the cytogenetic pattern t(11;14)/no del(13q) characterizes the most favorable prognostic group of MM, with sensitive disease to multiple lines of anti-MM therapy.