Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

Plasma cell leukemia (PCL) is an aggressive disease with poor prognosis and a median survival of only 2-6 months. Currently, no standard therapy is available, but intensive polychemotherapy appears to be more effective than the conventional melphalan plus prednisone. However, the efficacy of thalidomide in PCL has not yet been widely evaluated. Recently, treatment with thalidomide has been reported to yield promising results in refractory multiple myeloma. Here, we report on a patient with primary PCL in whom first-line treatment with thalidomide/dexamethasone resulted in a rapid response and achievement of a very good partial remission.

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

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.