Background Presenting the same histological diagnosis, multiple myeloma (MM) shows a large genomic variety, resulting in variable times of overall survival.Materials and methods To investigate major cytogenetic categories (any 14q-translocation, t(11;14), t(4;14), 13q-deletions, 17p-deletions) and their clinical consequences in MM after a pre-existing monoclonal gammopathy (MM post-MGUS), we performed a comparative analysis of 41 patients with MM post-MGUS and 287 patients with unknown prior history MM (U-MM).Results In MM post-MGUS, a t(11;14) was found to be more frequent than in U-MM (24% vs. 14%) and it was associated with significantly shortened survival (24 months vs. 70 months in U-MM; P = 0.01). MM post-MGUS was further characterized by a higher frequency of 13q-deletions only (absence of all other specific abnormalities; 28% vs. 12% in U-MM; P = 0.02). A 13q-deletion only was an indicator of long survival in MM post-MGUS (median not yet reached) as opposed to U-MM (median survival, 29 months; P = 0.001). 17p-deletions were infrequent in MM post-MGUS (3% vs. 16% in U-MM; P = 0.04). Survival times for patients with t(4;14) and/or 17p-deletions and other abnormalities were similar in both MM patient cohorts.Conclusions Our data suggest that t(11;14) and 13q-deletions have distinct prognostic implications in the context of MM post-MGUS.

Little is known about tumor-related prognostic factors, in particular specific chromosomal abnormalities, in young patients with multiple myeloma (MM). We therefore investigated the chromosomal pattern by interphase fluorescence in situ hybridization (chromosomes 13q14, 14q32-translocations, chromosomes associated with hyperdiploidy) in 38 young patients with MM (age 70 yr). All chromosomal patterns were not significantly different between the three age cohorts. Similarly, standard MM parameters were equally distributed between these MM patient populations. However, survival by the International Staging System (ISS) for MM revealed marked differences between stage I/II (median survival not yet reached) and stage III (23.4 months; P \u003c 0.0003) among young MM patients. A significant survival difference between ISS-stage I/II and ISS-stage III patients was also noted in the intermediate age group (median 65.4 months vs. 24.6 months; P = 0.0009). However, this difference disappeared among elderly MM patients (39.6 months in ISS-stage I/II vs. 32 months in ISS-stage III patients; P = 0.94), but it was unrelated to the cytogenetic pattern. Our results indicate that MM in young patients does not represent a distinct biologic entity, and that short survival of younger MM patients at ISS-stage III is independent of the molecular cytogenetic pattern.

Studies of bortezomib in patients with relapsed multiple myeloma (MM) suggested that bortezomib may be active even in the presence of adverse prognostic factors. We therefore evaluated 62 patients with relapsed/refractory MM who were treated with single-agent bortezomib, and addressed the question whether or not the negative prognostic impact of unfavorable cytogenetic abnormalities may be overcome by bortezomib. By interphase fluorescence in situ hybridization (FISH), a deletion of chromosome 13q14 [del(13q14)] was present in 33 patients (53%). Overall response rates to bortezomib were similar in patients with and without del(13q14) (45 versus 55%; P=0.66), and rates of complete remission (CR) near CR were also not different between the two patient populations (18 versus 14%). Three patients had a t(4;14)(p16;q32) in addition to del(13q14), and all of them had a >50% paraprotein reduction. Median duration of response was 12.3 months in patients with del(13q14) compared with 9.3 months in patients with normal 13q-status (P=0.25), and survival was also not different between the two patient populations. Patients not benefiting from single-agent bortezomib were characterized by the combined presence of a del(13q14) and low serum albumin (median survival 4.6 months). Our results provide evidence for remarkable activity of bortezomib in MM with del(13q14). Patients who do not respond to bortezomib and consecutively have short time to treatment failure and overall survival can be identified by low serum albumin in addition to del(13q14) and should be considered for bortezomib combinations.

Little is known about tumor-related prognostic factors, in particular specific chromosomal abnormalities, in young patients with multiple myeloma (MM). We therefore investigated the chromosomal pattern by interphase fluorescence in situ hybridization (chromosomes 13q14, 14q32-translocations, chromosomes associated with hyperdiploidy) in 38 young patients with MM (age <45 yr) and compared the results with those observed in 69 patients with intermediate age (45-70 yr) and 64 elderly patients (age >70 yr). All chromosomal patterns were not significantly different between the three age cohorts. Similarly, standard MM parameters were equally distributed between these MM patient populations. However, survival by the International Staging System (ISS) for MM revealed marked differences between stage I/II (median survival not yet reached) and stage III (23.4 months; P < 0.0003) among young MM patients. A significant survival difference between ISS-stage I/II and ISS-stage III patients was also noted in the intermediate age group (median 65.4 months vs. 24.6 months; P = 0.0009). However, this difference disappeared among elderly MM patients (39.6 months in ISS-stage I/II vs. 32 months in ISS-stage III patients; P = 0.94), but it was unrelated to the cytogenetic pattern. Our results indicate that MM in young patients does not represent a distinct biologic entity, and that short survival of younger MM patients at ISS-stage III is independent of the molecular cytogenetic pattern.

Presence of a chromosome 13q-deletion confers a poor prognosis to patients with multiple myeloma (MM) irrespective of the treatment modality (standard-dose chemotherapy, high-dose melphalan with autologous transplantation, allogeneic transplantation, thalidomide), which underlines the need for effective therapy in this high-risk MM patient population. Bortezomib (B) is the first compound of a new class of agents - the proteasome inhibitors - showing activitiy in relapsed and chemotherapy-refractory MM. Preliminary evidence suggests that B may also be active in MM with unfavorable standard prognostic factors. Therefore, the aim of our investigation was to study the activity of B in relapsed MM in the context of chromosomal aberrations (in particular deletion of chromosome 13q14 [del(13q14)] and 14q-translocations [t(14q32)]) as detected by interphase fluorescence in situ hybridization (FISH). Up to now, 52 patients with relapsed/refractory MM (47 after ≥2 lines of prior therapy) were treated with B (1.3 mg/m2 on days 1, 4, 8, 11; q21 days). Patients not achieving at least a minor response to single-agent B were treated with B plus dexamethasone (DEX; 8–20mg); subsequently, melphalan (10 mg/m2) or doxorubicin (9 mg/m2) was added to B/DEX treatment. To date 44 patients are evaluable for response, time to treatment failure (TTF), overall survival (OS), and association with prognostic factors. 23 evaluable patients (52%) experienced an objective response, with 8 patients (18%) achieving a CR/near-CR (>90% paraprotein reduction), 12 patients (27%) achieving a PR (50 – 90% paraprotein reduction), and 3 patients (75) showing a MR (25 – 50% paraprotein reduction). Median time to response was 3 weeks (range, 3 – 9 weeks). According to FISH, 22 patients (50%) had a del(13q14). B was effective for remission induction in both del(13q14) MM patients (18% CR/nearCR, 18% PR, 5% MR) and 13q-normal patients (18% CR/nearCR, 36% PR); however, median TTF (2.6 versus 6.7 months) and median OS (6.1 months versus not yet reached; P = .047) were shorter for del(13q14) patients compared to 13q-normal patients. Of note, failure to respond to B and short OS was observed in 2 patients with del(13q14) and concomitant amplification of CKS1B (1q21). Additional studies regarding 1q21 are in progress. Remission rates, TTF, and OS were similar in patients with and without a t(14q32). One patient with a t(4;14)(p16;q32) responded not only to single agent B with a remission lasting for 7 months, but later also responded to B/DEX and the B/DEX/chemotherapy combination with remissions lasting for several months each. On the other hand, only one of 5 patients with a t(11;14)(q13;q32) achieved a response (MR) to B. Beta-2-microglobulin did not influence treatment outcome after B. Significantly shortened OS following B treatment was noted in MM patients with serum albumin <3.5 g/dl (4.7 months versus median not yet reached) and bone marrow plasma cells >50% (6.4 months versus not yet reached). In conclusion, B is an effective salvage treatment for MM patients with relapsed/refractory MM, even in those with prognostically adverse cytogenetic features such as del(13q14). Due to the still short TTF and OS, MM patients with adverse prognostic indicators (unfavorable cytogenetics, low serum albumin, high bone marrow plasma cell infiltration) may derive a particular benefit from combining B with other anti-MM agents.

Objective: Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem celltransplantation in the context of ss(2) microglobulin and chromosome 13q. Methods: All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. Results: There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5-128) nine patients (70%) are still allive, and six of them have remained progression free. Among five patients with low ss(2) microglobulin and normal chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated ss(2) microglobulin and/or deletion of chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. Conclusions: Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.

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.

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:

BACKGROUND. Silencing of tumor suppressor genes (TSG) by aberrant methylation (referred to as methylation) contributes to the pathogenesis of various human malignancies. However, little is known about the methylation of known and putative TSGs in monoclonal gammopathies. Thus, the authors investigated the methylation frequencies of 10 genes in patients with monoclonal gammopathies.METHODS. The methylation patterns of the genes p16(INK4a) (p16), tissue inhibitor of metalloproteinase 3 (TIMP3), p15(INK4b) (p15), E-cadherin (ECAD), death-associated protein kinase (DAPK), p73, RAS-association domain family 1A (RASSF1A), p14, O-6-methylguanine DNA methyltransferase (MGMT), and retinoid acid receptor beta2 (RARbeta) were determined in patients with monoclonal gammopathy of undetermined significance (MGUS; n = 29), smoldering multiple myeloma (SMM; n = 5), 2 I multiple myeloma (MM; n = 113), or plasma cell leukemia (PCL; n = 7) by methylation-specific polymerase chain reaction analysis. 3RESULTS. Methylation frequencies for p16, TIMP3, p15, ECAD, DAPK, p73, RASSFIA, p14, MGMT, and RARbeta were as follows: 28%, 35%, 10%, 0%, 17%, 21%, 14%, 14%, 7%, and 0%, respectively, in patients with MGUS and 36%, 29%, 27%, 27%, 22%, 15%, 15%, 9%, 4%, and 0%, respectively, in patients with MM. Methylation of at least I of these genes was detected in 79% of patients with MGUS and in 80% of patients with MM. Although methylation of ECAD was not detected in patients with MGUS, it was observed frequently in patients with MM and with even greater frequency in patients with PCL. It is noteworthy that an association was found between ECAD methylation and poor prognostic markers in patients with MM.CONCLUSIONS. Methylation of certain genes can be detected frequently in patients with monoclonal gammopathies. The current data suggest that methylation of ECAD is a marker of disease progression in patients with MM and PCL. (C) 2004 American Cancer Society.

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.

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.

It has been established that high-dose chemotherapy (HDT) improves the therapeutic outcome of patients with multiple myeloma (MM) as compared with standard-dose therapy (SDT); however, little is known about the impact of HDT on different prognostic groups of MM patients. We therefore compared the survival times of 77 patients with previously untreated MM who were enrolled in HDT regimens with those of 64 similar patients <65 years old, who would be eligible for HDT but were treated by SDT. Overall, HDT was superior to SDT with respect to achievement of complete remissions (28% versus 2%; P <0.0001) and improvement of progression-free survival (PFS) (30.2 versus 21.2 months; P = 0.01) as well as overall survival (OS) (median 54.9 versus 49.4 months; P = 0.048). According to the chromosome 13q14 status as determined by fluorescence in situ hybridization and serum levels of beta(2)-microglobulin (beta(2)M), MM patients were separated into a standard-risk group (normal chromosome 13q14 and beta(2)M =4 mg/l) and a high-risk group (deletion of chromosome 13q14 and/or beta(2)M >4 mg/l). Among patients of the high-risk group, both PFS (26.4 versus 10.7 months; P = 0.004) and OS times (40 versus 23 months; P = 0.05) were longer in patients receiving HDT compared with patients treated by SDT. In the standard-risk group, PFS and OS times were not significantly different between HDT patients and SDT patients. Results of this retrospective analysis suggest that the beneficial effects of HDT are greater in MM patients with high-risk features than in patients with absence of such poor prognostic indicators.

PURPOSE:To determine the clinical relevance of p27(Kip1) in multiple myeloma (MM), we examined the relationship between p27(Kip1) expression at diagnosis and clinical as well as laboratory parameters, including response to chemotherapy and overall survival in 74 previously untreated patients with MM. EXPERIMENTAL DESIGN:Expression of p27(Kip1) was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded bone marrow biopsies. p27(Kip1) expression was classified as low (=5% p27(Kip1)-positive myeloma cells) or high (>5% p27(Kip1)-positive myeloma cells). RESULTS:Low p27(Kip1) expression was observed in 23 (31%) patients. The response rate to standard dose chemotherapy (including vincristine, doxorubicin, and dexamethasone induction before high-dose chemotherapy) was 70%, with no significant difference between patients with low or high p27(Kip1) expression (83 versus 65%; P = 0.1). Kaplan-Meier analysis of all 74 patients revealed that patients with low p27(Kip1) expression had a significantly shorter overall survival (median, 3.7 years versus 4.7 years; P = 0.03) than those with high p27(Kip1) expression. Patients with high p27(Kip1) expression receiving high-dose chemotherapy experienced prolonged overall survival as compared with those with low p27(Kip1) expression (median not yet reached versus 2.9 years; P = 0.008). By multivariate Cox regression analyses, low p27(Kip1)(P = 0.03), deletion of chromosome 13q14 (P = 0.02), and beta(2)-microglobulin (P = 0.01) were identified as independent adverse prognostic factors for overall survival. According to the number of independent unfavorable prognostic factors present in each patient, low-risk, intermediate-risk, and high-risk patients with different overall survival times were defined (median overall survival, 6.3 versus 4.2 versus 1.8 years; P < 0.001). CONCLUSIONS:Low p27(Kip1) expression is an independent adverse prognostic factor in patients with MM. The proposed risk score might be useful for risk-adapted treatment in the future.

Remarkable results of the treatment of refractory multiple myeloma with thalidomide have been reported. In most preceding studies, the given thalidomide dose was escalated to a maximum tolerated dose of up to 800 mg/d. The frequency of adverse effects correlates with dose intensity. Since a significant gain of therapeutic effects could not be observed as thalidomide dosage was escalated, the optimal dose of thalidomide remains to be determined. We report the results of a study with low dose thalidomide (median administered dose 100 mg/d, range 50-400 mg/d). Twenty-four relapsed (n = 19) or resistant (n = 5) multiple myeloma patients were included in the study. Twelve patients (50%) received thalidomide as monotherapy, 8 patients (33%) received a combination of thalidomide and dexamethasone (every 4 weeks 40 mg/day for 4 days) and 4 patients (17%) who were resistant to vincristine, doxorubicin, dexamethasone (VAD) received VAD combined with thalidomide. Overall, a response was observed in 12 patients (50%). Of the 12 patients treated with low dose thalidomide alone 5 (42%) responded, of the 8 patients who received a combination of thalidomide and dexamethasone 5 (63%) responded and of the 4 patients who had thalidomide in addition to VAD 2 patients (50%) responded. In 3 patients, thalidomide treatment had to be discontinued because of side effects and 1 patient died before response could be assessed. We conclude that low dose thalidomide is an effective and safe rescue therapy in relapsing or refractory multiple myeloma. Response to thalidomide might be dependent on prognostic parameters and tumor burden. To answer these questions larger prospective studies are necessary.